重度癌痛止痛的“自学自救”方案

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重度癌痛止痛的“自学自救”方案，核心要点在于：

1、联用非阿片类止痛药增强或取代阿片类止痛药

2、通过抑制p-gp蛋白等外排转运蛋白，增强阿片类药物入脑从而“减量增效”；通过抑制药物代谢酶、延长药物代谢时间等药代动力学方法对阿片类药物“减量增效”（不对普通读者展开）

3、止痛药副作用的精妙治疗

非阿片类药物止痛方案我在自学自救群讲过多次，相关文章散见于我微信公众号，今重新整理予以扩充完善。

我查找非阿片类止痛药的根本原则在于：

1、止痛迅速、效果好、副作用小

2、廉价、易得、操作简单，可及性强（真实世界很难实用诸如静脉注射碳酸氢钠+DMSO之类的止痛方案）

3、一个止痛药的副作用尽量用另外一个止痛药去治疗。

非阿片类药物“自学自救”止痛方案：奥氮平+度洛西汀+可乐定+乌司他丁+元芍止痛汤+拉帕替尼（便秘时可用）+右美沙芬（幻肢疼时用）+针灸艾灸（有条件实施者）

一、奥氮平

奥氮平是对肿瘤患者极其友好的药物，止痛、止吐止恶心、缓解焦虑、安眠、增进食欲、抑制BIRC5延缓抗癌药耐药。

1、奥氮平止痛，剂量在每天5-20毫克。

（1）《奥氮平对肺癌骨转移重度疼痛的控制效果》
“选取２０１６年５月至２０１８年１１月本院收治的５４例肺癌骨转移重度疼痛患者，依据不同就诊顺序分为对照组和试验组，每组２７例。” “对照组采用常规治疗。盐酸羟考酮缓释片（萌蒂制药有限公司生产，国药准字Ｊ２０１１００１４，１０ｍｇ）口服，起始剂量为１０～２０ｍｇ，整片吞服，２次／ｄ。根据患者实际疼痛度调整用药剂量，最大剂量为１００ｍｇ／次。连续治疗１个月。试验组采用奥氮平（江苏豪森药业股份有限公司生产，国药准字Ｈ２００１０７９９，１０ｍｇ）治疗，口服，５ｍｇ／次，１次／ｄ。连续治疗１个月。” “试验组的治疗总有效率（９６．３０％）明显优于对照组（７４．０７％），差异有统计学意义（Ｐ＜０．０５）。” “试验组的不良反应发生率（１１．１１％）明显低于对照组（３３．３３％），差异有统计学意义（Ｐ＜０．０５）。” “试验组ＮＲＳ评分、ＳＡＳ评分及ＳＤＳ评分均优于对照组，差异均有统计学意义（均Ｐ＜０．０５）。”

（2）《Decreased pain and improved quality of life in fibromyalgia patients treated with olanzapine, an atypical neuroleptic》

Therefore, this study assessed the efficacy of the atypical neuroleptic olanzapine for the treatment of fibromyalgia symptoms. To examine the efficacy of olanzapine for the treatment of fibromyalgia symptoms, the charts of 51 patients treated with olanzapine were evaluated for improvements in pain and daily life functioning. At the time of initial assessment, patients had been diagnosed with a variety of medical and psychiatric disorders and a history of neuroleptic treatment. Pain was widespread and characteristic of pain associated with fibromyalgia. Pretreatment ratings on pain and the interference scales averaged 6.54-8.69 on a 0-10 scale. Post-treatment ratings on the same scales revealed significant improvement on virtually all scales.

Only 6 patients (14.6%) required doses of at least 20 mg daily.

2、根据《Adverse effects associated with high-dose olanzapine therapy in patients admitted to inpatient psychiatric care》等论文所述，目前治疗精神疾病的医疗实践中，奥氮平的使用剂量不断加大，有些甚至达到了每天160毫克（当然副作用也是频现）。

没有查到止痛用这么高剂量的文献。是否突破20毫克的剂量，患者根据自己的耐受情况决定，时刻注意副作用。

3、奥氮平的嗜睡、体重增加等常见副作用，对已经到了重度癌痛程度的肿瘤患者来说不算个事情，毕竟不是要去开飞机和选美。需要关注和针对治疗的是低血压、胰腺炎、血栓、便秘等不常见副作用。

（1）方案中要联用度洛西汀，度洛西汀的常见副作用是高血压，两个副作用互相抵消。

（2）方案中要联用消炎药乌司他丁，乌司他丁的适应症就是治疗胰腺炎。

（3）方案中要联用元芍止痛汤，元胡、白芍都有活血作用；乌司他丁也有抗凝作用。

（4）方案中要联用拉帕替尼，拉帕替尼的最常见副作用就是腹泻，两个副作用相互抵消。

（5）需要注意的是，副作用的出现，与剂量大小并无直接关系。根据奥氮平治疗精神疾病的一些研究表明，有些患者在用5毫克小剂量时就出现了副作用，而一些患者用100毫克的大剂量也未出现副作用。个体差异所致，所以用小剂量也不应该掉以轻心。

二、度洛西汀

1、度洛西汀止痛的常用剂量在每天20-120毫克

（1）《Additive Duloxetine for Cancer-Related Neuropathic Pain Nonresponsive or Intolerant to Opioid-Pregabalin Therapy: A Randomized Controlled Trial (JORTC-PAL08)》

Patients were administered duloxetine 20 mg/day titrated to 40 mg/day or placebo for 10 days.

