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- 1. NSAIDS, COX-2 Inhibitors & Pain Management Eric S Hsu, M.D. Department of Anesthesiology UCLA Pain Management Center
- 3. Classification of Pain Acute Chronic vs Duration Nociceptive Neuropathic vs Pathophysiology
- 6. Classification of Pain by Pathophysiology Mixed Type ( eg, Postoperative pain, chronic back pain) Nociceptive Pain Neuropathic Pain Visceral Abdominal Obstetrical Head Headache Orofacial Postherpetic Neuralgia Low Back Pain CRPS CRPS = complex regional pain syndrome. Central Poststroke Pain Trigeminal Neuralgia Distal Polyneuropathy (eg, diabetic, HIV) Musculoskeletal Osteoarthritis Rheumatoid Arthritis Low Back Pain Other Postoperative Cancer Pain
- 10. Central Sensitization COX-2 Dependent Central Modulation Woolf CJ, Salter MW. Science. 2000;288:1765-68 . C-fiber terminal AMPA NMDA Ca ++ Substance P Glutamate PKC P P (+) (+) (+) COX-2 induction PGE 2 (-) PGE 2 Na + Dorsal Horn Neuron
- 15. Pain Management NSAIDs vs. COX-2 – Specific Inhibitors Mediate inflammation, pain, and fever COX-2 – specific inhibitors Protect gastroduodenal mucosa Supports platelet function COX-1 COX-2 Nonspecific NSAIDs Dubois RN et al. FASEB J . 1998;12:1063-1073. Prostaglandins Thromboxane Prostaglandins Arachidonic Acid
- 31. Introduction of COX-2 – Specific Inhibitors CH 3 F 3 C N N S O O NH 2 S CH 3 O O O O Celecoxib (Celebrex ® ) Rofecoxib (Vioxx ® ) Valdecoxib (Bextra ® ) N O CH 3 S NH 2 O O Sulfone-based Sulfonamide-based Sulfonamide-based
- 33. Adjusted Hazard Estimates for Hospitalization for UGI Hemorrhage Among Elderly Using Prescribed NSAIDs Patients Hospitalized (%) 0.35 0.30 0.25 0.20 0.15 0.10 0.05 0.00 0 60 120 180 240 295 Time From index Date (days) Mamdani et al. BMJ. 2002;325:624-627. Observational Study Nonselective NSAIDs 4.0 (2.3 to 6.9) Diclofenac + misoprostol 3.0 (1.7 to 5.6) Rofecoxib 1.9 (1.3 to 2.8) Celecoxib 1.0 (0.7 to 1.6) Controls 1.0 Rate ratio (95% CI)
- 34. Incidence of GDUs After 12 Weeks of Treatment Patients who are at high-risk of GI bleeding, have a history of intolerance to non-selective NSAIDs, or are not doing well on non-selective NSAIDs, may be appropriate candidates for CELEBREX. CELEBREX should be administered at the lowest effective dose. ND=not done. * P <.001 vs all other treatments. 1. Data on file. Pfizer Inc., New York, NY; 2. Simon LS et al. JAMA . 1999;282:1921-1928. Pooled Analysis 0 5 10 15 20 25 30 Placebo 100 400 OA patients 1 (n=1215) RA patients 2 (n=1149) 50 200 Naproxen (500 mg BID) Celecoxib (mg BID) Patients with ulcer (%) * ND ND *
- 35. CLASS and VIGOR : Symptomatic Ulcer/Ulcer Complication Rates: Non-ASA Users VIGOR CLASS Annualized Incidence (%) Celecoxib 400 mg bid Nonselective NSAIDs Rofecoxib 50 mg qd Naproxen 500 mg bid Annual Incidence (%) 52% reduction 53% reduction P <.001 P ≤.05 Arthritis Advisory Committee; February 7, 2001. Available at http://www.fda.gov/ohrms/dockets/ac/ Silverstein et al JAMA ;2000. 284:1247-1255 Bombardier et al. N Engl J Med . 2000; 343: 1520-1528. CELEBREX is contraindicated in patients with known hypersensitivity to celecoxib; in patients who have demonstrated allergic-type reactions to sulfonamides; and in patients who have experienced asthma, urticaria, or allergic-type reactions after taking ASA or other NSAIDs.
- 36. CLASS : Clinically Significant Changes in Hct/Hgb (Decreases in Hct 10% Points and/or Hgb >2 g/dL) Diclofenac 75 mg bid Ibuprofen 800 mg tid Most common side effects with CELEBREX are dyspepsia, diarrhea, and abdominal pain, and are generally mild to moderate. * P .05 nonselective NSAIDs vs celecoxib. Pincus et al. Ann Rheum Dis. 2002;61(suppl 1):137(THU0266). Celecoxib 400 mg bid % of Patients 0 2 4 6 8 10 Non-ASA Users ASA Users * * * *
- 38. CVD Risk Factors in Patients General Population with & without OA OA General population without arthritis Hypertension (>140/90 mm Hg) Total Cholesterol ( ≥240 mg/dL ) Diabetes (MD diagnosed) % of Population Singh G et al. Am J Manag Care. 2002;8:S383-S391.
