101年藥師持續教育課程 口醫部黃振勳 醫師 5/05 (六) 08:30~10:10 第三講堂 睡眠呼吸障礙症 及牙科止鼾器的治療 101年藥師持續教育課程 口醫部黃振勳 醫師 5/05 (六) 08:30~10:10 第三講堂

睡眠呼吸障礙症 及牙科止鼾器的治療 課程題目 睡眠呼吸障礙症及牙科止鼾器的治療 教學目標 瞭解睡眠呼吸障礙的致病機轉，牙科止鼾器的治療時機及作用。 綱要說明 認識睡眠呼吸障礙的病因 睡眠呼吸障礙的治療 睡眠呼吸障礙的藥物治療新近發展

認識睡眠呼吸障礙的病因 睡眠呼吸障礙是一種疾病。 會影響日常生活作息及工作速率與安全。 會發生許多共患病(COMORBIDITY) ，例如高血壓、心血管疾病、腦血管疾病、糖尿病等。 影響伴侶的睡眠品質，也會讓個人困擾。

健康青年人的睡眠圖表 睡眠分為兩種狀態：快速動眼睡眠(REM)和非快速動眼睡眠(NREM)，通過腦部調控，這兩種狀態每晚固定地交替出現。 一般熟睡後首先開始約80分鐘的非快速動眼睡眠，跟隨轉為快速動眼睡眠約10分鐘，如此在整個過程中重複4至6次。 非快速動眼睡眠時，腦部及軀體的生理功能都降下；快速動眼睡眠時，腦部及軀體功能則呈短暫性活躍。 http://www.shen-nong.com/chi/lifestyles/tcmrole_sleep_facts.html

人類睡眠的結構 比較青年人與老年人的睡眠，老年人睡眠時間較短，深層睡眠期(3, 4)較少，容易被吵醒。(Harrison) Stages of REM sleep (solid bars), the four stages of NREM sleep, and wakefulness over the course of the entire night for representative young and older adult men. Characteristic features of sleep in older people include reduction of slow-wave sleep, frequent spontaneous awakenings, early sleep onset, and early morning awakening. 比較青年人與老年人的睡眠，老年人睡眠時間較短，深層睡眠期(3, 4)較少，容易被吵醒。(Harrison)

口咽(上呼吸道)的構造 口咽位於口腔後面，承上連接鼻咽腔，向下連結下咽腔。 前方為軟顎懸壅垂及舌部，後方為咽喉壁。 兩側咽喉壁有扁桃腺，上方有時有腺樣體。 張口發“啊”的聲音時，於軟顎及舌部之間即可看到一部分口咽腔。

睡眠呼吸障礙 罹患睡眠呼吸障礙者的呼吸道較正常人狹窄，白天清醒時，咽喉部肌肉收縮，使呼吸道保持暢通開放。 但是夜間睡眠時，因為神經的興奮性下降，造成肌肉鬆弛：舌頭、軟顎後垂，咽喉收縮肌鬆弛，因此呼吸道變狹窄。

鼾聲發作的原因 鼾聲發作的原因主要是睡眠時，口腔軟組織(舌頭、軟顎或懸壅垂)肌肉放鬆，垂向後方喉嚨，造成呼吸通道狹窄；當呼吸氣流通過時，在此造成氣體迴流而發出聲響。

睡眠時，因為上呼吸道的肌肉張力放鬆；造成舌部、軟顎及口咽肌肉鬆弛，上呼吸道狹窄。

睡眠呼吸障礙 (OSA) 當病患深睡時，上呼吸道的肌肉放鬆，造成呼吸道狹窄或阻塞。 血氧濃度會降低，而刺激呼吸中樞；病患由深睡變為淺睡或覺醒。 這時病患會發出鼾聲或倒抽一口氣，而恢復正常呼吸換氣。 但是隨著病患熟睡，上述情形週而復始，反覆發生；病患沒有良好的睡眠。

睡眠呼吸障礙的症狀 打鼾，睡眠時常發生嗆到或倒吸一口氣。 早上起床沒有精神或頭痛。 白天嗜睡、疲倦。 記憶或認知退化。 焦慮或躁動易怒。

睡眠呼吸障礙症

睡眠時的呼吸狀態 睡眠時正常的呼吸 打鼾 阻塞性睡眠呼吸中止

睡眠呼吸障礙 中華民國胸腔醫學會在民國八十年就曾針對國人睡眠時的打鼾情形，在頭份、大溪地區進行盛行率調查； 發現我國四十歲以上的人口在睡眠中呈現打鼾的盛行率是43.48%，其中男性51.69%、女性35.52%。 其中輕度、中度、重度鼾聲的盛行率分別為26.83%、13.21%與3.44% 。 〈蕭光明、1995〉

打鼾者的比率 在台灣，有86％的男性及65％的女性自述會打鼾，其中有44％的男性及14％的女性是每天都會打鼾。 體重越重者[即身體質量指數（BMI）越高者]以及年紀越大者，打鼾的機率也愈高。 打鼾者中有10％至15％的病患合併有阻塞型睡眠呼吸中止症。 陳濘宏 等 2007

打鼾者的健康風險 31％的每天打鼾者有高血壓，為正常人的三倍，11％的打鼾者合併有心臟病，是正常人的四倍。 打鼾者有心肌梗塞、氣喘、慢性肺病，以及過敏性鼻炎等病變的機率都比沒有打鼾者高。 陳濘宏 等 2007

睡眠呼吸障礙 根據Young等學者〈1993、1997〉的研究發現美國一般中年男性約24%、中年女性約9%有睡眠呼吸障礙；倘若這些病患併有習慣性打鼾情形，則他們罹患中、重度阻塞性睡眠呼吸終止的比例大為增加。 而臨床統計發現大部分的睡眠呼吸障礙患者並未被診斷出來，或接受妥善的醫療照護。 Young等學者(1993、1997)