（2）《Preoperative Duloxetine to improve acute pain and quality of recovery in patients undergoing modified radical mastectomy: A dose-ranging randomized controlled trial》

Preoperative oral Duloxetine of 60 mg, for patients subjected to MRM is the optimal dose considering its analgesic efficacy and side effects.

（3）《Duloxetine and pregabalin in neuropathic pain of lung cancer patients》

duloxetine was used once a day with a dose of 60 mg

（4）《Duloxetine and pregabalin: high-dose monotherapy or their combination? The "COMBO-DN study"--a multinational, randomized, double-blind, parallel-group study in patients with diabetic peripheral neuropathic pain》

only nonresponders received 120 mg/day duloxetine (group 1)

2、度洛西汀的常见副作用有恶心呕吐、焦虑、食欲不振、头昏头疼、便秘腹泻、腹痛、口干多汗、高血压等等。

（1）恶心呕吐、焦虑、食欲不振、头昏头疼等副作用由方案中联用的奥氮平来治疗

（2）便秘副作用由方案中联用的拉帕替尼来治疗。

（3）腹痛副作用由方案中联用的元胡来治疗。

（4）高血压副作用由方案中联用的可乐定、奥氮平来治疗。

三、乌司他丁

1、《An Applied Study of Ulinastatin in Pain Management After Hip Replacement: Impact on Opioid Use》

Methods: A total of 108 patients undergoing elective hip replacement were randomly allocated into either the experimental group (56 cases, standard pain relief treatment plus 60 IU ulinastatin) or the control group (40 cases, standard pain relief treatment). The main outcomes measured were the total consumption of opioids at 24, 48, and 72 h postoperatively. Secondary outcomes comprised patient-reported pain indices and levels of satisfaction with pain control. The frequency of adverse events evaluated medication safety.

Results: There were no statistically significant differences in age, sex, or underlying diseases between the two groups. Over 24 hours, opioid consumption was higher in the standard treatment group (66.6 mg; mean difference [MD]: 4.43 mg; 95% CI: 57.6-75.5) than in the intervention group (54.5 mg; MD: 1.91 mg; 95% CI: 50.7-58.3). The standard treatment group exhibited a notably higher incidence of adverse reactions. However, there was no disparity in post-discharge satisfaction between the groups, with an odds ratio of 1.058 (95% CI: 0.62-1.82; P > 0.05). Additionally, significant differences in C-reactive protein levels were observed immediately and 6 h after surgery between the two groups.

Conclusion: Within 72 h post-surgery, ulinastatin was effective in substantially reducing the use of opioids while maintaining adequate pain control. Ulinastatin may be beneficial for postoperative pain management and for reducing the risks associated with opioid use.

2、根据《乌司他丁用于临床常见急危重症的专家共识》，乌司他丁常用剂量在10-60万U/次，1~4次/d，静脉滴注/静脉推注；根据患者的实际情况做调整。
3、乌司他丁有可能会出现过敏反应，可在输液前用抗组胺药。根据《Antihistamines as analgesics》等论文所述，H1抗组胺药也有止痛作用。

四、可乐定
可乐定有口服药、注射液、透皮贴多个剂型，止痛时能做鞘内注射、硬膜外注射、静脉注射、口服、外敷多种给药方式。盐酸可乐定片说明书上止痛的剂量是“3、严重痛经。口服0.025mg，每日2次，在月经前及月经时，共服14日。4、偏头痛。一次0.025mg，每日2-4次，最多为0.05mg，每日3次。”
多个口服可乐定止痛的临床试验，剂量则远超这个说明书剂量：

1、《Oral Clonidine Premedication Enhances the Quality of Postoperative Analgesia by Intrathecal Morphine》

“ the clonidine group (n = 13) received oral clonidine approximately 5 micro gram/kg”

如果患者是60公斤的话，那就要口服0.3mg的可乐定

2、《Clonidine in Heroin Withdrawal Syndrome: a controlled study in India》
This is probably because Gold et al. (1980) have used a higher dosage of clonidine (0.9-1.3 mg per day) than that of the present study。

患者可根据自身实际情况调整剂量。

五、元芍止痛汤
元胡活血,行气,止痛，性味辛,苦,温。白芍药味苦、酸,性微寒，养血敛阴、柔肝止痛。

可100克元胡+100克白芍熬煮汤药；亦可根据患者自身情况加减量。

六、拉帕替尼

拉帕替尼是her2-tki，常用于乳腺癌治疗。拉帕替尼同时是mPGES-1抑制剂，mPGES-1是一个极其重要的炎症因子。从拉帕替尼的各项临床试验中挖掘数据发现，拉帕替尼有极强的止痛作用。

