第三届双氯芬酸(扶他林)止痛世家高层论坛报道

第三届双氯芬酸(扶他林)止痛世家高层论坛报道 第三届双氯芬酸(扶他林)止痛世家高层论坛于2007年9月8日在云南丽江落下帷幕,50多名全国各地骨科和风湿科专家、学者济济一堂,共同探讨非类固醇类抗炎药(NSAID)对骨、关节和软组织疾病所致疼痛临床治疗的前沿问,并运用大量循证医学证据讨论了NSAID的应用体会及其不可替代的临床价值。同时,对已有30余年历史的双氯芬酸系列产品的疗效和安全性给予了进一步肯定,认为双氯氛酸以抗炎镇痛疗效确切,安全性可信赖、性价比理想和有多种剂型等特点,仍为治疗多种急慢性疼痛的首选药物。同时,扶他林乳胶剂在今年5月获得批准用于治疗骨性关节炎,为医师和患者提供了更多的治疗选择。|z[     本次会议由解放军总医院施桂英教授担任大会主席。会上,施教授对传统NSAID与COX-2抑制剂的安全性进行了比较,上海瑞金医院冯建民教授介绍了外用制剂在骨性关节炎治疗中的应用,北京大学人民医院栗占国教授作了类风湿关节炎诊治指南及其临床应用的,对目前类风湿关节炎的诊断与治疗提出了一些新的观点。分会场的内容也精彩纷呈。骨科分会场中,北京大学附属第三医院党耕町教授介绍了胸椎管狭窄症,积水潭医院田伟教授介绍了计算机辅助脊柱外科手术。本届大会除专家精彩演讲外,还专门设立了辩论赛,针对目前倍受关注的热点问题,如在镇痛方面,传统NSAID和COX-2抑制剂孰优孰劣?强直性脊柱炎和类风湿关节炎的治疗是否应该使用糖皮质激素?正反两方以循证医学证据为论据展开了精彩辩论。     传统NSAID与COX-2抑制剂的安全性比较     解放军总医院风湿科 施桂英     已有百年历史的NSAID是一类具有抗炎、镇痛、解热及抗血小板聚集作用的药物,临床上广泛用于治疗许多急、慢性疼痛,包括类风湿关节炎(RA)、骨性关节炎(OA)、强直性脊柱炎、软组织风湿病、头痛、痛经及术后疼痛等。最先诞生的阿司匹林以抗炎、镇痛、解热和抗血栓作用而百年不衰,但其引起的不良反应常见,有的甚至很严重。二十世纪五六十年代上市的保泰松和吲哚美辛抗炎效果虽好,但毒性反应大,已很少使用或仅用于治疗强直性脊柱炎和退热。七十年代上市的布洛芬、萘普生、双氯芬酸等与以往药物疗效相当,但不良反应明显减少。八十年代后上市的美洛昔康和萘丁美酮等,在长期大规模临床观察中亦显示出较好的疗效及安全性。     阿司匹林通过抑制环氧合酶(COX)阻断前列腺素(PG)生成而发挥抗炎作用,但也可能因此引发不良反应。二十世纪九十年代初发现COX有2种同工酶,即COX-1和COX-2。在此基础上人们推测,NSAID所致胃肠反应与抑制COX-1有关,而其抗炎止痛作用则与抑制COX-2相关,并认为传统NSAID因无选择地抑制两种COX,故疗效和不良反应并存。为减少胃肠道不良反应,选择性COX-2抑制剂应运而生。     初期临床试验显示,COX-2抑制剂对RA和OA患者的疗效及副作用与传统NSAID相当。一项在RA患者中进行的为期12周的双盲对照研究显示,塞来昔布200 mg/d、400 mg/d和800 mg/d的疗效分别为41%、44%和38%,与对照组萘普生1000 mg/d相比无统计学差异,两组胃肠道反应发生率亦无显著差异。另一项罗非昔布50 mg/d和萘普生1000 mg/d治疗RA的研究显示,两药疗效相当,但罗非昔布组心肌梗死(MI)发生率明显高于萘普生组(0.4% 对 0.1%,P<0.05)。其他不良反应如高血压和水肿发生率,昔布类与双氯芬酸和布洛芬相比无显著差异。     12周的镜下对比观察发现,塞来昔布和罗非昔布治疗者溃疡发生率分别低于相应对照药物萘普生和布洛芬,但塞来昔布问世不久即有3例下肢动脉栓塞和1例肺动脉栓塞的报道。因此,从初期临床数据中可见,COX-2抑制剂临床疗效并未增加,整体不良反应发生率也未降低,镜下溃疡发生率虽较低,但存在MI及栓塞危险。 COX-2抑制剂所致心血管和肾脏等不良反应已经引起关注。近期塞来昔布预防结肠腺瘤(APC)研究显示,塞来昔布增加心血管事件危险, 400 mg组发生致死性或非致死性心血管事件危险是安慰剂组的2.5倍,800 mg组是安慰剂组的3.4倍。据报道,FDA收到264例昔布类药物导致肾衰的报告,平均发病时间为10天,最短在治疗3天后。在塞来昔布所致肾衰患者中,64%需住院治疗,罗非昔布导致肾衰患者,69.9%需住院治疗。两种药物治疗者中均有因肾衰死亡的报告,因此,昔布类的肾毒性已引起重视。 由于COX-2抑制剂不抑制COX-1,尽管该药溃疡发生率略低于非选择性COX抑制剂,但总体副作用并未减少,疗效也未提高。COX-2抑制剂对COX-2高度抑制,虽有抗炎疗效,但也出现了新的心血管和肾脏等副作用。2004年罗非昔布因心血管安全性问题撤市,美国、澳大利亚和欧洲市场塞来昔布处方量大幅下降,使人们不得不重新关注传统NSAID的安全性。2005年FDA声明中明确要求,在抗炎药物说明中加上黑框,注明塞来昔布存在心血管以及胃肠道危险,传统NSAID存在心血管以及胃肠道的潜在风险。     实际上,传统NSAID药物中不同药物所致胃肠道损害差别较大。长期临床研究明,阿司匹林、吲哚美辛、吡罗昔康、萘普生不良反应较大,而萘丁美酮、双氯芬酸、布洛芬、美洛昔康胃肠道不良反应较小。     长达6个月和12个月的CLASS研究充分表明,塞来昔布的胃肠道安全性与双氯芬酸相比无差异。FDA对CLASS和VIGOR试验中的不良事件发生率和死亡率进行后显示,严重不良事件发生率(包括死亡、住院、危及生命的事件),COX-2抑制剂组明显高于传统NSAID组。 SUCCESS-1研究也显示,治疗骨性关节炎,塞来昔布组胃肠道及严重不良事件发生率与双氯芬酸组无显著差异。     MEDAL研究显示,第二代COX-2抑制剂依托昔布(etoricoxib)和双氯芬酸治疗骨性关节炎和类风湿关节炎时,轻度上消化道不良反应发生率依托昔布组低于双氯芬酸组,但严重消化道不良反应两组无差异(该结果被质疑为自相矛盾的结果);并且依托昔布组心血管不良事件及因心血管不良事件退出治疗的患者比例高于双氯芬酸组。另一种二代COX-2抑制剂voldicoxib因致严重皮肤毒性反应,上市不久即被FDA下令停售。     从上述对比资料中可见,选择性COX-2抑制剂的临床疗效未增,胃肠道优势的证据仍欠缺,其心脏和肾脏及皮肤不良反应危险突出,高危人群广泛,并非首选用药。与众多NSAID相比,双氯芬酸(扶他林)的疗效和安全性较好,是治疗风湿性和非风湿性疾病有效且安全的药物之一。自1974年上市以来,双氯芬酸已在全球120余个国家(使用者超过8亿)广泛应用,深受医师和患者信任。      正反双方引用了众多基础研究和大型国际临床试验数据,对该问题进行了全方位回顾和论述,最终认为:对COX-2抑制剂和传统NSAID的临床应用应持辩证态度。一些COX-2抑制剂存在胃溃疡发生率未明显降低,心血管不良事件增多等问题,不能过分夸大COX-2抑制剂的临床安全性,需对其重新评估。相反,传统NSAID有明显优于昔布类的抗炎、镇痛和解热作用,应重新认识传统NSAID,合理治疗其引发的胃肠道不良反应,更好地发挥药物疗效。 大量随机对照研究表明,COX-2抑制剂疗效未超越非选择性NSAID。Emery研究证实,双氯芬酸的疗效未被塞来昔布超越。655例RA患者分别接受双氯芬酸150 mg或塞来昔布400 mg治疗。结果显示,塞来昔布与双氯芬酸在控制RA的各种疼痛和炎症方面疗效无显著差异。著名的SUCCESS-1研究显示,塞来昔布100 mg每日2次与NSAID的疗效无显著差异,再次证实了NSAID的疗效并未被塞来昔布超越。     对于临床医生关注的NSAID心血管安全性问题,从CLASS研究数据可以看出,虽未达到统计学意义,但双氯芬酸组MI发病率低于塞来昔布和布洛芬组。