對於術前心理壓力下的個案，於週術期短暫使用新一代抗憂鬱劑的效果

Abstract

研究背景與目的： 經歷重大手術與治療疾病對個人而言，身體與心理在週術期(perioperative period)都面臨了重大的壓力。手術前焦慮情緒與憂鬱的發生率分別約為60%與20-40%。在過去許多研究中發現，術前的焦慮與憂鬱，不僅增加了手術中麻醉藥物的使用量，也確實影響了病人術後的恢復。術前的焦慮與憂鬱是術後嚴重疼痛、術後噁心嘔吐的預測因子之一，也與產婦剖腹產後的滿意度成負相關。焦慮與憂鬱是心臟手術術後預後不良的重要危險因子，也影響了腰椎手術與全膝置換術之後的疼痛程度、功能的恢復及病人術後的滿意度，與在器官移植手術之後，病人的調適與生活品質改善的程度。 常用的抗焦慮或安眠藥物(例如benzodiazepine類與α2 agonist類)雖然對術前的焦慮症狀有幫助，卻可能會影響術中或術後的生命徵象(例如心跳、血壓與血氧濃度)，而並沒有在術前被廣泛使用。抗憂鬱藥物可能對這些病人有幫助，但臨床上，確鮮少有對術前心理受到壓力的病人，在術前使用預防性抗憂鬱藥物的研究。 Mirtazapine(Remeron SolTab)為heterocyclic antidepressants抗憂鬱劑，以口溶的方式服用，服用後約2個小時即有作用。此藥物作用為中樞α2、5-HT2、5-HT3、及H1 receptor的拮抗劑，有抗憂鬱、抗焦慮的作用，並可以改善睡眠障礙。此外，對術後的嚴重疼痛，可能也有預防的效果。 這個研究的主要目的是要探討，在週術期每晚睡前使用Remeron (mirtazapine)，對於手術後焦慮情緒與憂鬱、睡眠障礙與疼痛的影響；次要目的為短期使用mirtazapine 之藥效與副作用的探討。 研究方法： 這是一個單一醫學中心、開放的、半實驗的( single-center, open-labeled, quasi-experimental)臨床試驗。受試期間為術前一天至術後第三天。在醫學中心中，需經重大腹部手術的病人中找尋受試者。若簡式健康表的分術大於六分，則定義為術前心理壓力下的個案。受試者將依其意願分成兩組：治療組在手術前一天、手術當天、至手術後第二天，每晚睡前服用mirtazapine 30 mg (Remeron Tab)；治療組在受試期間，可以自行決定當晚是否服藥；而不治療組均不做任何的介入治療。所有的受試者在受試期間內，不給予其他任何的鎮靜安眠劑。兩組的病人在術前一天，術後第一天及第三天，均接受醫院焦慮與憂鬱量表(HADS)及失眠自我評量表(AIS)的評估；術後的第一天至第三天均評估其疼痛指數(pains score, NRS)並記錄其嗎啡止痛劑的用量。統計方面，受試者的基本資料將以敘述統計的方式呈現，單變項分析每個時間點的HADS，AIS與疼痛指數及嗎啡用量將用paired t test 來比較，同一時間點兩組間的差別用two-sample t test來比較。此外，在多變項分析中，我們使用傾向分數(propensity score)來減少研究中選擇與自我選擇的偏差(selection and self-selection bias)，並將其納入與時間相關資料(longitudinal data)之迴歸分析General estimating equation (GEE) method，做為regression adjustment，將治療組與不治療組、服藥與沒有服藥的病人做統計上平衡兩組間的差異，可間接消弭因為非隨機分派治療組別所造成的分組偏差，使其回復到如隨機分派的特性，以求更精確的評估Remeron的藥效。 結果： 從2007年9月至2008年12月，我們一共接觸了539位需接受重大腹部手術的病人，其中簡式健康表(BRBS-5)大於等於六分的有150位，其中有86位病人願意進入此臨床試驗。86人中有53人選擇吃藥，33人不願吃藥，兩組中分別有3與4人術後非預期進入加護病房無法持續追蹤而離開試驗。其餘的受試者(non treatment: 29; treatment: 50)都有完成五天的評估。 多變項分析與傾向分數分析顯示，在評估HADS前兩晚有服mirtazapine藥物的病人，確實會降低其HADS分數；服用mirtazapine藥物，則對AIS的白天指數有顯著的降低，並且有改善夜眠指數的趨勢；服用mirtazapine藥物雖有降低嗎啡日用量與術中嗎啡類止痛藥物的趨勢，但未達統計顯著( p =0.2 )。 臨床意義與未來展望： 這是一個在週術期使用mirtazapine抗憂鬱劑來治療術前遭受心理壓力的病人之先趨臨床研究。本研究證實了mirtazapine確實能降低術前有心理壓力病人週術期的焦慮與憂鬱程度，改善其術後睡眠及白天生活品質，並有減少術中及術後使用鴉片類止痛劑的趨勢，提升這些病人週術期的生活品質。 未來可針對術前有心理壓力的病人，探討使用mirtazapine藥物是否可以改善週術期的併發症，及病人短期與長期的預後。此外，mirtazapine對週術期睡眠架構的影響與對疼痛路徑的影響機轉，都是可以再深入研究的領域。