《Clinical data mining reveals analgesic effects of lapatinib in cancer patients》

Microsomal prostaglandin E2 synthase 1 (mPGES-1) is recognized as a promising target for a next generation of anti-inflammatory drugs that are not expected to have the side effects of currently available anti-inflammatory drugs. Lapatinib, an FDA-approved drug for cancer treatment, has recently been identified as an mPGES-1 inhibitor. But the efficacy of lapatinib as an analgesic remains to be evaluated. In the present clinical data mining (CDM) study, we have collected and analyzed all lapatinib-related clinical data retrieved from clinicaltrials.gov. Our CDM utilized a meta-analysis protocol, but the clinical data analyzed were not limited to the primary and secondary outcomes of clinical trials, unlike conventional meta-analyses. All the pain-related data were used to determine the numbers and odd ratios (ORs) of various forms of pain in cancer patients with lapatinib treatment. The ORs, 95% confidence intervals, and P values for the differences in pain were calculated and the heterogeneous data across the trials were evaluated. For all forms of pain analyzed, the patients received lapatinib treatment have a reduced occurrence (OR 0.79; CI 0.70-0.89; P = 0.0002 for the overall effect). According to our CDM results, available clinical data for 12,765 patients enrolled in 20 randomized clinical trials indicate that lapatinib therapy is associated with a significant reduction in various forms of pain, including musculoskeletal pain, bone pain, headache, arthralgia, and pain in extremity, in cancer patients. Our CDM results have demonstrated the significant analgesic effects of lapatinib, suggesting that lapatinib may be repurposed as a novel type of analgesic.
拉帕替尼止痛没有特定剂量，可以按照正常说明书剂量来用。

拉帕替尼的最常见副作用就是腹泻，阿片类药物、奥氮平、度洛西汀等止痛药常见副作用包括便秘；副作用可相互抵消。

七、右美沙芬

如果手术截肢的肿瘤患者有幻肢痛，可以用右美沙芬止痛。

《Dextromethorphan mitigates phantom pain in cancer amputees》

Background: Hyperexcitability of N-methyl-D-aspartate (NMDA) receptors may play a role in the persistence of phantom pain. Dextromethorphan (DM) blocks NMDA receptors.
Methods: Eight cancer and two noncancer amputees with established, disabling phantom pain received oral DM 60 or 90 mg twice daily (BID) in a three-period double-blind crossover placebo-controlled trial. This followed an open-phase trial in which either dose was given three times daily if pain relief during the double-blind phase was <50% of pretreatment intensity. Patients then underwent a 3-month phase of treatment with the best regimen and a subsequent 1-month posttreatment follow-up.
Results: All patients reported a >50% decrease in pain intensity, better mood, and lower sedation in each treatment phase. Four individuals reported this level of pain relief with the 60-mg and one with the 90-mg BID regimen during the double-blind phase, whereas two amputees benefited from the 60-mg and three from the 90-mg thrice-daily regimen in the open-phase trial. One reported exacerbation of pain with the 90-mg BID regimen, and three reported pain rebound at the 1-month posttreatment follow-up phase. Three patients stopped all previous analgesic use during the study.
Conclusions: Persistent phantom pain probably involves NMDA receptor hyperexcitability because DM 120 to 270 mg/day mitigated the pain satisfactorily.

八、针灸艾灸

1、《调神止痛针刺法治疗中重度癌痛临床观察》
“穴位处方：百会、四神聪、水沟、阴郄、郄门、内关、神门、合谷、太冲、三阴交、足三里、阿是穴(在疼痛局部不超过3个),以及相应的背俞穴(如呼吸系统肿瘤取肺俞，消化系统肿瘤取脾俞、胃俞、大肠俞，乳腺癌取肝俞，胰腺癌取胃脘下俞等);并且可根据患者用药后的反应随证增加穴位，如头晕配合凤池、太阳，印堂等，恶心呕吐配合中脘、梁门、上巨虚，便秘配合支沟、天枢、大肠俞，排尿不畅或尿潴留配合水道、中极、膀胱俞。腧穴定位进针及行针手法均参照《针灸治疗学》:患者取卧位，背俞穴采取俯卧位或侧卧位，局部穴位消毒后，采用华佗牌1.5寸一次性针灸针进行针刺治疗，得气后采取平补平泻法，留针半小时，留针期间行针2次，研究期间共针刺治疗10次(每周5次，共2周),其中水沟穴向上斜刺，进针0.3～0.5寸，采用雀啄法，以眼球湿润为佳。”

2、《温阳艾灸法联合三阶梯止痛法对癌痛患者止痛效果和生活质量的影响》

取穴: 中脘、神阙、关元。方法: 嘱患者取仰卧位，医者清洁患者腹部皮肤，将艾条一段点燃，在距离患者中脘、神阙、关元穴位 2 ～ 3 cm 的高度进行熏烤，炙至局部灼热红晕为度。每次 20 min，每日 2 次。治疗过程中及时询问患者感觉，观察局部皮肤情况及有无不良反应。若患者感觉皮肤灼痛或局部出现皮疹、水泡等，应停止治疗。

[基础知识] 重度癌痛止痛的“自学自救”方案

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