嗜睡度量表 (The Epworth Sleepiness Scale) 說明: 請依據您最近的生活情形，評估下列情況中打瞌睡的可能性， 0 = 從未：不會打瞌睡， 1 = 很少：稍微打瞌睡(大都能維持清醒) ， 2 = 一半以上：中度打瞌睡(可能維持清醒) ， 3 = 幾乎都會：高度打瞌睡(很少能維持清醒)， 然後選出最適合的數字(0-3)。 請問您在下列情況 打瞌睡的可能性 靜坐閱讀書報時？ 0 = 從未、1 = 很少、2 = 一半以上、3 = 幾乎都會。 ( ) 觀看電視節目時？ 0 = 從未、1 = 很少、2 = 一半以上、3 = 幾乎都會。 ( ) 靜坐於未有活動的公共場合時？ 0 = 從未、1 = 很少、2 = 一半以上、3 = 幾乎都會。 ( ) 靜坐於連續開了一個小時的車子時(乘客) ？ 0 = 從未、1 = 很少、2 = 一半以上、3 = 幾乎都會。 ( ) 下午躺下來休息時(環境許可) ？ 0 = 從未、1 = 很少、2 = 一半以上、3 = 幾乎都會。 ( ) 靜坐與別人交談時？ 0 = 從未、1 = 很少、2 = 一半以上、3 = 幾乎都會。 ( ) 午餐後安靜坐著時(未曾喝酒) ？ 0 = 從未、1 = 很少、2 = 一半以上、3 = 幾乎都會。 ( ) 乘坐車子停頓幾分鐘時？ 0 = 從未、1 = 很少、2 = 一半以上、3 = 幾乎都會。 ( )

愛普渥斯嗜睡度量表 (The Epworth Sleepiness Scale) 分析結果 0~7 分 您的嗜睡情況正常 8~9 分 您的嗜睡情況稍多 10~15 分 您的嗜睡情況明顯，很可能患有睡眠呼吸中止症，請視情況諮詢醫生意見及安排睡眠檢查。 16~24 分 您的嗜睡情況嚴重，應立即諮詢醫生意見以及安排睡眠檢查。

睡眠呼吸障礙的檢查 口腔鼻咽腔呼吸道的臨床檢查 牙科X光檢查及側顱X光分析 電腦斷層或核磁共振影像分析檢查 身高、體重及BMI 頭圍、頸圍及腰圍 睡眠研究分析 診斷睡眠呼吸障礙最重要的檢查是睡眠分析

睡眠呼吸障礙的檢查

牙科X光分析

睡眠呼吸障礙的口腔表現

Mallampati score & Tonsil grade

正常和睡眠呼吸障礙的呼吸道

睡眠呼吸障礙 危險因子 BMI: >25 kg/m2 頸圍Neck Size Men: > 17inches Women: > 16 inches 家族史 年齡 > 40 男性 高血壓 促進因子 飲酒l: 解剖構造: 巨舌 腺狀腫 扁桃腺腫 下巴後縮 肥胖 Tallent, 2008

STOP-Bang評分系統 大於3項回答是者，是阻塞型睡眠呼吸終止高危險群。 Chung et al. 2009

Polysomnography是 睡眠呼吸障礙的最重要的檢查 診斷睡眠窒息症最好的方法是進行睡眠的監測,這是在特定的睡眠中心進行的一種夜間試驗,多種監控器被用來測量睡眠時各種不同的生理信號，測理的參數包括： 1.呼吸: 氣流監控儀可以發現睡眠窒息症的長度和頻度。呼吸停止在10秒鐘以上稱作為暫停，呼吸不足通常是指呼吸氣流下降50%以上。 2. 血氧飽合度: 血氧飽合度的下降是OSAS病人的一個關鍵的表現。 3. 肌肉運動: 胸部運動的監測可以幫助診斷暫停是中樞性的還是阻塞性的。其它種類的睡眠疾病可表現為腿部的運動，下頜緊閉及其它特徵性的運動等。 4. 腦電波: 睡眠根據腦電波可以被分為不同的典型階段，即快相及慢相（深、淺睡眠），這可以用儀器進行監測。 5. 心電圖 (ECG): 如前所述，部分OSAS病人可以出現心律的異常。 6. 身體的位置: 睡眠窒息症最易發生於平臥位，這時舌根後墜，容易阻塞上呼吸道。 睡眠的研究是一個非常複雜的問題，所有的結果者應該認真的加以解釋，以正確判斷睡眠疾病的嚴重程度。其中有兩種評估方法經常被引用來概括睡眠監測結果。 Polysomnography Procedure and Results. Polysomnography is an overnight study and is painless. It is usually done at a sleep center overnight where you may have to spend about 6 hours. The following physiological activities in your body are recorded during polysomnography. Brain activity is measured with EEG (electroencephalogram) Read sleep cycle to know brain activity which is measured in the form of brain waves by the EEG and which tells if your sleep consists of all stages of the sleep cycle or whether it is disturbed. Disruptions in sleep stages may suggest narcolepsy or REM sleep behavior disorder. Eye movements are recorded with a EOG (electro-oculargram). This helps to determine the presence of sleep stages particularly REM sleep stage. Muscle activity such as face twitches, teeth grinding and leg movements, is measured by EMG (electromyogram). This helps to determine if the REM sleep is present during sleep. Frequent leg movements may indicate a periodic limb disorder such as restless leg syndrome which is a sleep disorder because these movements often disrupt your sleep. Airflow in and out of the lungs while you are asleep is measured with a nasal airflow sensor. Snoring activity is measured with the help of snoring microphone. Very loud snoring is indicative of sleep apnea The percentage of oxygen in your blood is measured (oxymetry) by a bandage like oxymeter probe or sleeve that fits painlessly on one of your fingers. Low oxygen levels may indicate a sleep apnea.

