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作者：Fran Lowry  
出處：WebMD醫學新聞

　　March 11, 2010 – 根據發表於3月美國醫學期刊的前瞻研究結果，固定使用阿斯匹靈、非類固醇抗發炎藥物(NSAIDs)或乙醯胺酚，可能會增加男性聽力損失的風險，且對60歲以下者的影響更大。
　　
　　麻州波士頓布萊根婦女醫院的Sharon G. Curhan醫師等人寫道，阿斯匹靈、乙醯胺酚和ibuprofen是美國最常用的三種藥物，因為止痛藥會導致耳蝸的病理生理改變，而固定使用這些藥物的情況又是如此普遍，這些藥物與聽力損失的關聯將是重要的公共衛生議題。
　　
　　不過，Curhan醫師等人指出，他們的研究有一些會影響結果的研究限制。兩名獨立評論者在接受Medscape Family Medicine訪問時重申這些限制，且強調，無法從研究結果確認因果關係，但是，這兩人都同意此研究聚焦在一個重要議題。
　　
　　【研究發現】
　　該研究的目標，在於確認固定使用止痛藥物和聽力損失的風險之間有無關聯。
　　
　　研究對象屬於「Health Professionals Follow-up Study」這項研究的參與者，於1986年開始，納入年紀40-75歲的51,529名男性牙醫、驗光師、整骨師、藥師、足科醫師和獸醫，研究對象在開始時填寫有關飲食、醫療史、藥物使用情況(包括阿斯匹靈、NSAIDs與乙醯胺酚)的詳細問卷，之後每兩年填寫一次，固定使用止痛藥的定義是每週服用兩次以上。
　　
　　2004年時，以問卷詢問研究對象是否有聽力損失的專業診斷，如果有，在哪一年診斷，偶發案例之定義為1986年後的聽力損失診斷。
　　
　　作者們從原始世代中分析了26,917名男性，排除了在1986年前診斷有聽力損失者、曾經曝露於耳毒性化學治療劑者，此外，因為年紀是一個強力風險因素且年長者有相當高比率的聽力損失，也排除了那些在追蹤期間年紀到達75歲者。
　　
　　在369,079人-年的追蹤期中，有3488例聽力損失報告，固定使用這三種止痛藥物都與聽力損失風險增加有獨立相關。
　　
　　控制年紀、種族、專業別、身體質量指數、飲酒、葉酸攝取、體能活力、抽菸、高血壓、糖尿病、使用其他類止痛藥等因素之後，固定使用者相較於那些使用阿斯匹靈、NSAIDs、或乙醯胺酚次數小於每週兩次者的風險比分別是，1.12 (95%信心區間[CI]為1.04 - 1.20)相較於阿斯匹靈、1.21 (95% CI，1.11 - 1.33)相較於NSAIDs，以及1.22 (95% CI，1.07 - 1.39)相較於乙醯胺酚。
　　
　　研究作者報告指出，這些結果後續校正了膽固醇值上升、心血管疾病、使用furosemide利尿劑、類風濕性關節炎、骨關節炎等病史之後，結果依舊相同。
　　
　　研究者報告指出，固定使用的期間越久者，聽力損失風險更高，固定使用阿斯匹靈1-4年的男性發生聽力損失的風險比其他人多28% (95% CI，17% - 40%)，不過，非固定使用期間增加則未增加風險。
　　
　　使用NSAIDs達4年以上的男性發生聽力損失的風險增加33% (95% CI，18% - 49%)，使用乙醯胺酚4年以上的男性發生聽力損失的風險也是增加33% (95% CI，14% - 56%)。
　　
　　研究作者也報告指出，年輕人使用止痛藥和聽力損失的關聯性更高，對於50歲以下男性，固定使用阿斯匹靈的聽力損失風險比(HR)是1.33、NSAIDs是1.61、乙醯胺酚是1.99，而60歲以上男性中並未觀察到此一關聯。
　　
　　研究作者報告指出，併用兩類止痛藥也會增加聽力損失風險，風險最高的是併用NSAIDs和乙醯胺酚時(HR，1.58；95% CI，1.16 - 2.16)。
　　
　　【研究限制】
　　該研究的其中一個限制是採用自我報告的聽力損失，另一個限制是缺乏終身噪音曝露情況的資料，這也是已知的聽力損失風險因素。
　　
　　研究作者寫道，此外，研究對象主要是白人男性，因此，結果無法推論到其他種族，需要進行女性、年輕男性與其他種族的研究，探討是否有類似之使用止痛藥與聽力損失的關係。
　　
　　研究作者結論表示，固定使用止痛藥引起的聽力損失是一個重要的公共衛生議題，因為有相當多人固定使用止痛藥物，聽力不佳對健康和社交都會有所影響。
　　
　　【該研究可以做出明確的結論嗎？】
　　紐約大學醫學院的Pamela Roehm博士接受Medscape Family Medicine訪問，對該研究發表評論時表示，它相當有趣，但是因為有一些限制而無法做出任何明確結論。
　　
　　Roehm博士對於作者們所提的限制提出看法，研究設計並未針對聽力損失和使用止痛藥的關聯探討，他們未測量任何的噪音曝露，而這是個大問題，特別是男性的感覺神經型聽力損失。
　　
　　此外，也未提及家族的聽力損失情況、或聽力損失類型。她表示，該研究未將聽力損失的基因傾向納入考量，而且，這是針對高加索裔男性專業人士進行的研究，他們可能有一些聽力損失的基因傾向，但是卻未納入研究考量。
　　
　　她同意使用NSAID和聽力損失之間的關聯還有待解釋，不過，已經知道阿斯匹靈和聽力損失之間的關聯是可逆的，因此不難補救。
　　
　　至於乙醯胺酚和聽力損失之間的關聯，Roehm博士表示，她寧可去瞭解可待因(codeine)是否也有關聯。
　　
　　她表示，有關乙醯胺酚和聽力損失之關聯的文獻不多，事實上，我完全找不到，但是，最近有相當多併用乙醯胺酚和可待因對於感覺神經型聽力損失之影響的研究，此研究點出有趣的關聯，但是仍有諸多有待探討之處。
　　
　　Medscape Family Medicine也邀請了馬里蘭州巴爾的摩約翰霍普金斯醫學中心耳鼻喉科主任John K. Niparko醫師對該研究進行獨立評論，Niparko醫師向Medscape Family Medicine表示，事實上，對於該研究而言，缺乏噪音曝露情況的資料是很嚴重的限制。
　　
　　他表示，這是一個觀察型研究，所提出的關聯無法證明這些藥物引起聽力損失，這些藥物對於許多疾病來說是很有價值的用藥，所以我們必須小心詮釋研究提出的關聯，但是無法證實因果關係。
　　
　　不過，他也對研究作者探究可能的聽力損失原因致意，因為這已經變成美國一個重要的公共衛生焦點。
　　
　　國家健康研究中心以及麻州眼耳醫院基金會支持該研究。Curhan、Roehm、 Niparko等醫師皆宣告沒有相關財務關係。  


