CN1133009A - 应用左旋丁哌卡因治疗慢性疼痛 - Google Patents

应用左旋丁哌卡因治疗慢性疼痛 Download PDF

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CN1133009A
CN1133009A CN94193775A CN94193775A CN1133009A CN 1133009 A CN1133009 A CN 1133009A CN 94193775 A CN94193775 A CN 94193775A CN 94193775 A CN94193775 A CN 94193775A CN 1133009 A CN1133009 A CN 1133009A
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H·J·巴兹利
L·马瑟
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    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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Abstract

左旋丁哌卡因用于治疗慢性疼痛。

Description

应用左旋丁哌卡因治疗慢性疼痛
本发明涉及已知的止痛剂，即丁哌卡因或1-丁基-N-(2，6-二甲基苯基)-2-哌啶甲酰胺的新的治疗应用。
在某些疼痛症中，可利用缓慢给予长效局麻药消旋丁哌卡因作为止痛剂。然而，消旋丁哌卡因具有心脏毒性，它对心脏的电生理和机械作用具有抑制作用。因此，心脏病患者在应用时要小心。
已知左旋丁哌卡因的心脏毒性可能小于右旋丁哌卡因和消旋丁哌卡因。例如见Vanhoutte等人Br.J.Pharmacol.103：1275-1281(1991)，和Denson等人Regionul Anaesthesia，17：311-316(1992).Vanhoutle等人研究了丁哌卡因对映体对荷兰猪离体乳头肌电生理特性的影响；这依据了他们的陈述，即“丁哌卡因的心脏毒性似乎主要源于电生理”。
Berrisford等人在Br.J.Anaesthesia70：201-204(1993)中公开了在连续胸膜外肋间神经阻断过程中，给予经历胸廓切开术的病人丁哌卡因及其对映体作为止痛剂。连续输注丁哌卡因直至手术后第五天早晨。
DuPen等人在Pain49：293-300(1992)中报道了在难以控制的癌症疼痛中，利用缓慢硬膜外给药并且输注鸦片样物质-浓度为0.1-0.5％的丁哌卡因。治疗适中的时间为60-120天，最长的输注时间可持续277天。据报道丁哌卡因的清除率逐渐减小。
在较低单剂量时，心脏毒性通常不是临床上的问题，例如可以通过硬膜外使用或神经阻断解决。然而缓慢给药时，心脏可能不得不抵抗局麻药可能存在的蓄积性心肌中毒的副作用。
Who Analgesic Ladder已对痛疼进行了分级也见Ashburn和Lipman的综述“癌症病人疼痛的处理”。轻度至中度疼痛为分级的第一级，要求用非鸦片样物质±辅药来冶疗。如果疼痛持续或增加，应该用适于轻度至中度疼痛的鸦片样物质加上非鸦片样物质±辅药来冶疗。如果疼痛持续或增加超过该第二级，要求用适于中等至严重疼痛的片样物质，有或无非鸦鸦片样物质和/或辅药。癌症和术后疼痛典型地为该第三级。
每个人在任何时候都可能处在该疼痛分级的任何级。患急性疼痛的病人将随着时间的推移倾于降低的分级；患慢性疼痛或恶性肿瘤的病人随着时间的推移可能倾向高的分级，因此要求愈来愈强的止痛剂来控制与疾病进展相关的恶化的疼痛。
现已发现，左旋丁哌卡因从组织摄入室和脑中的量小于右旋丁哌卡因。因此左旋丁哌卡因显示出清除率增中。联想到左旋丁哌卡因的心脏毒性小于右旋丁哌卡因，这支持应用左旋丁哌卡因作为改善的实用长效止痛剂，即用于慢性疼痛的冶疗。该发现对(但不限定于)心功能受损害和中枢神经系统受破坏的病人或那些易于患这些疾病的人来说可能是特别有益的。尤其，癌症患者可能是从该止痛剂中获益的一群人。
该止痛剂可以是单一的异构体，但有效地是不含右旋丁哌卡因，例如：其对映体含量至少为80％，更优选至少90％，并且最优选至少99％。也可以使用任何常规的盐，例如盐酸盐。
为了实现本发明的目的，治疗慢性疼痛包括给予左旋丁哌卡因至少2天时间，优选至少30天，例如持续60天或更多天。如上所述，慢性疼痛可能涉及癌症。其它适宜的对象是那些患术后疼痛或由其它长期药物性疾病引起的严重疼痛的人。