認識睡眠呼吸障礙的診斷 Severity AHI: events/hour Mild 5-15 Moderate 16-30 Severe >30 阻塞性睡眠呼吸暫停低通氣綜合征（obstructive sleep apnea-hypopnea syndrome, OSAHS）是指睡時上氣道塌陷阻塞引起的呼吸暫停和通氣不足、伴有打鼾、睡眠結構紊亂、頻繁發生血氧飽和度下降、白天嗜睡等病徵。 呼吸暫停是指睡眠過程中口鼻氣流停止≥10s. 低通氣（通氣不足）是指睡眠過程中呼吸氣流強度較基礎水平降低50%。 以上，並伴血氧飽和度（SaO）3%或伴有覺醒。 睡眠呼吸暫停低通氣（通氣不足）指數（apnea-hypopnea index, AHI）是指平均每小時睡眠中呼吸暫停和低通氣（通氣不足）的次數。 (AASM)

打鼾及睡眠呼吸終止的治療 正壓呼吸輔助器 止鼾手術 養成良好睡眠習慣 減重 側睡 選擇合適的枕頭 睡前宵夜勿吃太飽或油膩 下頜前伸矯正器

睡眠呼吸障礙的治療 http://www.health.am/images/uploads-sleep/1-6.php

CPAP的作用機轉

正壓持續呼吸器 (CPAP) 正壓持續呼吸器是傳統、非侵襲性及有效的治療方式(睡眠呼吸障礙的治療最優先選擇是CPAP) Device, mask, humidifier. 台灣睡眠呼吸中止症的人口估計約有６０萬人 戴CPAP約兩周便可顯出效果 可能3成在第一周便顯出效果 第一個月約有6成顯出效果 但是初期戴CPAP可能不適會自動拿下每晚約戴4小時 TSSM Sleep Forum

正壓持續呼吸器 (CPAP) 呼吸器將空氣經由面罩送入口咽腔，調整壓力維持上呼吸道的暢通。 空氣的壓力則需要依個人條件調整。 Air is pushed from the flow generator through the tubing and mask, the air then passes through the nose and into the throat, where the slight pressure keeps the upper airway open. Adjustment of the CPAP device so that it delivers the correct treatment pressure

Oral Surgery Surgery is site-specific, meaning it requires the identification of specific anatomic area contributing to airway obstruction. Maxillomandibular advancement Anterior inferior mandibular osteotomy

Uvulopalatopharyngoplasty Fijita et al. (1981) suggested that the anatomical indications for UPPP were a long uvula, redundant pharyngeal wall tissue and/or excess tonsillar tissue.

Maxillo-Mandibular Advancement Genioplasty or geniotubercular advancement may augment the pharyngeal space further when combined maxillary/mandibular advancement

牙科止鼾裝置的作用原理 利用牙科裝置套在牙齒上 將下顎向前牽引以增加口腔空間 並將舌部及口底組織牽引向前 以增加口咽腔的空間 讓呼吸的空氣流動順暢 http://www.elements4health.com/images/stories/conditions/sleep-apnea-device.jpg

牙科止鼾裝置 牙科下顎前移裝置適用於輕及中度睡眠呼吸障礙 調整上下顎關係 可調節式 不可調節式 配戴時開口活動 可以開口 不可以開口

下頜前伸矯正器的種類 可調整 可開口 1. 是 否 2. 3.

牙科睡眠止鼾裝置治療同意書 病患因睡眠呼吸障礙接受牙科睡眠止鼾裝置的治療 此一裝置是在睡眠時，佩戴依附於牙齒上(上顎或下顎牙齒或兩者) 目的在於幫助病患在睡眠時的呼吸順暢， 在初期佩戴時，有異物感或壓痛，需門診調整處理 晚上佩戴時，有些病患會覺得影響睡眠 晚上佩戴時，可能會有口腔呼吸及口乾症狀 早上起來，可能會有短暫的咬合改變或上下牙齒咬不起來，一般在用完早餐後會改善 一般使用約一年需視個人使用及保養情形，以及是否有磨牙情況 睡眠時有誤吞的可能性 長期配戴的影響，可能有顳顎關節障礙或牙齒咬合改變(牙齒移位) 所以必須定期回診檢查，定期潔牙保健 如有上述情形發生，則須接受進一步的治療

止鼾器的佩戴

配帶前後的側顱X光分析

佩戴止鼾器前後比較--口咽區範圍變寬

可能的副作用 唾液淤積 顳顎關節障礙或疼痛 早晨醒來牙齒或牙齦不舒服 牙齒咬合關係改變

不適合使用的狀況 中樞型睡眠中止症Central sleep apnea 不適用於重度睡眠呼吸中止 有顳顎關節障礙的病患 鼻腔阻塞 扁桃腺增生或腫

下頜前伸矯正器的保養 請保持清潔定期使用清潔劑清洗 未佩帶使用請至於清水中保持濕潤以免變形 裝在矯正器盒中以免遺失或撞斷變形 定期檢查是否有裂痕或掛鉤鬆動 定期回門診檢查保養 http://www.dentaid.es/