- 39. The Implications of NSAID Selectivity Adapted from Antman EM, et al. Circulation . 2007;115:1634-1642. Bleeding Ulcer Complications Degree of Selectivity Blood Pressure Increase Discontinuation Thrombosis, Myocardial Infarction Etoricoxib Celecoxib Diclofenac Rofecoxib Naproxen Ibuprofen Discontinuation Cardiovascular Risk Gastrointestinal Risk COX-2 COX-1
- 41. CRESCENT Trial: 24-hr Systolic BP at Baseline and Week 6 00:00=Midnight. ABPM initiated at 09:00 ± 2 hr; morning dose administered within 5 min of initiating ABPM. 120 125 130 135 140 145 00:00 04:00 08:00 12:00 16:00 20:00 Time of Day mm Hg 120 125 130 135 140 145 00:00 04:00 08:00 12:00 16:00 20:00 Time of Day mm Hg 120 125 130 135 140 145 00:00 04:00 08:00 12:00 16:00 20:00 Time of Day mm hg Celecoxib Rofecoxib Naproxen Baseline Week 6 Daytime Adapted from Sowers JR, et al. Arch Intern Med . 2005;165:161-168. Daytime Daytime
- 42. Thromboembolic CV Adverse Events in CLASS (Celecoxib Study) Similar risks were not seen in the analogous CLASS study as they were with VIGOR. Adapted from White WB, et al. Am J Cardiol. 2002;89:425-430. Non-ASA Users ASA Users Days Days P =0.899 P =0.947 0 0.5 1.0 1.5 2.0 2.5 3.0 3.5 4.5 5.0 4.0 0 40 80 120 160 200 240 280 320 360 40 80 120 160 200 240 280 320 360 Celecoxib 400 mg BID (n=882) % of Patients NSAIDs (n=857) Celecoxib 400 mg BID (n=3105) NSAIDs (n=3124) 0 0.5 1.0 1.5 2.0 2.5 3.0 3.5 4.5 5.0 4.0 0
- 43. Risk of AMI and SCD With Current Use of COX-2 Selective and NS-NSAIDs vs Remote NSAID Use Control (remote use) Celecoxib Ibuprofen Naproxen Rofecoxib >25 mg Other NSAIDs Indomethacin Diclofenac Adjusted † Odds Ratio (95% CI) 1.00 (reference) 0.86 (0.69-1.07) 1.09 (0.99-1.21) 1.18 (1.04-1.35) 1.16 (1.04-1.30) 1.33 (1.09-1.63) 1.69 (0.97-2.93) P =.01 P <.01 P =.005 Rofecoxib 25 mg 1.29 (0.93-1.79) P =.06 AMI=acute myocardial infarction; SCD=sudden cardiac death. † Adjusted for age, gender, health plan region, medical history, smoking, and medication use. Adapted from Graham DJ, et al. Lancet . 2005;365:475-481. P <.01 3.15 (1.14-8.75)
- 47. Efficacy: Celecoxib vs Naproxen in OA WOMAC OA Index Composite Scores at Week 12 CELEBREX is contraindicated in patients with known hypersensitivity to celecoxib; in patients who have demonstrated allergic-type reactions to sulfonamides; and in patients who have experienced asthma, urticaria, or allergic-type reactions after taking ASA or NSAIDs. * P <.05 vs placebo. WOMAC=Western Ontario and McMaster Universities. Bensen et al. Mayo Clin Proc . 1999;74:1095-1105. Placebo (n=203) Celecoxib 100 mg bid (n=197) Naproxen 500 mg bid (n=198) Greater Improvement Mean Improvement From Baseline
- 50. NSAID Therapy in Post-Rofecoxib/Valdecoxib Age Gastroprotective agent + traditional NSAID Consider non-NSAID therapy Traditional NSAID +PPI Consider non-NSAID therapy Cardiovascular risk (consider aspirin) Traditional NSAID + PPI or Coxib +PPI Consider non-NSAID Traditional NSAID No cardiovascular risk (no aspirin) NSAID GI risk No/low NSAID GI risk Risk
Notes de l'éditeur
- The definition of pain according to the International Association for the Study of Pain (IASP) is: “An unpleasant sensory and emotional experience associated with actual or potential tissue damage, or described in terms of such damage&quot; (Merskey and Bogduk, 1994).
- There are a variety of approaches for classifying pain. The two that are used most frequently are based on pain duration (ie, acute vs chronic pain) and underlying pathophysiology (ie, nociceptive vs neuropathic pain).
- In contrast to chronic pain, relatively high levels of pathology usually accompany acute pain and the pain resolves with healing of the underlying injury. Common sources of acute pain include trauma, surgery, labor, medical procedures, and acute disease states. Acute pain serves an important biological function, as it warns of the potential for or extent of injury. Acute pain becomes chronic when it persists 3 or 6 months beyond onset or beyond the expected period of healing (Turk and Okifuji, 2001). By this definition PHN is categorized as chronic pain since it is pain arising or persisting in areas affected by herpes zoster at least 3 months after healing of the skin lesion (shingles) (Rowbotham and Fields, 1989). Chronic pain is associated with low levels of identified underlying pathology that do not explain the presence or the extent of the pain (Jacobsen and Mariano, 2001). Chronic pain has also been defined as pain that ceases to serve a protective function, and instead degrades health and functional capability (Chapman and Stillman, 1996). The severity of pain in PHN is frequently sufficient to completely disrupt the lives of otherwise healthy individuals (Bonezzi and Demartini, 1999). Finally, a major problem for patients with chronic pain is that, in addition to their somatic complaints, they often have significant psychiatric disturbance (Fields, 1991).
