【作者】 邱小弟；

【导师】 佘守章；

【作者基本信息】 广州医学院 ， 麻醉学， 2010， 硕士

【摘要】 从20世纪70年代晚期开始,阿片类药物应用于椎管内镇痛已经是临床上常规的治疗手段之一。随着硬膜外镇痛技术广泛应用于术后疼痛、产科疼痛以及顽固性癌痛的治疗领域,在过去的10余年里,新型脊髓活性药(如舒芬太尼、喷他佐辛等亲脂性阿片类药、左旋布比卡因等低毒性局麻药)的基础和临床研究在蓬勃地发展[1]。喷他佐辛(Pentazocine)是高脂溶性的阿片受体激动-拮抗药,主要激动阿片κ受体,较大剂量时可激动σ受体,对μ受体具有部分拮抗作用[2~4]。喷他佐辛的呼吸抑制作用和成瘾性均低于吗啡,常被用于癌痛或术后疼痛的治疗[5,6]。虽然喷他佐辛在1967年由美国斯德林温斯洛伯集团(Stering Winthrop Group LTD)研制成功上市[7~11],在国外应用的临床经验已有数十年,但近些年人们仍然关注着它的应用,并发掘出其更优越的效应[12]。在国内,近几年由北京双鹤药业股份有限公司研制成功,并逐渐在国内开始应用。我们在临床应用中发现,喷他佐辛用于术后镇痛的镇痛效果确切,且不良反应少,尤其是恶心、呕吐、瘙痒等不良反应的发生率更低[13~16],是较好的镇痛药物。然而,喷他佐辛在国内的临床经验尚少,尤其是术后镇痛的应用目前仍处于摸索阶段,仍缺乏大样本多中心的临床研究,其最佳的使用方案、适用人群、合理配伍等问题值得研究。因此,本文从喷他佐辛椎管内的临床效应和脊髓镇痛的机制进行研究,以探索喷他佐辛椎管内镇痛的最佳方案及其脊髓镇痛的机制,为喷他佐辛更好地应用于临床提供参考。第一部分不同浓度喷他佐辛复合左旋布比卡因对剖宫产术后硬膜外镇痛效应的影响目的研究不同浓度喷他佐辛复合0.2%左旋布比卡因对产妇剖宫产术后硬膜外自控镇痛(PCEA)效应的影响。方法选择120例择期行剖宫产初产妇(ASA I~II级),随机分成六组(n=20),P1组:0.1%喷他佐辛复合0.2%左旋布比卡因,P2组:0.12%喷他佐辛复合0.2%左旋布比卡因,P3组~P6组分别给予0.14%、0.16%、0.18%、0.2%喷他佐辛复合0.2%左旋布比卡因,各组镇痛药液总量共100ml。均采用LCP模式给药:负荷剂量5ml,背景剂量2ml/h,单次追加剂量2ml,锁定时间15min,镇痛24h。观察和记录术后第1h、2h、4h、8h、16h及24h的静息疼痛、动态疼痛、子宫收缩痛VAS评分,PCA泵的按压次数(D1)及实际有效次数(D2),Ramesay镇静评分,改良Bromage分级,肛门排气时间及可能发生的不良反应。结果六组产妇术后各时点静息镇痛效果良好,各组随着喷他佐辛的剂量增大而VAS评分降低,即P1组≈P2组>P3组≈P4组>P5组≈P6组,其中动态疼痛及宫缩痛术后4h、8h及16h明显降低;PCA按压次数及D1/D2比值P5组和P6组小于P1组~P4组(P<0.05);六组产妇中恶心发生情况:P1组、P2组、P4组及P6组各1例(5%),P3组及P5组各2例(10%),(P>0.05),各组未出现呕吐、瘙痒、呼吸抑制、低血压或高血压等不良反应。结论0.18%或0.2%喷他佐辛复合0.2%左旋布比卡因用于产妇剖宫产术后硬膜外自控镇痛的效果良好,优于0.1%、0.12%、0.14%或0.16%喷他佐辛复合0.2%左旋布比卡因,不良反应未见增加;可作为剖宫产术后首选镇痛方案之一。第二部分喷他佐辛鞘内注射对切口痛大鼠背根神经节ERK1/2磷酸化表达的影响目的观察喷他佐辛鞘内注射对切口痛大鼠背根神经节ERK1/2磷酸化表达的影响,以探讨喷他佐辛脊髓镇痛的机制。方法选择鞘内置管成功的SD大鼠80只,随机分为4组(n=20):假手术组(S组)、切口痛组(P0组)、喷他佐辛40μg组(P1组)和喷他佐辛120μg组(P2组)。S组仅予吸入异氟烷麻醉,不做手术;P0组、P1组和P2组吸入异氟醚麻醉后做切口痛模型手术,并且于术前10min、术后24h、48h和72h分别鞘内注射0.9%生理盐水20μl、喷他佐辛40μg和喷他佐辛120μg。各组于术前1h、术后2h、6h、24h、48h和72h时采用von Frey纤维丝测定机械缩足反射阈值(MWT),并于术后痛阈测定结束后分别处死4只大鼠,取其术侧L4和L5背根神经节用于免疫组化法测定磷酸化ERK1/2(p-ERK1/2)的阳性细胞比率。结果与S组比较,P0组术后2h~72h时MWT均降低,P1组和P2组术后2h~24h时MWT降低,但与P0组比较,P1组和P2组术后2h~48h时MWT上升,且P2组上升更大(P<0.05)。S组背根神经节p-ERK1/2有微弱表达,P0组、P1组和P2组术后2h~72h时p-ERK1/2出现强表达,但与P0组比较,P1组和P2组p-ERK1/2表达下调,而且P2组下调幅度更大(P<0.05)。结论喷他佐辛鞘内注射可提高切口痛大鼠痛阈,且与剂量相关,其机制可能与抑制背根神经节p-ERK1/2表达有关。更多还原

【Abstract】 Opioids used in clinical intraspinal analgesia had been one of the conventional means of treatment Since the late 20th century, 70. With the vigorous development of experimental studies and clinical researches of novel agonists, such as sufentanil, pentazocine, levobupivacaine ect, used intraspinal in the past more than 10 years, the technology of epidural analgesia was widely used in the treatment of postoperative pain, obstetric pain, and refractory cancer pain, ect.Pentazocine (PTZ), a benzomorphan derivative, is an opioid analgesic that has mixed opioid agonist and antagonist actions with high lipophilicity, and is the first mixed agonist-antagonist analgesic to be marketed. It exerts powerful antions at the kappa opioid receptors and has a weak antagonist