CPAP Efficacy vs. Oral Appliance Effectiveness

比較CPAP與OA療效 Oral appliances for treating sleepiness, quality of life and markers of sleep disruption in people with obstructive sleep ap- noea/hypopnoea (OSAH) Lim et al. 2009 OSAH is characterized by recurrent episodes of partial or complete upper airway obstruction during sleep, leading to a variety of symptoms including excessive daytime sleepiness. The current first choice therapy is CPAP that keeps the upper airway patent during sleep. However, this treatment can be difficult for some patients to tolerate and comply with on a long-term basis. OA are now widely used as an alternative to CPAP therapy. They are designed to keep the upper airway open by either advancing the lower jaw forward or by keeping the mouth open during sleep. This review found that OA should not be considered as first choice therapy for OSAH, where symptoms and sleep disruption are severe. There has not been a sufficient amount of research that examines the effects of OA compared with CPAP in terms of symptoms and quality of life. Although CPAP was clearly more effective at reducing the disruption to sleep, some people with OSAH may prefer using them if they are found to be tolerable and more convenient than CPAP. When an active OA was compared with an inactive OA , there were improvements in daytime sleepiness and apnoea/hypopnoea severity. OA may be more effective than corrective upper airway surgery. Further research should consider whether people with more distinctly severe symptoms respond in a similar way to those patients represented in the studies we have included in the review. Lim et al. 2009

Oral appliances for obstructive sleep apnoea (Review) OA versus control appliances (six studies): OA在白天嗜睡及AHI的改善較對照組好。 OA versus CPAP (ten studies): CPAP能有效改善AHI及血氧濃度效果較OA好，兩者在症狀改善沒有顯著差異，但是病患較喜歡OA。 OA versus corrective upper airway surgery (one study): 手術後一年內白天嗜睡的症狀改善教OA明顯，但是長期來看OA效果較好。 Lim et al. 2009. Seventeen studies (831 participants) met the inclusion criteria. All the studies had some shortcomings, such as small sample size, underreporting of methods and data, and lack of blinding. OA versus control appliances (six studies): OA reduced daytime sleepiness in two crossover trials (ESS score -1.81; 95%CI -2.72 to -0.90), and improved apnoea-hypopnoea index (AHI) (-10.78 events/hr; 95% CI- 15.53 to -6.03 parallel group data - five studies). OA versus CPAP (ten studies): There was no statistically significant difference in symptoms for either parallel or crossover studies, although OAs were less effective than CPAP in reducing apnoea-hypopnoea index in parallel and crossover studies. CPAP was more effective at improving minimum arterial oxygen saturation during sleep compared with OA. In two small crossover studies, participants preferred OA therapy to CPAP. OA versus corrective upper airway surgery (one study): Symptoms of daytime sleepiness were initially lower with surgery, but this difference disappeared at 12 months. AHI did not differ significantly initially, but did so after 12 months in favour of OA.

治療睡眠呼吸障礙症的藥物 改善睡眠呼吸障礙症的藥物 睡眠呼吸障礙症的輔助藥物

改善睡眠呼吸終止症的藥物 Selective serotonin reuptake inhibitors Estrogen and Progesterone Cardiac/ Cardiovascular medication Theophylline increases ventilatory drive

Theophylline 可能經由抑制adenosine，來增加ventilatory drive。 在一個雙盲交叉實驗12位OSA病患接受800mg theophylline 4 週。 只有輕微降低AHI (40 vs 49/hr of sleep)，但降低睡眠品質。 Mulloy et al. 1992

Antihypertensives Most of the studies used different antihypertensive agents, which variably affect OSA. As an example, propranolol may worsen OSA, while metoprolol may have beneficial effects . In light of the potential risks and uncertain effect, antihypertensive agents are not recommended as a primary therapy for OSA. Atwood et al. 2012

OSA 與 REM 呼吸中止（apnea）可以發生在非快速動眼期（NREM）或快速動眼期（REM）睡眠，通常非快速動眼期較常發生呼吸中止，而發生在快速動眼期則較嚴重。

三環類抗抑鬱藥 Protriptyline是 tricyclic antidepressant, 抑制 REM sleep。 有 anticholinergic副作用。 Protriptyline在小型的雙盲交叉實驗，可以減少REM時間及白天嗜睡症狀，其中部分可以降低AHI。 Brownellet al. 1982 Protriptyline — Protriptyline is a tricyclic antidepressant that potently suppresses REM sleep. In theory, decreasing REM sleep may decrease the frequency or severity of obstructive events because OSA is often most severe during this stage of sleep. This was tested in two trials: A double-blind crossover trial compared the effect of protriptyline to placebo in five patients with OSA. Protriptyline reduced REM sleep time and subjective daytime sleepiness. Three patients had a statistically significant, but probably not a clinically significant, reduction in their AHI after six months of protriptyline therapy (56 versus 71 events per hour). A controlled trial randomly assigned 10 patients with OSA to receive protriptyline, acetazolamide, or placebo for two weeks. Protriptyline did not have a significant effect on symptoms or the frequency of apneas, hypopneas, arousals, or desaturations, compared to placebo. Protriptyline is highly anticholinergic and is associated with dry mouth, constipation, and urinary retention. Protriptyline should not be used in the routine management of patients with OSA because side effects are likely and efficacy unproven.