- The IASP defines nociception as being the pain initiated or caused by activation of peripheral nociceptors (IASP, 1986). It serves as an “alarm” and protective system against noxious stimuli (Serra, 1999). According to the IASP Task Force, neuropathic pain is defined as pain initiated or caused by a primary lesion or dysfunction in the nervous system (Merskey and Bogduk, 1994). It is pain in the absence of nociceptor stimulation by trauma or disease (Bowsher, 1991) since neuropathic pain is only a symptom of a neurologic dysfunction and is not a disease in itself (Serra, 1999). PHN is classified as neuropathic pain because it involves aberrant somatosensory processing in the peripheral and/or central nervous system (Bonezzi and Demartini, 1999).
- Nociceptive, or inflammatory, pain is pain resulting from activity in neural pathways caused by potentially tissue-damaging stimuli. 1 Examples include postoperative pain, arthritis, mechanical low back pain, sickle cell crisis, and sports or exercise injuries. Neuropathic pain is pain caused by a primary lesion or dysfunction in the peripheral and/or central nervous systems. 2 Examples of peripheral neuropathic pain syndromes include HIV sensory neuropathy, postherpetic neuralgia (PHN), and diabetic neuropathy. Examples of central neuropathic pain include central poststroke pain, spinal cord injury pain, trigeminal neuralgia, and multiple sclerosis pain. As indicated by the “mixed type” area on the slide, chronic pain can be of mixed etiology with both nociceptive and neuropathic characteristics. Two types of neuropathic pain—PHN and diabetic neuropathy—will be emphasized within this module. These types of pain are being stressed because the great majority of randomized controlled trials of treatments for neuropathic pain have examined these two disorders, and because our understanding of the mechanisms of neuropathic pain is largely derived from those studies. 1. Portenoy RK, Kanner RM. Definition and Assessment of Pain. In: Portenoy RK, Kanner RM, eds. Pain Management: Theory and Practice . Philadelphia, Pa: FA Davis Company; 1996:4. 2. Galer BS, Dworkin RH. A Clinical Guide to Neuropathic Pain . Minneapolis, Minn: The McGraw-Hill Companies Inc; 2000:8-9.
- Several differences distinguish the COX-1 and COX-2 enzymes: COX-1 is present in most tissues and produces PGs that regulate normal cell activity. 1 It is especially important in maintaining the integrity of the gastric mucosa, renal blood flow, and vascular homeostasis. 2 In contrast, COX-2 is generally undetectable in most tissues, except in cases of acute and chronic inflammation and pain. Its primary role is to produce PGs at the site of inflammation. 1 COX-2 has been found in several cell types —including mononuclear cells, endothelial cells, and synovial fibroblasts— in the synovium from human RA. 3 It would be an oversimplification to think of COX-1 and COX-2 as constitutive and inducible, respectively. COX-2 has been isolated from several organ tissues — such as brain, kidney, and female genitourinary tissues — in the absence of inflammation, but its exact role in those organs needs further delineation. 2 Needleman P, Isakson PC. The discovery and function of COX-2. J Rheumatol. 1997;24(suppl 49):6-8. Dubois RN, Abramson SB, Crofford L, et al. Cyclooxygenase in biology and disease. FASEB J . 1998;12:1063-1073. Crofford LJ, Wilder RL, Ristimäki AP, et al. Cyclooxygenase-1 and -2 expression in rheumatoid synovial tissues. J Clin Invest . 1994;93:1095-1101.
- Peripheral inflammation results in the induction of COX-2 at both the peripheral and central levels. COX-2 is produced locally at the site of tissue injury and inflammation by IL-1 , a process that generally takes several hours. Recent findings indicate that following peripheral inflammation, there is a widespread induction of COX-2 expression in CNS neurons with an associated increase in prostaglandins. 1 Even with complete sensory nerve block prior to the initiation of peripheral inflammatory stimulation, COX-2 in the CNS is increased, thus demonstrating that induction of COX-2 in the CNS following stimulus is independent of PNS transmission. 1 Upregulation of central COX-2 is primarily influenced by IL-1ß in the CNS. However, circulating IL-1ß does not appear to increase IL-1ß in the CSF. Another signal, presumably IL-6, is responsible for the elevation of central IL-1ß. 1 In CNS, as well as the PNS, COX-2 induction results in increased prostaglandin synthesis. In the CNS, an elevation of prostaglandins, including PGE 2 , leads to hyperalgesia. 2 Exactly how PGE 2 contributes to central sensitization is not fully understood, but it appears that NMDA receptors play an important role. 3 Thus, COX-2 plays an important role in both peripheral and central mechanisms of pain, contributing to the development of inflammatory pain sensitivity. 1 Consequently, an ideal agent for acute inflammatory pain is one that can inhibit COX-2 in both the peripheral and central arenas. Samad TA, Moore KA, Sapirstein A, et al. Interleukin-1beta-mediated induction of Cox-2 in the CNS contributes to inflammatory pain hypersensitivity. Nature. 2001;410:471-475. Smith CJ, Zhang Y, Koboldt CM, et al. Pharmacological analysis of cyclooxygenase-1 in inflammation. Proc Natl Acad Sci USA . 1998; 95:13313-13318. Terman GW, Bonica JJ. Spinal mechanisms and their modulation. In: Loeser JD, Butler SH, Chapman CR, Turk DC, eds. Bonica’s Management of Pain . 3rd ed. Philadelphia, PA: Lippincott Williams & Wilkins: 2001:73-152.