在使用本发明中，可提供左旋丁哌卡因的溶液，用于输注给药。这可以用常规装置来进行，例如包括按要求为病人输注的工具。例如根据所设想的过程，所给予的可有效利用的左旋丁哌卡因的浓度为0.25％，0.5％或0.75％。可以给予单剂量最多为60ml。通常的给药途径为浸润，硬膜外，脊髓和外周神经阻断。根据麻醉惯例也可以连续输注低浓度例如0.125％的含或不含鸦片样物质的止痛剂。
可以将活性止痛剂直接给到脊柱或硬膜外空间。这样将活性止痛剂提供到要求的部位。与常规药物需要通过血-脑屏障相反，活性止痛剂发挥作用，然后进入血中清除。避免了蓄积；本发明依赖已知的丁哌卡因的活性和意外的发现，即左旋丁哌卡因不象其它消旋丁哌卡因组分(右旋丁哌卡因)那样在心脏和脑中蓄积。因此临床医生可以利用本发明而没有招致与消旋丁哌卡因中右旋丁哌卡因含量有关的长期问题的可能性。本发明疗法，即缓解慢性疼痛的作用与使用丁哌卡因作局麻药，即避免诱导性疼痛的作用是有区别的。
本文使用的术语“慢性疼痛”是指通常与使用消旋丁哌卡因作为局麻药有关的长期疼痛状态。因此，本发明包括对患有熟练临床医生可能称之为“急性疼痛”的病人的冶疗。与使用左旋丁哌卡因有关的中毒危险减小证明长期给药并且使用高浓度将会带来显著的治疗益处。
表1给出疼痛的分类。
                              表1
疼痛类型 急性 慢性(非恶性) 慢性(恶性)
持续时间 数小时-数天 数月-数年 不可预见
相关的病理改变 出现 通常没有 通常出现
预后 可预见 不可预见 疼痛加重同时可能变形和害怕死亡
相关的问题 不常见 抑郁焦急 很多，尤其是恐惧
神经传导 加快 减慢 减慢
自主神经系统 出现 通常不出现 出现或不出现
生物与社会效应 非常小 低或不出现 可变的，通常是显著的
治疗 初级的止痛剂 多种方式：通常主要注意行为方面药物发挥次要的作用 多种方式：药物通常发挥主要作用
由于下列原因，在治疗严重的疼痛中，左旋丁哌卡因可有效地用作鸦片样物质的辅药：
1)尽管使用了鸦片样物质，但也可能未止住疼痛，并且影响中枢或传入神经通路的神经性疼痛通常对这些止痛剂反应很差。
2)大多数癌症患者都具有一种以上的病因的疼痛并且每种都必须分别冶疗。
3)在治疗晚期的疼痛时，药物如吗啡具有其它止痛剂不出现的上述最高限(ceilling)作用，而且副作用增加并且有时可见耐受性。
4)尽管大多数患者通过口服途径来治疗，但60％的人在生命的最后四周需要通过其它的途径或交替的途径来给药。
使用左旋丁哌卡因控制术后疼痛可能是较简单的事情。已证明丁哌卡因可有效地控制术后疼痛，并且可有效地减小疝修补术后恢复期病人对鸦片样物质的需求量。在该项研究中，外科手术的伤口在闭合前，用麻醉药浸润。使用0.25％的低浓度；用左旋丁哌卡因时，较高的浓度可能引起临床效益的改善。
如下证明组织选择性摄入：
四只羊，重39-49kg(平均44，标准差4kg)逐渐增加盐酸消旋丁哌卡因药团的给予剂量(从40mg开始)。经过PVC套管至少间隔一天来给予药物直至产生致死的后果。在死后20分钟内取出心脏和脑，分析丁哌卡因的浓度。通过在主动脉瓣上方约20mm的大血管和右心房尾侧边缘下20mm横切取出心脏。立即将血液从心腔中压出，并且分别得到左、右心房和心室的标本，涂污并冷冻保存(-20℃)以备分析使用。在脑桥下边缘处横切取出脑，同心脏组织一样，涂污并冻冷保存。
表2列出丁哌卡因对映体的组织浓度。在死后测定的组织浓度中，反映出致死剂量(80-200mg)的变异性。在心房和心室中，丁哌卡因两对映体浓度的巨大差异是明显的。在心室和脑中，由于这些组织摄入(+)-(R)-丁哌卡因的量比(-)-(R)-丁哌卡因的量多，所以丁哌卡因对映体浓度的显著性差异(经Students配对t检验测定二者P＝0.03)是明显的。在心房中不是这样。
羊编号 致死剂量(mg) 对映体 组织浓度(μg/g)
心房 心室 脑
1234 8080200200 R-S-R∶SR-S-R∶SR-S-R∶SR-S-R∶S 5.706.220.923.943.651.0817.918.00.9921.521.21.02 9.938.441.187.707.361.0545.644.11.0334.133.31.03 6.916.531.064.974.591.0812.711.71.0917.216.31.08
左旋丁哌卡因相对于消旋丁哌卡因其它的好处是它对心脏的抑制作用减小。因此特别适用于心脏病患者的治疗。在本申表人Chiroscience Limited等，以相同的题目同一天申请的其它国际专利申请中更充分地描述了这一点，本文引入该内容供参考。