Regular Analgesic Use May Increase Risk for Hearing Loss

By Fran Lowry
Medscape Medical News

March 11, 2010 – Regular use of aspirin, nonsteroidal anti-inflammatory drugs (NSAIDs), or acetaminophen may increase the risk for hearing loss in men, and the impact is larger on those younger than 60 years, according to a prospective study published in the March issue of the American Journal of Medicine.

"Aspirin, acetaminophen, and ibuprofen are the 3 most commonly used drugs in the US," write Sharon G. Curhan, MD, ScM, from Brigham and Women's Hospital, Boston, Massachusetts, and colleagues. "Given that analgesic use might result in pathophysiologic changes in the cochlea and that regular use of these analgesics is so common, the relation of these medications and hearing loss might be an important public health issue."

However, Curhan and colleagues point out several study limitations that may affect the results of their study. Two independent commentators interviewed by Medscape Family Medicine reiterate these limitations and emphasize that causality cannot be determined from the study results. Yet, both agree that the study focuses on an important issue.

Findings of the Study

The aim of this study was to determine if there was an association between regular analgesic use and the risk for hearing loss.

The study subjects were participants in the Health Professionals Follow-up Study, which enrolled 51,529 male dentists, optometrists, osteopathic physicians, pharmacists, podiatrists, and veterinarians aged 40 to 75 years at baseline in 1986. The participants filled out detailed questionnaires about their diet, medical history, and medication use, including their use of aspirin, NSAIDs, and acetaminophen, at baseline and every 2 years thereafter. Regular analgesic use was defined as 2 or more times per week.

In 2004, the questionnaire asked participants if they had been professionally diagnosed with hearing loss and, if so, the year of their diagnosis. Incident cases were defined as hearing loss diagnosed after 1986.

The authors analyzed 26,917 men from the original cohort. They excluded men who were diagnosed with hearing loss before 1986; those who had been exposed to ototoxic chemotherapeutic agents; and, because age is such a strong risk factor and the prevalence of hearing loss is so high among the elderly population, those who had reached age 75 years during follow-up.