SUCCESS-1研究也得出相同结论,虽无统计学意义,但塞来昔布组MI发生率为55/100患者-年,萘普生组为0.11/100患者-年,而双氯芬酸组无患者出现MI。一项评估罗非昔布25 mg预防结肠直肠息肉复发效果的研究中,治疗18个月后,与安慰剂相比,罗非昔布治疗者确定的心血管事件发生相对危险增加。因此,2004年上市5年的COX-2特异性抑制剂罗非昔布撤市。     对大量相关研究综合分析显示,昔布类的心血管事件风险高于传统NSAID。而传统NSAID如、吲哚美辛类药物由于相关不良反应发生率高,临床上已较少应用。但是对于双氯芬酸类药物,长达30年的临床经验充分证明了其有效性和安全性。日本的上市后研究显示,双氯芬酸的胃肠道不良事件发生率为6%,且以轻度为主,不影响患者继续用药。     因此,镇痛药的临床应用要结合患者的个体情况,细化地评估分析药物的心血管风险,选择最小有效剂量,短疗程,合理用药。 新英格兰医学杂志的发热待查病例，这才叫水平 Case 26-2007 — A 61-Year-Old Man with Recurrent Fevers Gregg S. Meyer, M.D., Charles A. Hales, M.D., Philip C. Amrein, M.D., Amita Sharma, M.D., and Richard L. Kradin, M.D. Presentation of Case Dr. James J. Tolle (Pulmonary and Critical Care Medicine): A 61-year-old man was admitted to this hospital because of recurrent fevers. He had been well until approximately 3.5 months earlier, when chills, fevers, and fatigue developed. He had no cough or production of sputum. He saw his primary care physician, who sent him to the emergency department of another hospital. A chest radiograph revealed a left basilar opacity, and a diagnosis of community-acquired pneumonia was made. A 5-day course of azithromycin was begun. His symptoms persisted, and he was admitted to the same hospital 5 days later. A chest radiograph obtained on admission revealed clear lungs. However, on the third hospital day, a repeated chest radiograph revealed a focal opacity in the posterior right base, and intravenous ceftriaxone and oral doxycycline were begun. Computed tomography (CT) of the chest on the fourth hospital day disclosed an opacity in the right lower lobe, bilateral pleural effusions, and patchy ground-glass opacities in the right upper lobe. A repeated chest CT scan on the 11th day showed resolution of the infiltrates and effusions, but daily fevers to 38.9°C continued. Cultures of blood and urine, thin and thick smears for malaria, and serologic tests for cytomegalovirus and Epstein–Barr virus were negative. A transthoracic echocardiogram was negative for vegetations. A diagnosis of type 2 diabetes mellitus was made, and treatment with insulin was begun. He was transferred to this hospital on the 20th hospital day. At the time of admission, his major symptom was persistent daily fever to 38.9°C; he did not have a cough or sputum production. He had been born and raised in Bangladesh and had immigrated to the United States 4 years earlier; he had last traveled to Bangladesh 9 months before admission and had remained there for 4 months. He was a retired marketing manager. He was married with two children and lived with his family in a suburb of Boston. His wife and children were well. He did not use tobacco, alcohol, or illicit drugs. His medications included ibuprofen as needed, for the fever, and insulin. He had no known drug allergies. The temperature was 36.2°C, and the respirations were 18 breaths per minute. Physical examination was normal, except for pitting edema (1+) in both legs to the level of the midcalf. While the patient was in the hospital, the temperature rose daily to between 38.0°C and 38.9°C. Cultures of blood, urine, and stool; thin and thick smears for malaria and babesiosis; serologic studies for bartonella and brucella; and tests for cytomegalovirus and histoplasma antigens were negative. A test for hepatitis B surface antibody was positive, and tests for hepatitis B surface