Selective serotonin reuptake inhibitors Serotonin是一個主要的神經傳導物質 (neurotransmitter) ，可以調控上呼吸道肌肉的張力 (upper airway tone) 。 Hypoglossal nerve 支配genioglossus 肌肉會被serotonin去極化。 在睡眠時(尤其REM睡眠期 )serotonergic output to hypoglossal nucleus會減少，顯示在神經核增加serotonin的濃度，有助於增加上呼吸道肌肉的張力，進而改善睡眠呼吸障礙。 Sunderram et al. (2000) 研究正常受試者睡眠時genioglossus 的肌電圖 (electromyography) 發現使用paroxetine (SSRI) 可以顯著增加genioglossus的張力。

SSRI 對於 genioglossus的作用(OSA) Berry et al. (1999)提供8位嚴重睡眠呼吸抑制病患睡前40mg paroxetine，結果顯示genioglossus activity 增加(the peak inspiratory EMGgg (29.8+/-2.4 (SE) versus 24.4+/-2.7 % max, p<0.05)。 但是對於AHI並無顯著改善(paroxetine: 75.2+/-5.5 versus placebo: 73.7+/-6.9 events/hour)。 Acute effects of paroxetine on genioglossus activity in obstructive sleep apnea Abstract STUDY OBJECTIVE: To determine the acute effects of paroxetine on genioglossus activity during NREM sleep. DESIGN: A single dose of Paroxetine (40 mg) or placebo was administered four hours before bedtime on nights separated by one week in a double blind randomized crossover manner. The moving time average of genioglossus muscle activity (EMGgg) expressed as a percentage of maximum was measured using a mouthpiece electrode customized for each subject. The peak inspiratory and tonic values of EMGgg and the corresponding esophageal pressure deflections (DP) during the last three occluded breaths of obstructive apneas during NREM sleep were analyzed. SETTING: NA. PARTICIPANTS: 8 adult men with severe obstructive sleep apnea (OSA). INTERVENTIONS: MEASUREMENTS AND RESULTS: Paroxetine increased the peak inspiratory EMGgg (29.8+/-2.4 (SE) versus 24.4+/-2.7 % max, p<0.05) and peak EMGgg/DP ratio (0.78+/-0.12 versus 0.65+/-0.11 % max/cm H2O, p<0.01) but not the tonic EMGgg (11.6+/-0.9 versus 9.8+/-0.7 % max) nor the DP (39.4+/-2.2 versus 38.2+/-2.8 cm H2O). Linear regression analysis of the peak inspiratory EMGgg versus DP relationship showed that paroxetine increased the slope (0.62+/-0.11 versus 0.49+/-0.09 % max/cm H2O, p<0.01). However, the apnea + hypopnea index (paroxetine: 75.2+/-5.5 versus placebo: 73.7+/-6.9 events/hour) did not differ. CONCLUSIONS: Paroxetine augmented peak inspiratory genioglossus activity during NREM sleep but this effect was not sufficient to decrease the frequency of obstructive apnea in this group with severe OSA. Berry et al. 1999 58

SSRI 對OSA及AHI的作用 Kraiczi et al. (1999) 進行paroxetine的病例對照交叉試驗(case-controlled crossover trial)， 20mg paroxetine 或placebo各6週，中間wash out 4週。 AHI在NREM sleep，paroxetine對placebo sleep (30 vs 36 events/per hour; -35%, p = 0.003)，有顯著改善(not during REM sleep )。 但在OSA症狀並沒有明顯改善。 Effect of serotonin uptake inhibition on breathing during sleep and daytime symptoms in obstructive sleep apnea. Sleep. 1999 Feb 1;22(1):61-7. Pharmacologic enhancement of serotonergic transmission by serotonin uptake inhibition has been suggested as one approach to improve upper-airway patency and thus nocturnal breathing in patients with obstructive sleep apnea (OSA). To test this hypothesis, we performed a double-blind, randomized, placebo-controlled crossover study testing the effect of paroxetine (20 mg od) on polysomnographic and psychopathologic outcomes in 20 male OSA patients (mean age 52.1 years, mean BMI 28.7 kg/m2, mean oxygen desaturation index on a previous screening 25.4/hour). The two treatment periods of 6 weeks and the separating washout period of 4 weeks were completed by 17 patients. Paroxetine reduced the apnea index during NREM sleep (-35%, p = 0.003), but not during REM sleep. No significant effect on hypopnea indices was found. With the exception of a previously described REM-postponing effect (p = 0.05), sleep architecture was not significantly influenced by paroxetine. Similarly, the effect of paroxetine on apnea was not associated with a significant overall alleviation of psychopathologic symptoms as rated on the Comprehensive Psychopathological Rating Scale or OSA-related daytime complaints assessed by visual analog scales. We conclude that enhanced serotonergic transmission improves breathing during NREM sleep in OSA. This effect is poorly related to effects on sleep architecture or daytime symptoms. Kraiczi et al. 1999 59

Hormone Replacement Therapy Post-menopause women的AHI較 pre-menopause women高。 50歲以上使用HRT的婦女，罹患睡眠呼吸障礙(AHI>15)是非使用者的一半。 the Wisconsin Sleep Cohort Study of 907 but limiting the analysis to 589 women participants, Sleep-Disordered Breathing was 2.6 times more likely to occur postmenopausally than perimenopausally. Avidan 2005 60

AHI of 15 or More versus AHI of Less Than 5 Odds Ratio (95% CI) AHI of 5 or More versus
 AHI of Less Than 5 AHI of 15 or More versus
 AHI of Less Than 5 Unadjusted model Premenopause Reference category Perimenopause 1.66 (1.05, 2.60) 1.18 (0.83, 1.69) Peri/Postmenopause 2.82 (1.41, 5.65) 1.82 (1.04, 3.21) Postmenopause 3.22 (2.23, 4.66) 2.59 (1.64, 4.09) Adjusted model* 1.23 (0.68, 2.22) 1.07 (0.52, 2.20) Peri/postmenopause 1.80 (0.79, 4.12) 3.13 (1.06, 9.20) 2.60 (1.41, 4.81) 3.49 (1.38, 8.78) Age, 5 yr 1.17 (0.98, 1.38) 1.10 (0.82, 1.48) BMI, kg/m2 1.14 (1.11, 1.17) 1.20 (1.15, 1.25)