Background: Perioperative period may be one of the most unpleasant experience during one’s life. The incidence of preoperative anxiety and depression were reported to be 60% and 20-40%. In the literature review, higher the preoperative anxiety and depression level are associated with more severe postoperative pain, less postoperative satisfaction, and more mortality rate. Although conventional anxiolytic premedication (such as benzodiazepine and α 2 agonist) may be helpful to ameliorate preoperative anxiety symptoms and attenuate postoperative stress response, most anesthesiologists are uncertain to provide sedative medication because those drugs might compromise intra- and postoperative vital signs and patient safety. Moreover, those drugs show no benefit in reducing postoperative depression and anxiety. Currently, there are no standardized preoperative evaluation and treatment for preoperative psychologically distressed patients. Mirtazapine is a unique antidepressant with the potential of fast onset. The overall effects of the drug are antidepressant, anxiolytic, and sleep-enhancer. Moreover, it might play a role in eliminating postoperative severe pain. The primary goal of this study is to test that perioperative use of mirtazapine in preoperative psychologically distressed patients can reduce perioperative anxiety and depression level, enhance sleep quality, and to reduce the level of postoperative pain. Method: This is a single-center, open-labeled, quasi-experimental clinical trail. Patients undergoing major abdominal surgery whose Brief Symptom Rating Scale (BSRS-5) were more than 6 were defined as “preoperative psychologically distressed” cases were invited to the trail. Patients were assigned to treatment group or non-treatment group by their own decision. In the treatment group, patients could take mirtazapine 30 mg (Remeron) every night from preoperative day 1 to post operative day 3 by their own will. There were no other intervention in the non-treatment group. Hospital Anxiety and Depression Scale(HADS) ,Athens Insomnia Scale (AIS), and pain score were accessed in all participants on pre-op day 1, post op day 1 and day 3. The demographic data were summarized by descriptive statistics. HADS, AIS scores, pain scores, and morphine consumptions of each day were compared using paired t test within each of two groups and using two-sample t test between two groups in the univariate analysis. In the multivariate analysis, we used the propensity score method to adjust the self-selection bias in our regression analysis of Remoron’s effects on the outcome variables under study. Marginal regression models were fitted to our correlated longitudinal data using the generalized estimating equations (GEE) method to estimate the population average effects of time-varying Remeron usage on the mean values of HADS, AIS, pain scores, and daily morphine consumptions. Results: 539 patients prepared to receive major abdominal surgery from September 2007 to December 2008 were eligible for this study. Among them, 150 patients whose BRBS-5 score ≥ 6 were asked to participate in this study. Only 86 patients agreed to be enrolled in the study: 53 of them chose to be in the treatment group on the day of admission, and the other 33 patients were in the non-treatment group on the day of admission. Yet, 3 and 4 patients in each group could not complete the study due to unplanned post-operative ICU care. Propensity score and multivariate analysis showed that mirtazapine did reduce HADS in 2 days in the peri-op psychologically distressed patients. Mirtazapine can decrease AIS day index, and had a trend to decrease night index also. The effect of mirtazapine had the trend of decreasing the amount of morphine consumption, but did not reach statically significance (p = 0.2). In conclusion, mirtazapine can decrease anxiety and depression score and insomnia score in perioperative psychologically distressed patients. Further studies are required to investigate mirtazapine’s effects on peri-op complication, short and long term outcome of those patients.