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作者：Laurie Barclay, MD  
出處：WebMD醫學新聞

　　December 28, 2009 — 一篇發表於12月15日美國家庭醫學科期刊(American Family Physician)的回顧文獻，提出於第一線照護開立非抗發炎類固醇藥物(NSAIDs)處方的建議。
　　
　　波特蘭奧勒剛健康科學大學的Amanda Risser醫師等人寫道，藉由阻斷環氧合酶(COX)而減少前列腺素合成，NSAIDs一般用於治療發炎、疼痛、與發燒，兩大類型的COX(COX-1和COX-2)都受到非選擇性NSAIDs的抑制，COX-2也會受到選擇性NSAIDs的抑制。所有的非選擇性NSAIDs會透過抑制COX-1和血栓素A2(TXA2)路徑而抑制血小板凝集。
　　
　　雖然NSAIDs被廣為使用，但有一些風險，包括明顯的上腸胃道出血(特別是年長者)，使用抗凝血治療者、有與使用NSAID相關上胃腸道出血病史之病患也有風險。併用NSAID與質子幫浦抑制劑(PPI)或組織胺H2受體拮抗劑可以降低消化不良、腹痛、胃腸道不適、胃腸道出血。
　　
　　儘管阿斯匹靈對心臟有保護性，其他的NSAIDs可能有心臟方面的副作用，包括惡化鬱血性心衰竭、血壓上升、心肌梗塞以及局部缺血。COX-2抑制劑的心肌梗塞風險增加，然而，美國目前唯一的COX-2抑制劑celecoxib，在心血管效果方面可能是安全的。
　　
　　NSAIDs不應用於肝硬化病患，因為這類病患的出血和腎衰竭風險更大。不過，NSAIDs很少引起肝損傷，對於肝臟的任何影響通常也是可逆的。比較會引起肝臟問題的NSAIDs有sulindac和diclofenac。
　　
　　當開立NSAIDs處方給使用抗凝血劑治療者、血小板功能不佳者、或馬上要進行手術者時需謹慎。
　　
　　NSAIDs的中樞神經系統副作用，包括無菌性腦膜炎、精神病與耳鳴，NSAIDs也會引起或惡化氣喘。對於氣喘病患，特別是那些鼻息肉或復發鼻竇炎者，應避免使用NSAIDs和阿斯匹靈。
　　
　　懷孕最後6到8週時，應避免使用NSAIDs，以免因為抑制前列腺素合成而延長妊娠、動脈導管過早關閉，血小板活化而引起母嬰併發症。不過，多數的NSAIDs在懷孕期間是安全的，對於哺乳婦女，可以安全使用ibuprofen、indomethacin與naproxen。應教育病患正確的NSAID劑量資訊，以及將其存放在孩童無法開啟的容器，以免發生孩童NSAID過量風險。
　　
　　【主要建議】
　　提供給開業醫師的主要臨床建議與相關證據等級如下：
　　* 對於有NSAID相關潰瘍但必須服用NSAIDs者，醫師需考慮同時處方PPIs、加倍劑量的組織胺H2受體拮抗劑或misoprostol。這些病患也可以單獨使用Celecoxib，但是心肌梗塞風險增加的病患應避免使用此藥。可能懷孕的婦女也應避免服用misoprostol (證據等級C)。兩篇系統性回顧指出，這類病患使用NSAIDs可以預防內視鏡潰瘍(endoscopic ulcers)。
　　* 為了預防急性腎衰竭，腎臟病、鬱血性心衰竭或肝硬化患者應避免使用NSAIDs (證據等級C，根據文獻回顧以及共識指引之綜述)。
　　* 至於腎衰竭風險病患，以及服用血管收縮素轉化酶抑制劑和血管張力素受器阻斷劑者，醫師在處方NSAIDs之後，應考慮監測血清肌酸酐濃度(證據等級C，根據共識指引之綜述)。
　　* 對於服用抗凝血劑的病患，如果可以的話，儘量避免NSAIDs與阿斯匹靈。如果需併用NSAIDs和抗凝血劑，則國際標準比(INR)預期會升高。這些病患應有適當的INR監測、調整warfarin劑量以及胃腸道方面的預防(證據等級C，根據系統性回顧)。
　　* 至於哺乳婦女，可以安全地使用ibuprofen、indomethacin和naproxen(證據等級C，根據共識指引)。
　　
　　【編輯：增加心血管顧慮】
　　丹麥哥本哈根大學Gentofte醫院的Gunnar H. Gislason博士在編輯評論中表示，有關NSAIDs之心血管安全性的顧慮增加，在過去10年越趨明朗，雖然最初認為這些顧慮是與COX-2抑制劑有關，最近也發現非選擇性NSAIDs與心血管風險的關聯。
　　
　　因為總是有一些病患有需服用NSAIDs的疼痛狀況，在開始NSAID治療之前，應聚焦在風險與利益的平衡上。
　　
　　Gislason博士寫道，這對於已經有心血管疾病的病患特別重要，這些人一定要優先考量使用心臟風險低的藥物(例如acetaminophen、弱效鴉片類)來治療疼痛。對於需要NSAID治療者，應考量使用具有高度COX-1 選擇性的NSAIDs(例如naproxen、ibuprofen、阿斯匹靈)，且儘可能以最低劑量、最短期間治療。若要較強的止痛效果，可以考慮併用其他類止痛藥。
　　
　　至於輔助止痛治療，Gislason博士建議考慮非藥物療法，例如物理治療和運動。
　　
　　Gislason博士結論表示，流行病學研究顯示，一般人廣泛使用NSAIDs，已經有心臟疾病者也是，此外，在許多國家中，NSAIDs是以成藥販售，無須處方和專家建議，應限制它們的使用，或者提供可能的副作用的資訊。這也表示需要再度評估目前有關使用NSAID的治療策略，以及NSAIDs對於大家沒有傷害的誤解。
　　
　　回顧作者與編輯皆宣告沒有相關財務關係。