停經婦女與睡眠呼吸障礙 Prevalence of SDB indicated by an AHI of 5 or greater for premenopausal women and perimenopausal plus postmenopausal women by body mass index (BMI). Values represent a 5-unit moving average. Young et al. 2003 Menopausal Status and Sleep-disordered Breathing in the Wisconsin Sleep Cohort Study Menopause is considered to be a risk factor for sleep-disordered breathing, but this hypothesis has not been adequately tested. The association of premenopause, perimenopause, and postmenopause with sleep-disordered breathing was investigated with a population-based sample of 589 women enrolled in the Wisconsin Sleep Cohort Study. Menopausal status was determined from menstrual history, gynecologic surgery, hormone replacement therapy, follicle-stimulating hormone, and vasomotor symptoms. Sleep-disordered breathing was indicated by the frequency of apnea and hypopnea events per hour of sleep, measured by in-laboratory polysomnography. Multivariable logistic regression was used to estimate odds ratios for having 5 or more and 15 or more apnea and hypopnea events per hour. Odds ratios (95% confidence interval), adjusted for age, body habitus, smoking, and other potential confounding factors, for 5 or more apnea and hypopnea events per hour were 1.2 (0.7, 2.2) with perimenopause and 2.6 (1.4, 4.8) with postmenopause; odds ratios for 15 or more apnea and hypopnea events per hour were 1.1 (0.5, 2.2) with perimenopause and 3.5 (1.4, 8.8) with postmenopause. The menopausal transition is significantly associated with an increased likelihood of having sleep-disordered breathing, independent of known confounding factors. Evaluation for sleep-disordered breathing should be a priority for menopausal women with complaints of snoring, daytime sleepiness, or unsatisfactory sleep. 62

疼經婦女睡眠呼吸障礙的荷爾蒙治療 While the data are preliminary and based on a small number of subjects, estrogen appeared to have a substantial beneficial effect on measures of SDB in postmenopausal women. Overall, no additional benefit was seen with the addition of progesterone. In fact, progesterone attenuated the beneficial effects of estrogen in 4 out of the 6 participants. Manber et al. 2003 The Effects of Hormone Replacement Therapy on Sleep-Disordered Breathing in Postmenopausal Women: A Pilot Study Study Objectives: To evaluate the impact of estrogen and estrogen plus progesterone hormone-replacement therapy (HRT) on mild-to-moderate sleep-disordered breathing (SDB) in postmenopausal women. Design and Setting: Within-subjects, progesterone placebo-controlled prospective HRT trial in a clinical laboratory. Participants: Six postmenopausal women, diagnosed with mild-moderate SDB. Intervention: Transdermal estradiol and oral micronized progesterone. Measurements and Results: Subjects underwent polysomnography (PSG) on four occasions: a screening/adaptation night; a baseline night on no HRT; and two nights on HRT: one night after 7 to 12 days on estrogen plus placebo followed by a second night after 7-13 days on estrogen plus progesterone. The PSG was performed with a Sandman computerized PSG system using a standard clinical montage. Modified sleep diaries were used in the baseline week and throughout the study period. Mood was measured with the 20-item version of the Positive and Negative Affect Schedule (PANAS). Estrogen monotherapy was associated with a significant reduction in the overall apnea-hypopnea index (AHI) (from a mean of 22.7 events per hour at baseline to a mean of 12.2 events per hour), but the AHI reduction on estradiol plus progesterone relative to baseline was not statistically significant (AHI=16.2 events per hour). Similar results were found for the percentages of total sleep time and of total non-rapid eye movement sleep time with oxygen saturation less than 90%. Estrogen, neither alone nor in combination with progesterone, significantly altered PSG- or diary-based measures of total sleep time, time to sleep onset, or time awake after sleep onset. Conclusions: While the data are preliminary and based on a small number of subjects, estrogen appeared to have a substantial beneficial effect on measures of SDB in postmenopausal women. Overall, no additional benefit was seen with the addition of progesterone. In fact, progesterone attenuated the beneficial effects of estrogen in 4 out of the 6 participants. Key Words: menopause, apnea, sleep-disordered breathing, estrogen, progesterone Citation: Manber R, Kuo TF, Cataldo N, et al. The effects of hormone replacement therapy on sleep-disordered breathing in postmenopausal women: a pilot study. SLEEP 2003;2:163-168. 63

睡眠呼吸障礙的荷爾蒙治療 Hormone replacement therapy in post-menopausal women may cause adverse health outcomes including breast cancer, venous thromboembolism, and symptomatic coronary heart disease. In light of the risks of hormonal therapy and the absence of consistent clinical benefit, the routine use of progestational agents in patients with OSA is not warranted Menopausal Status and Sleep-disordered Breathing in the Wisconsin Sleep Cohort Study Menopause is considered to be a risk factor for sleep-disordered breathing, but this hypothesis has not been adequately tested. The association of premenopause, perimenopause, and postmenopause with sleep-disordered breathing was investigated with a population-based sample of 589 women enrolled in the Wisconsin Sleep Cohort Study. Menopausal status was determined from menstrual history, gynecologic surgery, hormone replacement therapy, follicle-stimulating hormone, and vasomotor symptoms. Sleep-disordered breathing was indicated by the frequency of apnea and hypopnea events per hour of sleep, measured by in-laboratory polysomnography. Multivariable logistic regression was used to estimate odds ratios for having 5 or more and 15 or more apnea and hypopnea events per hour. Odds ratios (95% confidence interval), adjusted for age, body habitus, smoking, and other potential confounding factors, for 5 or more apnea and hypopnea events per hour were 1.2 (0.7, 2.2) with perimenopause and 2.6 (1.4, 4.8) with postmenopause; odds ratios for 15 or more apnea and hypopnea events per hour were 1.1 (0.5, 2.2) with perimenopause and 3.5 (1.4, 8.8) with postmenopause. The menopausal transition is significantly associated with an increased likelihood of having sleep-disordered breathing, independent of known confounding factors. Evaluation for sleep-disordered breathing should be a priority for menopausal women with complaints of snoring, daytime sleepiness, or unsatisfactory sleep. 64