- Pain that manifests in diverse diseases may operate through common mechanisms. No pain mechanism is an inevitable consequence of a particular disease process. A given pain mechanism could be responsible for many different symptoms. More than one mechanism can operate in a single patient, and these may change over time. The main neurotransmitter in primary afferents is the excitatory amino acid glutamate. Activation of nociceptors causes the release of glutamate from central terminals; this release acts on the ionotropic glutamate receptor amino-3-hydroxy-5-methylisoxazole-4-proprionic acid postsynaptically to cause a rapid depolarization of dorsal horn neurones and, if threshold is reached, action potential discharge. Transduction: noxious stimuli cause ion channels in the membranes of thermal, mechanical, and chemical receptors located in the skin and tissue to open. Ions enter the receptor and depolarize it. Transmission: a wave of depolarization, or action potential, travels toward the spinal cord via A-beta (thinly myelinated) fibers and C (unmyelinated) fibers and up the ascending pathway. A-beta (light touch) fibers may become sensitized by CNS mechanisms to produce allodynia. Modulation/Perception: the ascending pain pathway carries impulses from the nociceptor to the sensory cortex; thus the sensation of pain is perceived. Interpretation: impulses are carried by 1 st , 2 nd , and 3 rd order neurons. 1 st order neurons carry impulses from the nociceptor to the dorsal horn of the spinal cord. 2 nd order neurons carry impulses from the spinal cord to the thalamus, while 3 rd order neurons carry the impulse from the thalamus to the primary sensory cortex. Crossman AR, Neary D. Neuroanatomy , 2 nd ed. Churchill Livingstone, 2000. Galer B, Gammaitoni A, Alvarez N. 6. Immunology [XIV. Pain]. In: Dale DC, Federman DD, eds. WebMD Scientific American ® Medicine. New York, NY:WebMD Corporation; 2003. Guyton AC, Hall J. Textbook of Medical Physiology, 10 th Ed. Saunders, 2000. Woolf CJ, Mannion RJ. Neuropathic pain: aetiology, symptoms, mechanisms, and management. Lancet 1999;353:1959-1964.
- Current evidence suggests that the induction of COX-2 is a result of the modulation and modification of central pain neurons. Signals from peripheral nociceptors are partially responsible for COX-2 upregulation, but as mentioned earlier, there also appears to be a slow, humoral component to the transduction of the pain signal across the blood-brain barrier. 1 Once COX-2 is induced in the CNS, central prostaglandin production occurs. Prostaglandin E 2 (PGE 2 ) can directly depolarize neurons by acting via an EP-like receptor, and act at the presynaptic C-fiber terminal, facilitating the release of excitatory neurotransmitters from central nociceptors. Both actions enhance the dorsal horn neuron excitability. 2 Modification of dorsal horn neurons following inflammation or nerve damage leads to transcriptional changes in dorsal horn neurons, thereby altering gene expression and producing changes in receptors and transmitters. Transcriptional changes can also promote the induction of COX-2 in dorsal horn neurons. 3 Woolf CJ, Salter MW. Neuronal plasticity: increasing the gain in pain. Science. 2000;288:1765-1768. Baba H, Kohno T, Moore KA, Woolf CJ. Direct activation of rat spinal dorsal horn neurons by prostaglandin E2. J Neuroscience 2001;21:1750-1758. Samad TA, Moore KA, Sapirstein A, et al. Interleukin-1beta-mediated induction of Cox-2 in the CNS contributes to inflammatory pain hypersensitivity. Nature. 2001;410:471-475.
- Prostaglandin synthase is the enzyme that converts arachidonic acid into various forms of prostaglandin and is available in 2 distinct forms: COX-1 and COX-2. Nonselective NSAIDs inhibit both forms of the enzyme, causing a beneficial decrease in pain and inflammation but an adverse alteration in normal body homeostasis. When COX-2 specific inhibitors were developed, it was hoped that they would inhibit only the COX-2 enzyme, resulting in a reduction in pain and inflammation without the adverse effects caused by COX-1 inhibition. 1 FitzGerald GA, Patrono C. The coxibs, selective inhibitors of cyclooxygenase-2. N Engl J Med . 2001;345:433-442.