During 369,079 person-years of follow-up, 3488 cases of hearing loss were reported. Regular analgesic use was independently associated with an increased risk for hearing loss for all 3 types of analgesics.

After controlling for age, race, profession, body mass index, alcohol intake, folate intake, physical activity, smoking, hypertension, diabetes, and the use of other classes of analgesics, the hazard ratios of hearing loss in regular users vs those who used aspirin, NSAIDs, or acetaminophen less than twice per week were 1.12 (95% confidence interval [CI], 1.04 - 1.20) for aspirin, 1.21 (95% CI, 1.11 - 1.33) for NSAIDs, and 1.22 (95% CI, 1.07 - 1.39) for acetaminophen.

These results were further adjusted for a history of elevated cholesterol, cardiovascular disease, use of furosemide, rheumatoid arthritis, and osteoarthritis, and remained the same, the study authors report.

The risk for hearing loss also increased with longer duration of regular use. Men who used aspirin regularly for 1 to 4 years were 28% (95% CI, 17% - 40%) more likely to develop hearing loss than those who did not, although this risk did not increase with longer duration of use, the study authors report.

Men who used NSAIDs for 4 or more years were 33% (95% CI, 18% - 49%) more likely to develop hearing loss, and men who used acetaminophen for 4 or more years were also 33% (95% CI, 14% - 56%) more likely to develop hearing loss.

The study authors also report that the magnitude of the association between analgesic use and hearing loss was substantially higher in younger men. For men younger than 50 years, the hazard ratio (HR) for hearing loss was 1.33 for regular aspirin use, 1.61 for NSAIDs, and 1.99 for acetaminophen. No such association was observed in men 60 years and older.

Combining 2 classes of analgesics also increased the risk for hearing loss, the study authors report. The risk was highest when NSAIDs and acetaminophen were combined (HR, 1.58; 95% CI, 1.16 - 2.16).

Study Limitations

That the diagnosis of hearing loss was self-reported is a limitation of this study. Another is the lack of information on lifetime noise exposure, which is a known risk factor for hearing loss.

In addition, the study population consisted of predominantly white men; therefore, the results may not be generalizable to other racial groups. Other studies in women, younger men, and other racial groups are needed to examine whether similar associations between analgesic use and hearing loss exist in these groups, the study authors write.

Hearing loss because of regular use of analgesics represents an important public health issue, "given the high prevalence of regular analgesic use and health and social implications of hearing impairment," the study authors conclude.

Can Definitive Conclusions Be Made From the Study?

Commenting on the study in an interview with Medscape Family Medicine, Pamela Roehm, MD, PhD, of the New York University School of Medicine, New York, NY, said it was potentially interesting but had certain limitations that make it difficult to draw any definite conclusions.

Dr. Roehm comments on the limitations cited by the study authors: "The study was not designed to look at the link between hearing loss and analgesic use. They don't have any measures of noise exposure, and this is a huge issue, especially with sensory neural hearing loss in men."

The issue of familial hearing loss was not addressed, and neither was the type of hearing loss. "The genetic predilection for hearing loss was not taken into account. Also, this was a study of professional men, mainly Caucasian. There are going to be some genetic tendencies for hearing loss that have not been taken into account by the study," she said.

She agreed that the association between NSAID use and hearing loss has yet to be explained. However, the association between aspirin and hearing loss is well known to be reversible and therefore a problem that is easily remedied.

With regard to the link between acetaminophen and hearing loss, Dr. Roehm said she would have liked to know if codeine was also involved.

"There is not a lot of literature on acetaminophen on its own being linked to hearing loss. In fact, I couldn't find any at all. But there is quite a bit of recent literature on acetaminophen plus codeine and sensory neural hearing loss. This study brings up interesting associations, but a lot of avenues still need to be explored further," she said.

Medscape Family Medicine also interviewed John K. Niparko, MD, director of otolaryngology at Johns Hopkins Medicine in Baltimore, Maryland, for an independent comment on the study. Dr. Niparko told Medscape Family Medicine that the fact that there is no information about noise exposure is a very serious limitation of the study.

"This is a study of observation and association and does not prove that these medicines caused the hearing loss," he said. "These are very valuable medications for a variety of disorders, so we have to be cautious in interpreting results that show an association but do not prove causality."

However, he congratulated the study authors for investigating the potential causes of hearing loss, which "has become a major public health concern in the US."

This study was supported by the National Institutes of Health and the Massachusetts Eye and Ear Infirmary Foundation, Boston. Drs. Curhan, Roehm, and Niparko have have disclosed no relevant financial relationships.

Am J Med. 2010;123:231-237.