Thyroxine OSA與hypothyroidism有許多相同症狀。 Hypothyroidism的病患中罹患OSA有25%，而OSA病患中並有hypothyroidism者僅有3%。 Thyroxine therapy 對於hypothyroidism病患併有 OSA有初步療效。 The prevalence of OSA in patients with hypothyroidism may be greater than 25 percent. Conversely, the prevalence of hypothyroidism in patients with OSA is less than 3 percent. Thyroxine therapy in patients with coexisting hypothyroidism and OSA has eliminated the OSA in some studies, even in the absence of weight loss. 65

甲狀腺機能低下與睡眠呼吸障礙 Bahammam et al. 2011 66 Prevalence of thyroid disease in patients with obstructive sleep apnea Objectives Studies have suggested that ethnicity and environment may influence thyroid disease. We aim in this study to determine the prevalence of thyroid disease among Saudi (Arab) patients with laboratory-diagnosed obstructive sleep apnea (OSA) and the characteristics and predictors of thyroid disease associated with OSA. Methods Serum thyroid-stimulating hormone (TSH) and free-thyroxine (FT4) levels were measured in all patients referred to the sleep disorders center for an overnight sleep study. The levels were measured within 4 weeks of the sleep study. Type I attended polysomnography (PSG) was performed for all patients. Results During the study period, 271 patients with OSA and a mean age of 48.7 ± 14.1 yr, a body mass index (BMI) of 37.7 ± 9.6 kg/m2 and an AHI of 55.2 ± 37/hr as well as 76 non-OSA patients with a mean age of 40.8 ± 14.9 yr, a BMI of 33.7 ± 8.9 kg/m2 and an AHI of 3.8 ± 3.1/hr underwent thyroid function tests. In the OSA patients, the prevalence of newly diagnosed clinical hypothyroidism was 0.4%, and the prevalence of newly diagnosed subclinical hypothyroidism was 11.1%. In the non-OSA patients, the prevalence of newly diagnosed clinical hypothyroidism was 1.4%, and the prevalence of newly diagnosed subclinical hypothyroidism was 4%. There were no cases of clinical or subclinical hyperthyroidism in the studied group. Female gender was the only predictor of clinical hypothyroidism. Conclusion In the OSA patients, the prevalence of newly diagnosed clinical hypothyroidism was low; however, subclinical hypothyroidism was common among patients with OSA. Bahammam et al. 2011 66

Categories of pharmacological treatment options that have been used for OSA Drug Mechanism of action Outcome Protriptyline Tricyclic antidepressant Increased XII output, reduced rapid eye movement sleep, reduced AHI Fluoxetine Selective serotonin reuptake inhibitor Reduced rapid eye movement sleep, Reduced AHI Paroxetine Increased peak genioglossus activity NREM sleep. No change in tonic activity or OSA index Saboisky et al. 2009

Categories of pharmacological treatment options that have been used for OSA Drug Mechanism of action Outcome Thyroxine Thyroid substitution treatment Reduced OSA severity Acetazolamide Decreases blood pH Increased incidents of apnoeas Increased ventilation Medroxyprogesterone Increased ventilation (mixed responses, used in hypercapnic patients) Theophylline Inhibits adenosine Reduced central apnoeas Not useful in OSA Saboisky et al. 2009

Modafinil可改善CPAP療效 In this secondary analysis of data from patients with OSA and excessive sleepiness despite CPAP use, modafinil was associated with improvements in patients' functional outcomes and their ability to engage in a broad array of everyday activities Mean change from baseline in Functional Outcomes of Sleep Questionnaire (FOSQ) Total and individual domain scores for the combined populations with obstructive sleep apnea in the studies. p < 0.05 versus placebo. Values are shown as SEM. Modafinil Improves Functional Outcomes in Patients with Residual Excessive Sleepiness Associated with CPAP Treatment Objectives: The objective of this secondary analysis was to examine the effects of modafinil on the Functional Outcomes of Sleep Questionnaire (FOSQ) in patients with obstructive sleep apnea and residual excessive sleepiness with continuous positive airway pressure (CPAP) use. We also explored the association of improvement of functional status with the presenting level of subjective sleepiness. Methods: Data were pooled from 2 randomized placebo-controlled studies (4-week and 12-week interventions) of modafinil in patients with residual sleepiness (Epworth Sleepiness Scale score ≥ 10 on CPAP). Results: The analysis included 480 patients (FOSQ efficacy data n = 442 patients), 292 in the modafinil group and 188 in the placebo group. The mean age (SD) of the analyzed sample was 49.7 (9.2) years; 76% were men. Following administration with modafinil, there were greater improvements from baseline in the Total score (p < 0.0001) as well as 4 of the 5 domains (p < 0.05), compared with placebo. A greater proportion of patients who received modafinil were considered responders, compared with patients who received placebo (45% vs 25%; p < 0.001). Responder analysis based on the individual FOSQ domain items demonstrated that 18 of the 30 FOSQ items increased by at least 1 point for significantly more patients who received modafinil (p < 0.05). Improvements in functional status were not found to depend on patients' degree of subjective sleepiness at baseline. Conclusion: In this secondary analysis of data from patients with OSA and excessive sleepiness despite CPAP use, modafinil was associated with improvements in patients' functional outcomes and their ability to engage in a broad array of everyday activities. Weaver TE; Chasens ER; Arora S. Modafinil improves functional outcomes in patients with residual excessive sleepiness associated with CPAP treatment. J Clin Sleep Med 2009;5(6):499-505. Weaver et al. 2009 69