- This slide sets up the GI safety data slides that address endoscopic ulcer endpoints separately from ulcer complication endpoints. Speakers may want to clarify what is meant by “Upper GI Complications” (NS-NSAID-related GI side effects, including increased incidence of ulcers and ulcer complications). Analysis of data from the Arthritis, Rheumatism, and Aging Medical Information System (ARAMIS) data bank in the United States and Canada identified age as the primary risk factor for nonspecific, nonsteroidal anti-inflammatory drug (NS-NSAID)–related gastrointestinal (GI) complications in patients with rheumatoid arthritis (RA); other risk factors were a history of NS-NSAID–associated GI side effects, prior hospitalization for a GI event, the presence of significant arthritis-related disability, use of high-dose or multiple NS-NSAIDs, and concurrent use of prednisone. 1 The increased risk of ulcers in patients who take glucocorticoids appears to occur only in those who take concomitant NS-NSAIDs. 2 Several studies have shown an increasing risk of GI adverse effects with increasing NS-NSAID dose. 1,3-6 In a prospective study involving 1921 consecutively diagnosed patients with RA from 8 ARAMIS centers, it was reported that those who recently used H 2 -receptor antagonists and antacids, but did not experience an NS-NSAID–related side effect, were at increased risk for developing NS-NSAID–related GI complications. 7 References: 1. Fries JF. NSAID gastropathy: the second most deadly rheumatic disease? J Rheumatol. 1991;18:6–10. 2. Piper JM, Ray WA, Daugherty JR, Griffin MR. Corticosteroid use and peptic ulcer disease: role of nonsteroidal anti-inflammatory drugs. Ann Intern Med. 1991;114:735–740. 3. Griffin MR, Piper JM, Daugherty JR, Snowden M, Ray WA. Nonsteroidal anti-inflammatory drug use and increased risk for peptic ulcer disease in elderly persons. Ann Intern Med. 1991;114:257–263. 4. Langman MJS, Well J, Wainwright P, et al. Risks of bleeding peptic ulcer associated with individual non-steroidal anti-inflammatory drugs. Lancet. 1994;343:1075–1078. 5. Soll AH, Weinstein WM, Kurata J, McCarthy D. Nonsteroidal anti-inflammatory drugs and peptic ulcer disease. Ann Intern Med. 1991;114:307–319. 6. García Rodríguez LA, Jick H. Risk of upper gastrointestinal bleeding and perforation associated with individual non-steroidal anti-inflammatory drugs. Lancet. 1994;343:769–772. 7. Singh G, Ramey DR, Morfeld D, Shi H, Hatoum HT, Fries JF. Gastrointestinal tract complications of nonsteroidal anti-inflammatory drug treatment in rheumatoid arthritis: a prospective observational cohort study. Arch Intern Med. 1996;156:1530–1536.
- Hawkey CJ. Non-steroidal anti-inflammatory drugs and peptic ulcers. BMJ . 1990;300:278-284. Gabriel SE, Jaakkimainen L, Bombardier C. Risk for serious gastrointestinal complications related to use of nonsteroidal anti-inflammatory drugs: a meta-analysis. Ann Intern Med. 1991;115:787-796. Henry D, Lim LL, Garcia Rodriguez LA, et al. Variability in risk of gastrointestinal complications with individual non-steroidal antiinflammatory drugs: results of a collaborative meta-analysis. BMJ. 1996;312:1563-1566. Griffin MR, Piper JM, Daugherty JR, et al. Nonsteroidal anti-inflammatory drug use and increased risk for peptic ulcer disease in elderly persons. Ann Intern Med. 1991;114:257-263. Langman MJS, Weil J, Wainwright P, et al. Risks of bleeding peptic ulcer associated with individual non-steroidal anti-inflammatory drugs. Lancet . 1994;343:1075-1078. Singh G. Recent considerations in nonsteroidal anti-inflammatory drug gastropathy. Am J Med. 1998;105 (suppl 1B):31S-38S. Goldstein JL, Kivitz AJ, Verburg KM, et al. A comparison of the upper gastrointestinal mucosal effects of valdecoxib, naproxen, and placebo in healthy elderly subjects. Am J Gastroenterol . In press.
- Tram è r and colleagues sought to estimate the risk of death from bleeding or perforated gastroduodenal ulcers with chronic usage of non-steroidal anti-inflammatory drugs (NSAIDs) with greater precision A model to quantify the frequency of rare Aes which follow a biologic progression was developed. The model combined data from both RCTs and observational studies Researchers searched for any reports of chronic (>/=2 months) use of NSAIDs which gave information on gastroduodenal ulcer, bleed or perforation, death due to these complications, or progression from one level of harm to the next. Fifteen RCTs (19364 patients exposed to NSAIDs for 2-60 months), three cohort studies (215076 patients redeeming a NSAID prescription over a 3-12 month period), six case-control studies (2957 cases) and 20 case series (7406), and case reports (4447) were analyzed With at least 2 months of NSAID or ASA treatment: 1 in 5 patients will have endoscopic ulcer 1 in 70 patients will have a symptomatic ulcer 1 in 150 patients will have a bleeding ulcer 1 in 1200 patients will die of a bleeding ulcer On average 1 in 1200 patients taking NSAIDs for at least 2 months will die from gastroduodenal complications who would not have died had they not taken NSAIDs. This extrapolates to about 2000 deaths each year in the UK Reference Tramèr MR, et al. Pain . 2000;85:169-182.
- Three COX-2 – specific inhibitors are approved for use in the United States. These include sulfonamide-based agents (celecoxib and valdecoxib) and sulfone-based agents (rofecoxib). 1-3 Celecoxib (CELEBREX ® ) was the first to be approved by the Food and Drug Administration (FDA) in December 1998, followed by rofecoxib (VIOXX ® ) and then valdecoxib (BEXTRA ® ). References: 1. CELEBREX ® (celecoxib capsules) package insert. New York, NY: Pfizer Inc; 2002. 2. BEXTRA ® (valdecoxib tablets) package insert. New York, NY: Pfizer Inc; 2002. 3. VIOXX ® (rofecoxib tablets and oral suspension) package insert. Whitehouse Station, NJ: Merck & Co, Inc; 2002.