Recommendations for Prescribing NSAIDs in the Primary Care Setting

By Laurie Barclay, MD
Medscape Medical News

December 28, 2009 — A review article published in the December 15 issue of the American Family Physician offers recommendations for prescribing nonsteroidal anti-inflammatory drugs (NSAIDs) in the primary care setting.

"...NSAIDs are commonly used to treat inflammation, pain, and fever by decreasing prostaglandin synthesis through blockage of the cyclooxygenase (COX) enzyme," write Amanda Risser, MD, MPH, from Oregon Health and Science University in Portland, and colleagues. "The two major isoforms of COX (COX-1 and COX-2) are inhibited by nonselective NSAIDs. COX-2 is also inhibited by selective NSAIDs. All nonselective NSAIDs inhibit platelet aggregation through inhibition of COX-1 and the thromboxane A2 (TXA2) pathway."

Although NSAIDs are in widespread use, there are accompanying risks, including significant upper gastrointestinal (GI) tract bleeding (particularly in older persons), risks in those receiving anticoagulant therapy, and risks in patients with a history of upper GI tract bleeding associated with NSAID use. Dyspepsia, abdominal pain, GI discomfort, and GI bleeding may be reduced by combining the NSAID with a proton pump inhibitor (PPI) or histamine H2 blocker.

Despite the cardioprotective qualities of aspirin, other NSAIDs may have adverse cardiac effects, including worsening of congestive heart failure, increase in blood pressure, myocardial infarction, and ischemia. The risk for myocardial infarction is increased with COX-2 inhibitors, although celecoxib, which is the only COX-2 inhibitor still available in the United States, is somewhat safer regarding cardiovascular effects.

NSAIDs should not be used in patients with cirrhotic liver diseases because such patients are at greater risk of bleeding and for kidney failure. However, NSAIDs rarely cause hepatic damage, and any hepatic effects are usually reversible. NSAIDs with more potential for hepatic problems include sulindac and diclofenac.

Caution is advised when NSAIDs are prescribed in the setting of anticoagulant therapy, platelet dysfunction, or immediately before surgery.