antigen, hepatitis C antibody, and human immunodeficiency virus antibody were negative. The erythrocyte sedimentation rate ranged from 94 to 115 mm per hour during the admission. Results of other laboratory tests are shown in Table 1 and Table 2. Examination of a biopsy specimen of the bone marrow disclosed normal trilineage hematopoiesis; flow cytometry disclosed no abnormal cells, and cultures for fastidious bacteria, mycobacteria, and fungi were negative. A chest radiograph was normal. Doppler studies of the legs disclosed no deep venous thrombosis. CT of the chest showed a small left pleural effusion, bibasilar atelectasis, and mediastinal lymph nodes that were 1 cm in diameter. A bone scan was normal. CT of the abdomen showed multiple nonenhancing hepatic lesions, which were thought to represent cysts. Tests for antineutrophil cytoplasmic autoantibodies with both perinuclear and cytoplasmic patterns of staining were negative, as was a test for rheumatoid factor. There was a slight elevation in anti–smooth-muscle antibody to 1:40 dilution and a positive antinuclear antibody titer to 1:1280 dilution; tests for other autoantibodies were negative. The patient was discharged on the 11th day to follow-up in the outpatient rheumatology clinic. Six weeks later, he was seen in the rheumatology clinic. His fevers had resolved 2 weeks after discharge, his appetite had returned, and he felt well. Five weeks later, 2 weeks before this admission, daily fevers returned, accompanied by rigors. The day before admission, he had several episodes of diarrhea, and he noted a small amount of blood in the stool. The next day, shortness of breath developed, and he was readmitted to this hospital. The temperature was 35.8°C, the pulse 94 beats per minute, the blood pressure 156/80 mm Hg, and the oxygen saturation 98% while the patient was breathing 2 liters of oxygen per minute by nasal cannula. He appeared chronically ill but not in distress. Examination of the head, eyes, ears, nose, and throat was normal. The neck was supple without lymphadenopathy, and the jugular venous pressure was 6 cm. The heart rate and rhythm were regular, without murmurs, rubs, or gallops. Auscultation of the chest revealed crackles in both lower-lung fields. The remainder of the examination was normal. A chest radiograph showed no abnormalities. A CT angiogram of the chest showed no evidence of pulmonary embolus. Mediastinal and hilar lymph nodes were enlarged as compared with those seen on the chest CT scan from the first admission, and there were new scattered peripheral foci of ground-glass attenuation, interlobular septal thickening in the apexes, and a suggestion of peribronchial interstitial thickening. Bronchoscopy with bronchoalveolar lavage of the right lower lobe and transbronchial biopsy were performed on the second hospital day. Cultures revealed scanty normal flora and rare yeast forms. Fungal and acid-fast smears were negative. Pathological examination of a transbronchial biopsy specimen revealed no malignant cells or granulomas. Cultures of the tissue for fungi, mycobacteria, and cytomegalovirus were negative. Results of laboratory tests are shown in Table 1 and Table 2. A transthoracic echocardiogram on the second hospital day revealed no evidence of valvular vegetations. On the third hospital day, the