- Relative to celecoxib users, a higher risk of hospitalization for UGI hemorrhage was seen among users of NS-NSAIDs, diclofenac + misoprostol, and rofecoxib. Relative to rofecoxib, a significantly higher risk of UGI hemorrhage was observed for NS-NSAIDs but not diclofenac + misoprostol. Reference: 1. Mamdani M, Rochon PA, Juurlink DN, et al. Observational study of upper gastrointestinal hemorrhage in elderly patients given selective cyclo-oxygenase-2 inhibitors or conventional non-steroidal anti-inflammatory drugs. BMJ. 2002;325:624-627
- Two pivotal North American trials of celecoxib and naproxen in OA in flare1 and RA2 included upper GI ulcer assessments using endoscopy, which was performed at baseline to confirm a normal mucosa and at week 12 or early termination. This slide presents the incidences of endoscopically verified gastroduodenal ulcers (GDUs) after 3 months of treatment. 1,2 Ulceration was defined as a break in the mucosa of ≥0.3 cm in diameter with perceptible depth. Among the patients with OA in flare,1 the incidences of endoscopically confirmed ulcers after 12 weeks of treatment were similar to placebo for all celecoxib groups (celecoxib 400 mg BID was not assessed in this study). 1,2 None of the differences in the combined gastric and duodenal ulcer incidences among the celecoxib groups was statistically significantly different from placebo. The ulcer incidence with naproxen, however, was statistically significantly higher ( P <.001) versus all treatments. After 12 weeks of therapy in patients with RA in flare, 2 the endoscopically confirmed ulcer incidences were 4% for the placebo group (4/99 patients), 6% for celecoxib 100 mg BID (9/148 patients), 4% for celecoxib 200 mg BID (6/145 patients), 6% for celecoxib 400 mg BID (8/130 patients), and 26% for naproxen 500 mg BID (36/137 patients). Celecoxib 50 mg BID was not assessed in this study. 1 None of the differences in ulcer rates among the celecoxib groups was statistically significantly different, whereas the ulcer rate in the naproxen group was statistically significantly higher ( P <.001) compared with either placebo or the celecoxib groups. Neither of these studies was powered to compare the endoscopic ulcer rates of celecoxib and placebo. The recommended celecoxib dose for OA is 200 mg QD or 100 mg BID, and the recommended dose for RA is 100 mg to 200 mg BID. References: 1. Data on file. Pfizer Inc., New York, NY. 2. Simon LS, Weaver AL, Graham DY, et al. Anti-inflammatory and upper gastrointestinal effects of celecoxib in rheumatoid arthritis: a randomized controlled trial. JAMA. 1999;282:1921-1928.
- This slide compares Vioxx Gastrointestinal Outcomes Research (VIGOR) and Celecoxib Long-Term Arthritis Safety Study (CLASS) (non-ASA users), which are similar groups. There is an ~50% reduction in ulcer/ulcer complication rates in both CLASS and VIGOR when you compare similar populations (not exactly the same). References 1. Arthritis Advisory Committee. Update on the TNF- α blocking agents. FDA Briefing Document. March 4, 2003. Available at http://www.fda.gov/ohrms/dockets/ac/03/briefing/3930B1_01_B-TNF.Briefing.pdf. Accessed March 10, 2004. 2. Bombardier C, Laine L, Reicin A, et al, for the VIGOR Study Group. Comparison of upper gastrointestinal toxicity of rofecoxib and naproxen in patients with rheumatoid arthritis. N Engl J Med . 2000;343:1520-1528.
- In CLASS, there was significantly less GI blood loss, defined as a decrease in Hct ≥10% and HB >2 gm/dl, with celecoxib alone than with celecoxib+ASA [<0.001] and ibuprofen+ASA ( P <.009); but not between diclofenac with and without ASA ( P <.083). As in patients not receiving ASA prophylaxis, there was significantly less GI blood loss in celecoxib than either ibuprofen ( P <.05) or diclofenac ( P <.05). In the CLASS study, no statistically significant difference in UGI events was seen between the ASA-treated subgroups. The percentage of patients with moderate to severe abdominal pain, dyspepsia, and nausea was 3.2% for celecoxib and 6.5% for rofecoxib ( P =.03) in trials A and B together. In those patients taking concomitant ASA, the percentage of patients with UGI adverse events was significantly less in the celecoxib than rofecoxib treatment groups in both trials: A: 2% vs 11% ( P =.002); B: 0/7 vs 5.8% ( P =.002). Reference: 1. Pincus T, Strand V, Whelton A, et al. Celecoxib offers better GI tolerability that ibuprofen, diclofenac, or rofecoxib in patients receiving aspirin for cardiovascular prophylaxis. Ann Rheum Dis. 2002;61(suppl 1): 137(THU0266).
- COX-2 selective inhibitors. COX-2s represent an advancement in patient care, providing efficacy equivalent to that of the NS- NSAIDs, while at the same time providing an improved upper GI safety profile. The reduction in upper GI-related adverse events associated with the use of valdecoxib has been observed in both short-term (less than a week) and long-term (up to 6 months) studies (Eisen, 2002). Valdecoxib also demonstrates improved GI tolerability profiles compared with that of most NS-NSAIDs. Compared with NS-NSAIDs, the length of time to develop clinically significant upper GI events was markedly increased in patients taking celecoxib. In CLASS, there was significantly less GI blood loss, defined as a decrease in Hct >10% and HB >2 gm/dl, with celecoxib alone than with celecoxib+ASA and ibuprofen+ASA; but not between diclofenac with and without ASA. As measured by video capsule endoscopy, patients taking celecoxib demonstrated a significantly lower number of lower bowel lesions than those patients taking naproxen concomitantly with a PPI. Reference: 1. Eisen GM, Agrawal N, Kent JD, et al. Valdecoxib has a GI safety and tolerability profile superior to nonselective NSAIDs and similar to placebo in arthritis patients under 55 years. Abstract presented at: American College of Rheumatology Scientific Meeting; October 25-29, 2002; New Orleans, LA. 2. Arthritis Advisory Committee. Update on the TNF-a blocking agents. FDA Briefing Document. March 4, 2003. Available at http://www.fda.gov/ohrms/dockets/ac/03/briefing/3930B1_01_B-TNF.Briefing.pdf. Accessed March 10, 2004 3. Data on file. Pfizer Inc., New York, NY.