Claims (9)

1.应用左旋丁哌卡因或其盐，其本不含右旋丁哌卡因，来制备用于治疗病人慢性疼痛的药物。
2.权利要求1的应用，其中病人患癌症。
3.权利要求1或权利要求2的应用，其中疼痛为世界卫生组织分级的三级。
4.前面任一权利要求的应用，其中病人伴随用鸦片样物质冶疗。
5.前面任一权利要求的应用，其中病人为心脏病患者，例如患有New York Heart Association Index中2，3或4级心衰的病人。
6.前面任一权利要求的应用，其中疼痛持续时间超过2天。
7.权利要求6的应用，其中持续时间至少为30天。
8.权利要求6的应用，其中持续时间至少为30天。
9.前面任一权利要求的应用，其中相对于右旋丁哌卡因，左旋丁哌卡因至少占对映体的90％。
CN94193775A 1993-10-13 1994-10-13 应用左旋丁哌卡因治疗慢性疼痛 Expired - Lifetime CN1074919C (zh)

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DK0723444T3 (da) 1997-12-29
US5955479A (en) 1999-09-21
JPH09503777A (ja) 1997-04-15
AU7859394A (en) 1995-05-04
KR100343314B1 (ko) 2003-02-19
NO961478D0 (no) 1996-04-12
GR3024787T3 (en) 1998-01-30
ES2105766T3 (es) 1997-10-16
CA2173208C (en) 2007-01-30
HK1006421A1 (en) 1999-02-26
WO1995010276A1 (en) 1995-04-20
NO309304B1 (no) 2001-01-15
AU692477B2 (en) 1998-06-11
DE69403969D1 (de) 1997-07-31
GB9321061D0 (en) 1993-12-01
DE69403969T2 (de) 1997-11-20
NO961478L (no) 1996-06-11
CN1074919C (zh) 2001-11-21
EP0723444B1 (en) 1997-06-25

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