Central nervous system adverse effects of NSAIDs may include aseptic meningitis, psychosis, and tinnitus. NSAIDs may also trigger or exacerbate asthma. In patients with asthma, especially those with nasal polyps or recurrent sinusitis, NSAIDs and aspirin should be avoided.

During the last 6 to 8 weeks of pregnancy, NSAIDs should be avoided to prevent prolonged gestation from inhibition of prostaglandin synthesis, premature closure of the ductus arteriosus, and antiplatelet activity causing maternal and fetal complications. However, most NSAIDs are likely safe in pregnancy. In breast-feeding women, ibuprofen, indomethacin, and naproxen can be safely used. Parents should be educated regarding correct NSAID dosing and storage in childproof containers to prevent accidental NSAID overdose in children.

Key Recommendations

Specific key clinical recommendations for practice, and their accompanying level of evidence rating, are as follows:

Physicians should consider prescribing PPIs, double-dose histamine H2 blockers, or misoprostol with NSAIDs for persons who must take NSAIDs, although they have had an NSAID-associated ulcer. Celecoxib may also be used alone in these patients, but this drug should be avoided in patients at increased risk for myocardial infarction. Women who might become pregnant should not take misoprostol (level of evidence, C). Two systematic reviews describe the use of NSAIDs in this setting for the prevention of endoscopic ulcers.
For prevention of acute renal failure, NSAIDs should be avoided whenever possible in patients with preexisting kidney disease, congestive heart failure, or cirrhosis (level of evidence, C, based on a literature review and a summary of consensus guidelines).
For patients at risk for renal failure, and in those taking angiotensin-converting enzyme inhibitors and angiotensin receptor blockers, physicians should consider monitoring serum creatinine levels after prescribing treatment with NSAIDs (level of evidence, C, based on a summary of consensus guidelines).
In patients taking anticoagulants, NSAIDs and aspirin should be avoided if possible. An increase in international normalized ratio (INR) should be expected if concurrent use of NSAIDs and anticoagulants is required. These patients should have appropriate INR monitoring, dosage adjustments of warfarin, and GI prophylaxis (level of evidence, C, based on a systematic review).
In breast-feeding women, ibuprofen, indomethacin, and naproxen can be safely used (level of evidence, C, based on a consensus guideline).
Editorial: Increased Cardiovascular Concerns

In an accompanying editorial, Gunnar H. Gislason, MD, PhD, from Copenhagen University Hospital Gentofte in Copenhagen, Denmark, describes increased concerns regarding the cardiovascular safety profile of NSAIDs, which have come to light during the last decade. Although these concerns were first recognized for COX-2 inhibitors, increased cardiovascular risk associated with nonselective NSAIDs has recently been identified.

Because there will always be groups of patients with pain conditions who must take NSAIDs, there is a need to focus on the balance between risk and benefit before NSAID therapy is started.

"This is especially important in persons with established cardiovascular disease in whom alternative pain treatment with lower cardiac risk (e.g., acetaminophen, weak opiates) should always be the first choice," Dr. Gislason writes. "In persons needing NSAID treatment, NSAIDs with the highest COX-1 selectivity (e.g., naproxen, ibuprofen, aspirin) should be preferred and used in the lowest dosages and for the shortest durations possible. For stronger analgesic effect, a combination with other types of analgesics should be considered."

As supplements to analgesic therapy, Dr. Gislason also recommends considering nonpharmacologic treatment, such as physiotherapy and physical exercise.

"Epidemiologic studies have demonstrated extensive use of prescription NSAIDs in the general population, as well as in persons with established cardiac disease," Dr. Gislason concludes. "Also, in many countries, NSAIDs are sold without a prescription, expert advice, limits on their use, or information on potential adverse effects. This indicates the need for reevaluation of current treatment strategies regarding NSAID use and the misconception that NSAIDs are harmless for everyone."

The review authors and editorialist have disclosed no relevant financial relationships.

Am Fam Physician. 2009;80:1371-1378.