temperature rose to 38.6°C. A CT scan of the abdomen on the fourth day revealed no change from the previous study. During the next 24 hours, fever persisted, up to 39°C, and the oxygen saturation fell. Tachypnea worsened, and on the fifth day, oxygen at 4 liters per minute by means of nasal cannula was required to maintain saturation above 90%. Repeated CT scans of the chest, without contrast material, revealed new patchy opacification in the right upper lobe, persistent consolidation in the right lower lobe, bilateral free-flowing pleural effusions, and interlobular septal thickening consistent with pulmonary edema. Mediastinal and hilar lymph nodes had not increased in size. An 18F-fluorodeoxyglucose positron-emission tomographic (FDG-PET) scan on the sixth day disclosed uptake in the lung bases in the areas of consolidation seen on CT scans. There was also a diffuse, mild uptake of the material throughout the lungs. The hilar and mediastinal lymph nodes showed no uptake. Transesophageal echocardiography revealed diffuse thickening on the atrial surface of the anterior mitral valve. On the ninth day, a diagnostic procedure was performed. Differential Diagnosis Dr. Gregg S. Meyer: At the time of the patient's initial transfer to this hospital, he met the criteria established by Petersdorf and Beeson1 for the diagnosis of fever of unknown origin: fevers higher than 38.2°C on several occasions for more than 4 weeks, with no specific diagnosis despite extensive evaluation at another hospital. The general workup for a fever of unknown origin includes history taking and a physical examination, a complete blood count, a routine blood-chemical profile (including tests of liver function), urinalysis, multiple cultures, chest radiography,2 and CT scanning of the chest and abdomen.3 The only abnormal finding in this case was the presence of transient pulmonary infiltrates seen on CT scans of the chest. The history of recent travel raises the possibility of exposure to malaria or parasitic infection, but tests for these were negative. The fever responded to ibuprofen. I met the patient for the first time approximately 2 weeks after his first discharge from this hospital. At that time, his fevers had abated and he had gained back some of the weight that he had lost. I was faced with the unsatisfying situation of having no diagnosis for this patient. Despite our sophisticated diagnostic armamentarium, fever of unknown origin remains humbling for the diagnostician, since up to a third of patients with fever of unknown origin never receive a definitive diagnosis. At this point, a strategy of watchful waiting seemed reasonable, since patients in whom a diagnosis is not made after intensive evaluation generally improve.4 Remaining vigilant for serious disorders that could affect the patient's ultimate outcome, particularly hematologic malignant conditions, was our chief concern during the period of watchful waiting.4 The watchful-waiting approach had to be abandoned when the patient's fever recurred 3 months after discharge, accompanied by shortness of breath and hypoxemia. On readmission, he had weight loss, fever, sweats, and occasional rigors that did not respond to ibuprofen. The transaminase levels again became elevated; he had an episode of diarrhea with bright red blood from the