- Patients with OA are at higher risk than the general population for comorbid disorders, particularly those that contribute to overall cardiovascular disease (CVD) risk. 1 Hypertension, elevated total cholesterol, and diabetes are risk factors for CVD and potential subsequent CV events. Approximately 24.3 million adults (21% of the US population) have OA. 1 It is estimated that 40% of those with OA have hypertension compared with only 25% of those in the general population without arthritis; approximately 32% with OA also have hypercholesterolemia compared with 24% of the general population; and approximately 11% have diabetes compared with only 6% of the general population. 1 Reference: 1. Singh G, Miller JD, Lee FH, Pettitt D, Russell MW. Prevalence of cardiovascular disease risk factors among US adults with self-reported osteoarthritis: data from the Third National Health and Nutrition Examination Survey. Am J Manag Care. 2002;8:S383-S391.
- It has been postulated that the differences in relative selectivity for COX inhibition affect the likelihood of a patient experiencing adverse CV or GI complications as a consequence of using NSAIDs This figure illustrates the implication of the relative degrees of NSAID selectivity Increasing degrees of selectivity for COX-2 are associated with augmented cardiovascular risk, whereas increasing degrees of selectivity for COX-1 are associated with augmented GI risk This has important implications for interpretation of clinical trials. For example, a trial such as VIGOR (Vioxx Gastrointestinal Outcomes Research) is more likely to yield a signal of harm from a COX-2–selective agent given the comparison with naproxen In contrast, a comparison of etoricoxib with diclofenac, as in EDGE (part of the larger MEDAL program), is likely to yield similar risk profiles of the 2 agents but is unable to provide insight into other clinically important issues such as the relative risk of either etoricoxib or diclofenac against placebo or less COX-2–selective NSAIDs CLASS=Celecoxib Long-Term Arthritis Safety Study Reference Antman EM, et al. Circulation . 2007;115:1634-1642.
- Sowers and colleagues conducted a double-blind, randomized trial to evaluate the effects of celecoxib, rofecoxib, and naproxen on 24-hour BP in patients with type 2 diabetes, hypertension, and osteoarthritis Patients were randomly assigned to treatment with 200 mg of celecoxib once daily (n = 136), 25 mg of rofecoxib once daily (n = 138), or 500 mg of naproxen twice daily (n = 130) for 12 weeks. Twenty-four-hour ambulatory BP monitoring and validated arthritis efficacy assessments were conducted at baseline and at 1, 2, 6, and 12 weeks, ambulatory blood pressure and osteoarthritis were assessed at 6 and 12 weeks. The primary end point was the mean change from baseline in average 24-hour systolic BP at week 6 Reductions in osteoarthritis symptoms, including pain, mobility, and stiffness, were similar in all treatment groups The mean +/- SE 24-hour systolic BP following 6 weeks of therapy was increased significantly by rofecoxib (from 130.3 +/- 1.2 to 134.5 +/- 1.4 mm Hg; P < .001) but not by celecoxib (132.0 +/- 1.3 to 131.9 +/- 1.3 mm Hg; P = .54) or naproxen (133.7 +/- 1.5 to 133.0 +/- 1.4 mm Hg; P = .74) The BP difference between rofecoxib and celecoxib was 3.78 mm Hg (95% confidence interval, 1.18-6.38; P = .005); between rofecoxib and naproxen, 3.85 mm Hg (95% confidence interval, 1.15-6.55; P = .005). The proportion of patients with controlled HTN at baseline who developed ambulatory HTN by week 6 (24-hour systolic BP>135 mm Hg) was significantly greater with rofecoxib (30%) than with celecoxib (16%) ( P = .05) but not significantly greater than with naproxen (19%) At equally effective doses for osteoarthritis management, treatment with rofecoxib but not celecoxib or naproxen induced a significant increase in 24-hour systolic BP. However, destabilization of HTN control occurred to some extent in all 3 treatment groups; this phenomenon was seen more often in patients treated with rofecoxib than with the other therapies Reference Sowers JR, et al. Arch Intern Med . 2005;165:161-168.
