術後鴉片類藥物對肝細胞癌手術影響之研究

研究目的鴉片類藥物為目前術後廣泛被使用之止痛藥物，然而在過去的分子生物與動物實驗中發現鴉片類藥物有可能促使腫瘤細胞的增生、與抑制免疫反應；亦有回溯性臨床研究指出肺癌手術圍術期鴉片類使用劑量與癌症復發及死亡率相關，本研究旨在研究術後鴉片類藥物對於肝癌手術預後之影響。研究方法及資料本研究為回溯性世代研究，自台灣全民健保資料庫之承保抽樣歸人檔取得資料，以ICD-9與ICD-10編碼搜尋肝細胞癌診斷碼（155.0、C22.0），再從中串聯癌症登錄檔之巴塞隆納肝癌分期，篩選其中初次接受肝切除或肝臟移植之患者進行分析，為計算劑量效應，本研究將術後總鴉片類藥物用量依照等效鎮痛換算為等效口服嗎啡當量，分析方法以SAS 9.4版套裝軟體進行，以泊松回歸（Poisson regression）計算相對風險，Kaplan-Meier存活曲線分析存活率與無病存活率，以多變因COX比例風險模型分析估計風險度比，P值小於0.05為有統計意義。研究結果最終有812人納入最終分析，其中530人術後有使用鴉片類藥物，282人術後無使用鴉片類藥物，兩組之存活率與無病存活率之風險比為1.10 (95% CI 0.85-1.41)與1.15 (95% CI 0.91-1.46)；有使用鴉片類藥物組又依據等效口服嗎啡之三分衛數分為三組：少於40毫克為低劑量組、40至144毫克為中劑量組、145毫克以上為高劑量組；存活率之風險比在低劑量組為0.88 (95% CI 0.63-1.24)、在中劑量組為1.27(95% CI 0.92-1.74)、在高劑量組為1.14 (95% CI 0.83-1.58)；在巴塞隆納肝癌分期中0期與A期之患者在有使用鴉片類藥物組之死亡相對風險為1.24 (95% CI 0.85-1.80)、復發之相對風險為1.31 (95% CI 0.96-1.81)，在巴塞隆納肝癌分期中B期、C期與D期之患者在有使用鴉片類藥物組之死亡相對風險為0.97 (95% CI 0.69-1.38)、復發之相對風險為1.00 (95% CI 0.71-1.42)。結論與建議過去許多研究表明鴉片類藥物有促使癌症復發之疑慮，加上圍術期鴉片類用量被認為與術後噁心嘔吐、延遲恢復、長期鴉片類藥物使用等併發症有關，故近來有許多臨床醫師試圖施行無鴉片類藥物麻醉或無鴉片類藥物止痛法，然而本研究結果表示術後鴉片類藥物用量與肝癌切除手術或肝癌換肝手術之存活與無病存活並無關係，故未來於此類病人是否使用鴉片類藥物止痛之議題上肝癌預後並非重要的臨床考量。

ObjectiveHepatocellular carcinoma(HCC) is a fatal cancer worldwide, and surgical resection remains the standard treatment. Postoperative opioid prescription has been believed to affect cancer recurrence through complex biological pathways. We conducted a retrospective cohort study using the Longitudinal Health Insurance Database of Taiwan to evaluate the relationship between postoperative opioid use and long-term surgical outcomes of patients with HCC.Methods and MaterialsThis study had a retrospective cohort design. 812 patients older than 20 years who underwent hepatectomy because of HCC was included. The exposure group comprised patients who used opioids, during hospitalization postoperatively. The comparison group included those who never used opioids during hospitalization postoperatively. A Cox proportional hazards model was used to evaluate the overall survival or recurrence-free survival rate between the opioid group and nonopioid group.ResultsA total of 530 patients received opioids postoperatively, and 282 patients did not. The hazard ratios (HRs) of overall survival and recurrence-free survival were 1.10 (95% CI, 0.85-1.41) and 1.15 (95% CI, 0.91-1.46), respectively. Total postoperative opioids were converted into oral morphine milligram equivalents and then divided into three equal subgroups: low dose, <40 mg; medium dose, 40-144 mg; and high dose, ≥145 mg. The HRs of overall survival were 0.88 (95% CI, 0.63-1.24) for the low-dose group, 1.27 (95% CI, 0.92-1.74) for the medium-dose group, and 1.14 (95% CI, 0.83-1.58) for the high-dose group. For BCLC stage 0 and stage A patient, HR of overall survival in opioid group is 1.24 (95% CI 0.85-1.80), HR of recurrent free survival is 1.31 (95% CI 0.96-1.81). For BCLC stage B, stage C and stage D patient, HR of overall survival is 0.97 (95% CI 0.69-1.38), HR of recurrent free survival is 1.00 (95% CI 0.71-1.42).Conclusion and SuggestionPostoperative opioids do not affect overall and recurrence-free survival in patients undergoing hepatectomy or liver transplantation because of HCC. Cancer recurrence should not be a clinical concern regarding postoperative opioid prescription.