rectum, progressive impairment in renal function, and return of the pulmonary infiltrates. The development of pulmonary, hepatic, renal, and gastrointestinal involvement provided clues that helped narrow our differential diagnosis.5 May we review the imaging studies? Dr. Amita Sharma: The chest radiograph obtained on admission shows low lung volumes and a normal heart size. A CT scan of the chest performed the next day shows interlobular septal thickening and hilar and subcarinal lymphadenopathy (Figure 1A). The findings are most suggestive of interstitial pulmonary edema, although the differential diagnosis would include an atypical infection. Four days later, when his condition worsened, repeated CT scans of the chest demonstrate persistent hilar and subcarinal lymphadenopathy and interlobular septal thickening. There are new bilateral free-flowing pleural effusions and air-space opacities at the right apex and right base (Figure 1B). The appearances are suggestive of pulmonary edema and superimposed multifocal pneumonia. HYPERLINK "http://content.nejm.org/cgi/content/full/357/8/807/F1" INCLUDEPICTURE "http://content.nejm.org/content/vol357/issue8/images/small/12f1.gif" \* MERGEFORMATINET View larger version (92K): [in this window] [in a new window] HYPERLINK "http://content.nejm.org/cgi/powerpoint/357/8/807/F1" INCLUDEPICTURE "http://content.nejm.org/icons/powerpoint/get_pp_slide_center.gif" \* MERGEFORMATINET   Figure 1. CT Scans of the Chest. A CT image of the chest obtained on the day of the second admission at the level of the manubrium (Panel A) shows mild interlobular septal thickening and peribronchial thickening in the lung apexes, as well as scattered ground-glass opacities. A CT scan of the chest at the same level obtained 4 days later (Panel B) shows new free-flowing bilateral pleural effusions. A new peripheral ground-glass opacity is seen in the right upper lobe, and there is persistent interlobular septal and peribronchial thickening.   An FDG-PET scan performed the next day shows diffuse uptake of tracer throughout the lungs (Figure 2A and 2B). The changes are most pronounced at the site of the air-space opacities in the right apex and right base. There is no uptake within the enlarged hilar or subcarinal lymph nodes. Diffuse parenchymal uptake on FDG-PET scans is rare. It has been described in Pneumocystis carinii pneumonia, radiation pneumonitis, bleomycin pneumonitis, lymphangitic spread of carcinoma, and acute respiratory distress syndrome.6,7,8,9,10 Focal parenchymal uptake can occur in neoplastic conditions and in non-neoplastic conditions such as infection, sarcoidosis, aspiration pneumonia, and usual interstitial pneumonia.11,12,13 HYPERLINK "http://content.nejm.org/cgi/content/full/357/8/807/F2" INCLUDEPICTURE "http://content.nejm.org/content/vol357/issue8/images/small/12f2.gif" \* MERGEFORMATINET View larger version (60K): [in this window] [in a new window] HYPERLINK "http://content.nejm.org/cgi/powerpoint/357/8/807/F2" INCLUDEPICTURE "http://content.nejm.org/icons/powerpoint/get_pp_slide_center.gif" \* MERGEFORMATINET   Figure 2. Fluorodeoxyglucose Positron-Emission Tomographic Scan. Axial (Panel A) and coronal (Panel B) images at the level of the ventricles show diffuse tracer uptake throughout both lungs. No uptake is seen in the hilar and subcarinal lymph nodes.   