action at the mu receptor. Moreover, it may induce the undesirable effects associated with sigma receptor activity. It is wildly used in clinical practice for relief of moderate to severe pain, such as cancer-related or postoperative pain, because it is a reasonably potent analgesic with lower abuse liability than morphine. Pentazocine was developed by the Sterling Drug Company, Sterling-Winthrop Research Institute, of Rensselaer, New York. It was approved by the Food and Drug Administration in June 1967 after being favorably reviewed following testing on 12,000 patients in the United States. The analgesic compound was first made at Sterling in 1958. U.S. testing was conducted between 1961 - 1967. By mid 1967 Pentazocine was already being sold in Mexico, England, and Argentina, under different trade names. Althought the experimental studies and clinical application of pentazocine has been for several decades, since it was appeared on the market in 1967, many researchers are still paying close attention to the development of this analgesic recently. Furthermore, it shows that pentazocine is superior to other agents according to the most recent studies. In China, pentazocine was developed successfully by Beijing Double-crane Pharmaceutical Corporation Limited and appeared on the market of China most recent. Much of the latest information showed that pentazocine is efficient for patient-controlled analgesia, and the incidence of pruritus and postoperative nausea and vomiting (PONV) of pentazocine was low and other side effects were mild. Therefore, pentazocine may be a goog choice for the treatment of postoperative pain.However, pentazocine is a new drug and the application experience is inadequate in China, especially the experience of the treatment of postoperative pain is few. There is no large sample and multicenter studies about pentazocien in China, and whether it is suitable for chinese is not know. Therefore, the purpose of this study is to determine whice dose of pentazocine plus 0.2% levobupivacaine is the most efficient for parturient women patient-controlled epidural analgesia. Furthermore, we evaluate the effect of intrathecal pentazocine on expression of phosphorylated-ERK1/2 (p-ERK1/2) in dorsal root ganglion neurons in a rat model of incisional pain in order to investgate the mechanism of pentazocine using in intraspinal analgesia. Part one Effect of different-dose pentazocine on efficacy of levobupivacaine for Uterine-incision delivery women patient-controlled epidural analgesiaObjectiveTo study the effect of different-dose pentazocine on efficacy of levobupivacaine for Uterine-incision delivery women patient-controlled epidural analgesia.MethodsOne hundred and twenty ASAⅠorⅡparturient women undergoing Cesarean section received PCEA for 24 h after operation.The PCEA solution contained 0.2% levobupivacaine plus pentazocine 