輔助藥物 (Modafinil) Modanifil是wake-promoting agent，有助於改善OSA治療後殘餘的白天嗜睡問題。 但是不能取代傳統的OSA治療方式：CPAP、dental appliance等。 Modafinil for treatment of residual excessive sleepiness in nasal continuous positive airway pressure-treated obstructive sleep apnea/hypopnea syndrome. STUDY OBJECTIVES: Nasal continuous positive airway pressure (nCPAP) usually reduces sleepiness in patients with obstructive sleep apnea/hypopnea syndrome. However, even with regular use of nCPAP, some patients experience residual excessive sleepiness. We evaluated the efficacy and safety of the wake-promoting agent modafinil for treating residual excessive sleepiness in nCPAP-treated patients. DESIGN: 12-week, multicenter, randomized, double-blind, parallel-group, placebo-controlled trial. PATIENTS: Patients aged 18 to 70 years diagnosed with obstructive sleep apnea/hypopnea syndrome and having residual excessive sleepiness during nCPAP therapy were eligible. INTERVENTIONS: Once-daily modafinil, 200 mg or 400 mg, or placebo. MEASUREMENTS AND RESULTS: Assessments included the Maintenance of Wakefulness Test, Epworth Sleepiness Scale, Clinical Global Impression of Change, and Functional Outcomes of Sleep Questionnaire. Both doses of modafinil significantly improved mean (SD) sleep latency on the Maintenance of Wakefulness Test at weeks 4, 8, and 12 compared with placebo (week 12: modafinil 400 mg, 15.0 [5.3] minutes; 200 mg, 14.8 [5.3] minutes; placebo, 12.6 [5.8] minutes; P <.0001). The Epworth Sleepiness Scale score decreased more in patients taking modafinil compared with those in the placebo group (week 12: modafinil 400 mg, -4.5 [4.3]; 200 mg, -4.5 [4.7]; placebo, -1.8 [3.5]; P <.0001). At week 12, overall clinical condition improved for 61% and 68% of patients treated with modafinil 200 mg and 400 mg, respectively, versus 37% of placebo-treated patients (P <.001). Modafinil was generally well tolerated and did not adversely affect nighttime sleep or nCPAP use. CONCLUSIONS: These results confirm previous shorter-term controlled trials, indicating modafinil is a useful adjunct therapy for improving wakefulness in patients with residual excessive sleepiness associated with obstructive sleep apnea/hypopnea syndrome who were treated with nCPAP. Black & Hirshkowitz 2005 70

使用CPAP的配合度 Long-term use of CPAP therapy for sleep apnea/hypopnea syndrome. Proportion of patients continuing CPAP over time. The proportion adhering to CPAP continues to fall over the first 4 years of therapy. McArdle et al. 1999

Modafini Modafinil is a wakefulness-promoting agent that has been approved by the FDA as an adjunct for the management of residual sleepiness in patients with OSA who are receiving effective therapy for the underlying upper airway obstruction. The AASM recommends modafinil for the treatment of residual sleepiness in patients who receive effective PAP treatment with OSA and who lack any other identifiable causes for their sleepiness.

Drugs for OSA? Various drugs have been investigated as treatment for OSA. Acetazolamide, theophylline, nicotine, opioid antagonists and medroxyprogesterone have been used to increase respiratory drive. Clonidine has been tested with the aim of reducing rapid eye movement sleep when OSA is often most severe. Various antidepressants have been used to suppress rapid eye movement sleep and to preferentially activate the upper airway dilators Smith et al. 2004

Drugs for OSA? The drug trials have often been of poor design and none has included more than a few patients. Most of the drugs have been found to be ineffective and those that have worked for some patients (acetazolamide and protriptyline) have produced intolerable adverse effects. Smith et al. 2004

惡化睡眠呼吸終止症的藥物 有OSA病史的病患，使用anesthetics, analgesics, anticonvulsants, antihistamines, and antipsychotics需特別注意，這些藥物可能惡化OSA的症狀。

止痛藥品 Opioids抑制呼吸藉由直接作用於brainstem 的呼吸中樞，並降低對於CO2及缺氧(hypoxia)的呼吸反應。 。 77

鎮靜劑 Barbiturates治療anxiety disorders, mood disorders, and isomnia.也是術前常用的鎮靜劑。 Barbiturates有睡眠呼吸抑制及隔日hangover，白天嗜睡。 Barbiturates對於OSA病患的呼吸抑制效應難以估計，不建議使用於severe OSA病患。

Practice Parameters for the Medical Therapy of Obstructive Sleep Apnea  Standards of Practice Committee of the American Academy of Sleep Medicine Selective serotonergic uptake inhibitors (SSRIs) are not recommended for treatment of OSA. Protriptyline is not recommended as a primary treatment for OSA. Methylxanthine derivatives (aminophylline and theophylline) are not recommended for treatment of OSA. Estrogen therapy (estrogen preparations with or without progesterone) is not indicated for the treatment of OSA. Modafinil is recommended for the treatment of residual excessive daytime sleepiness in OSA patients who have sleepiness despite effective PAP treatment and who are lacking any other identifiable cause for their sleepiness.

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Pharmacotherapy for sleep bruxism Insufficient evidence-based data to draw definite concerning the effects of various drugs on bruxism. Dopaminogic, serotonergic, and adrenergic systems suppressor trials. Clonidine (adrenergic receptor antagonist) to reduce sleep bruxism motor activity by decreasing cardiac sympathetic tone in minutes before the onset of SB, thus preventing the the subuence ofautonomic sleep arousal that leads to motor activation in the genesis of SB. Lavigne 2009