Possible Causes of Fever of Unknown Origin             Infection Dr. Meyer: We focused on the three most likely causes of fever of unknown origin in this patient, the first of which is infection. This patient's travel to Bangladesh during the previous year was intriguing, but an extensive microbiologic and serologic workup was unrevealing. In addition, there was no evidence of a focal infectious process, such as a deep abscess on abdominal CT scan, sinusitis, prostatitis, or dental infection on the basis of radiologic studies and clinical examinations. A transesophageal echocardiogram showed no evidence of endocarditis. As a result of this workup, we believed that an infectious cause was unlikely.             Cancer The second possible cause is cancer. The elevated lactate dehydrogenase level and the markedly elevated erythrocyte sedimentation rate are suggestive of, but not specific for, a malignant tumor.14 The patient also had hilar lymph nodes that were believed to be borderline in size. However, he had no findings on physical examination, such as lymphadenopathy or splenomegaly, to suggest a malignant tumor. The bone marrow examination was normal, and an extensive workup — including CT scans of the chest and abdomen, bronchoscopy, and colonoscopy — for likely sources of metastatic disease was unrevealing. Despite the absence of findings, the presence of cancer could not be ruled in or out.             Autoimmune disorders The third category, noninfectious inflammatory disease, also remained in the differential diagnosis. The presence of an elevated erythrocyte sedimentation rate and waxing and waning pulmonary infiltrates made vasculitis a consideration. Despite a positive antinuclear antibody test, the patient had no arthritis, rash, or tenderness over the temporal artery. There was no evidence of a microangiopathic hemolytic anemia, and he had an active urinary sediment and a negative result on a test for antineutrophil cytoplasmic antibody. Testing for other autoantibodies was negative; therefore, a noninfectious inflammatory disease was unlikely. Use of FDG-PET scanning is reported to have a sensitivity of 84% and a specificity of 86% for localizing the source of fever of unknown origin.15 In this patient, the scan demonstrated diffuse uptake of tracer in the entire lung. Because of this finding, we consulted our colleagues from pulmonary medicine. Dr. Charles A. Hales: In this patient with fever for several months and a persistently elevated erythrocyte sedimentation rate, the important pulmonary findings were shortness of breath with exertion, tachycardia, bibasilar crackles, hypoxemia, and an abnormal diffusion capacity of the lung for carbon monoxide. Our dilemma from the beginning was to decide whether one disease could account for all the findings or whether there was a chronic underlying disease with a superimposed acute event. Crackles on physical examination, along with a chest radiograph that was thought to show interstitial edema and a pleural effusion, resulted in serious consideration of congestive heart failure. However, diuresis produced no clearing of the crackles, and the serum brain natriuretic peptide level and the left ventricular ejection fraction were normal, all making cardiogenic congestive heart failure unlikely. Pulmonary emboli