1.0,1.2,1.4,1.6,1.8 or 2.0mg·ml-1 (group P1,P2,P3,P4,P5,P6,n=20).The epidural PCA device was set up to deliver a 2ml bolus dose with a 15-min lockout interval and background infusion at 2ml·h-1 after a loading dose of 5ml.The following parameters were recorded at 1,2,4,8,16,24 h after pump infusion:the VAS score of rest pain,dynamic pain and uterine contraction pain,the times of self administration bolus(D1) and effective times(D2),Ramsay sedation score,modified Bromage score,BP,HR,RR,SpO2 and side effects.ResultsThe pain scores of parturients in group P1 and P2 were higher than those in the group P3 and P4,which were higher than those in the group P5 and P6,in short,group P1≈P2>P3≈P4>P5≈P6,the differences were statistically significant at 4,8,16h.The times of D1 and the D1/ D2 ratio of group P5 and P6 were the smallest in 6 groups(P<0.05).The incidences of PONV is 5% in group P1,P2,P4,P6,and 10% in group P3 and P5(P>0.05).Conclusions0.18% or 0.2% pentazocine plus 0.2% levobupivacaine is more efficient than 0.1%,0.12%,0.14% or 0.16% plus 0.2% levobupivacaine for parturient women patient-controlled epidural analgesia with low incidences of side effects. Part two Effect of intrathecal pentazocine on expression of phosphorylated-ERK1/2 in dorsal root ganglion neurons in a rat model of incisional painObjectiveTo evaluate the effect of intrathecal (IT) pentazocine on expression of phosphorylated-ERK1/2 (p-ERK1/2) in dorsal root ganglion neurons in a rat model of incisional pain.MethodsEighty healthy male SD rats,weighing 220~250g,in which IT catheter was successfully placed without any complication were randomly divided into 4 groups (n=20):groupⅠsham operation (group S);groupⅡincisional pain (group P0);groupⅢIT pentazocine 40μg + incisional pain (group P1);groupⅣIT pentazocine 120μg + incisional pain (group P2).Paw withdrawal threshold to von Frey filament stimulation was measured 1 hour before (baseline) and 2,6,24,48,72 h after operation.Four animals were killed at 2,6,24,48,72 h after operation.The dorsal root ganglions of L4 and L5 were removed to detect the proportion of p-ERK1/2 positive expression cell using immuno-histochemistry method.ResultsCompared with group S,mechanical pain threshold was significantly decreased in group P0 during 2 hours to 72 hours after operation and was significantly decreased in group P1 and group P2 during 2 hours to 24 hours after operation.However,compared with group P0,mechanical pain theshold was increased in group P1 and group P2.The expression of p-ERK1/2 in group S was weak.The expression of p-ERK1/2 was higher in group P0,group P1 and group P2 during 2 hours to 72 hours after operation.But compared with group P0,the expression of p-ERK1/2 was significantly decreased. ConclusionsIntrathecal pentazocine can reduce incisional pain by inhibiting the up-regulation of p-ERK1/2 expression in dorsal root ganglions.更多还原