- White and colleagues analyzed the data for celecoxib and NSAIDs from the Celecoxib Long-term Arthritis Safety Study to determine the incidences of serious CV thromboembolic events. This trial included 3987 persons randomized to celecoxib 400 mg twice daily (2320 person-years of exposure) and 3981 persons randomized to either ibuprofen 800 mg 3 times daily or diclofenac 75 mg twice daily (2203 person-years) Since ASA use for CV risk prophylaxis (< or =325 mg/day) was permitted, separate analyses were performed for all patients and those not taking ASA. The incidences of serious CV thromboembolic events (MI, stroke, CV deaths, and peripheral events) were similar, and not significantly different, between celecoxib and NSAID comparators (combined or individually) for all patients as well as the subgroup of patients not taking ASA. This observation was true both for all serious CV thromboembolic events, as well as for individual events. No increase in MI was apparent, even in patients not taking ASA who were candidates for secondary prophylaxis for myocardial infarction 21% of the CLASS trial participants were taking low-dose ASA, representing a relatively large number of patients with some form of underlying CV disorder. Approximately 40% of patients in CLASS had a history of CV disease including HTN, hypercholesterolemia, prior MI, and some manifestation of coronary artery disease. From a theoretical standpoint, the CLASS population had a fairly high proportion of patients with vascular disease at risk for events during this 1-year trial. However, for both the ASA and the non-ASA cohorts unprotected by aspirin’s platelet COX-1 blockade, the incidence of serious thromboembolic adverse effects for celecoxib (800 mg qd) and the comparator NSAID groups was 1.1% to 1.2%, respectively Reference White WB, et al. Am J Cardiol. 2002;89:425-430.
- Graham and colleagues sought to establish if risk was enhanced with rofecoxib at either high or standard doses compared with remote NSAID use or celecoxib use, because celecoxib was the most common alternative to rofecoxib Data from Kaiser Permanente in California were used to assemble a cohort of all patients age 18-84 years treated with a NSAID between Jan 1, 1999, and Dec 31, 2001, within which we did a nested case-control study. Cases of serious coronary heart disease (acute MI and SCD) were risk-set matched with four controls for age, sex, and health plan region. Current exposure to COX-2 selective and non-selective NSAIDs was compared with remote exposure to any NSAID, and rofecoxib was compared with celecoxib There were 8199 acute cardiac events within the study cohort (6,675 AMI; 1,524 SCD), with available enzyme confirmation (CK-MB or troponin I) for 5,836 (87.4%) hospitalized AMIs. As expected, the prevalence of prior CVD, emergency room visits and drug use was uniformly increased among cases The odds ratio are relative to the remote use of any NSAID. Risk of AMI and SCD was less with celecoxib compared with lower dose rofecoxib (≤25 mg) ( P =0.04) Researchers concluded that rofecoxib use increases the risk of serious coronary heart disease compared with celecoxib use. Naproxen use does not protect against serious CHD Reference Graham DJ, et al. Lancet . 2005;365:475-481.
- A number of controlled clinical trials have demonstrated that the newer COX-2–specific inhibitors are as effective as the older nonspecific, nonsteroidal anti-inflammatory drugs (NS-NSAIDs) for the treatment of pain in a wide variety of medical conditions. In a randomized, multicenter, double-blind, active- and placebo-controlled trials comparing celecoxib 100 mg bid with naproxen 500 mg bid in the management of osteoarthritis (OA) of the knee in flare using the Western Ontario and McMaster Universities (WOMAC) OA Index. 2 The WOMAC OA Index is a self-administered health-assessment questionnaire consisting of 24 component measures, with subscores for pain, stiffness, and physical function. Lower scores are associated with better health status. This slide presents the mean improvements from baseline in WOMAC OA Index composite scores for 3 subscales (includes pain, physical function, and joint stiffness scores) in the trial. At week 12, 1 the mean improvement from baseline in WOMAC composite scores among patients taking celecoxib 100 mg bid was significantly greater ( P <0.05) than that among patients taking placebo (13.3 vs 6.1, respectively) and was similar to the improvement in composite scores for patients taking naproxen 500 mg bid (11.9). References 1. Bensen WG, Fiechtner JJ, McMillen JI, et al. Treatment of osteoarthritis with celecoxib, a cyclooxygenase-2 inhibitor: a randomized controlled trial. Mayo Clin Proc. 1999;74:1095–1105. 2. Bellamy N, Buchanan WW, Goldsmith CH, Campbell J, Stitt LW. Validation study of WOMAC: a health status instrument for measuring clinically important patient-relevant outcomes to antirheumatic drug therapy in patients with osteoarthritis of the hip or knee. J Rheumatol . 1988;15:1833–1840.
- This slide provides an overview of the efficacy profile for celecoxib. A multi-center, randomized, double-blind, placebo-controlled trial of 1003 patients with knee OA received 50, 100, or 200 mg celecoxib bid, naproxen 500 mg bid or placebo for 12 weeks. All celecoxib doses were efficacious compared with placebo. The efficacy of higher doses of celecoxib was comparable to that of naproxen 500 mg bid. 1 A 12-week, multicenter, double-blind trial compared the efficacy of celecoxib with that of naproxen in a total of 1149 patients with symptomatic rheumatoid arthritis (RA).2 The patients were randomized to receive celecoxib 100 mg BID (n = 240), celecoxib 200 mg BID (n = 235), naproxen 500 mg BID (n = 225), or placebo (n = 231). An additional group was given celecoxib 400 mg BID. 2 The ACR-20 response rates were similar for patients taking celecoxib at dosages of 100 mg BID, 200 mg BID, or naproxen 500 mg BID, and were all significantly ( P <0.05) better than the ACR-20 response rates among patients taking placebo. 2 References: 1. Bensen WG, Fiechtner JJ, McMillen JI, et al. Treatment of osteoarthritis with celecoxib, a cyclooxygenase-2 inhibitor: a randomized controlled trial. Mayo Clin Proc. 1999;74:1095–1105. 2. Simon LS, Weaver AL, Graham DY, et al. Anti-inflammatory and upper gastrointestinal effects of celecoxib in rheumatoid arthritis. JAMA. 1999;282:1921–1928.