| Background:The pain caused by bone metastasis is one of the main reasons that affect the qual ity of life of patients with advanced tumor.Although radiotherapy,bone protection therapy and three-step analgesia have achieved certain clinical effects,there are still a considerable number of patients with pain from bone metastases has not been effectively relieved.And the treatment is accompanied by a series of problems,such as opioid resistance,physical and psychological dependence,respiratory depression,vomiting and constipation caused by opioids and gastrointestinal ulcers caused by nonsteroidal anti-inflammatory drugs.As an effective supplement of three-step analgesic,traditional Chinese medicine attaches equal importance to pain relief and tumor suppression,considers both the whole and the local,gives full play to its advantages of small toxic and side effects,and plays an important role in the treatment of pain from bone metastases.After long-term clinical practice,Professor Duan Fengwu,a famous old doctor of traditional Chinese medicine in our department,developed Xiaozheng Zhitong prescription for external use in the treatment of cancer pain,which has been used as a hospital preparation in Guang’anmen Hospital.Previous studies have shown that Xiaozheng Zhitong prescription combined with three-step analgesic has a good clinical effect in the treatment of all kinds of cancer pain,and the side effects are small.Basic experiments suggested a good prospect for the treatment of pain from bone metastases.However,the traditional dosage form of Xiaozheng Zhitong prescription is powder,and there are some problems in the process of use,such as complicated operation,not easy to fix,poor comfort of patients,limited application site and frequency,difficult to preserve,low transdermal rate and so on.In order to overcome the above shortcomings,this study used the gel form of Xiaozheng Zhitong prescription to carry out a randomized controlled clinical study on the treatment of pain from bone metastases and the experimental study of its related mechanism.Purpose:1.Based on the needs of clinical practice,research was carried out on the application of Xiaozheng Zhitong gel alone or combined with three-step analgesic in the treatment of pain from bone metastases of various pain levels,so as to clarify its clinical practical value in the treatment of pain from bone metastases.2.The specific molecular mechanism of Xiaozheng Zhitong gel in the treatment of pain from bone metastases was explored by using the mouse model of femoral cancer pain,so as to provide a new target for the treatment of pain from bone metastases by Chinese medicine.Methods:1.The clinical study was an open-label randomized controlled trial.Patients with metastatic pain from bone metastases who were hospitalized in the Oncology Department of Guang ’anmen Hospital,China Academy of Traditional Chinese Medical Sciences from January 2021 to January 2022 were enrolled according to the inclusion criteria after informed consent.After the running-in period,stratified randomization was performed according to whether they used three-step analgesic or not.On the basis of routine anti-tumor treatment,the control group applied or abandoned the three-step analgesic treatment according to the subjective needs of the patients,and the Xiaozheng Zhitong gel group was treated with Xiaozheng Zhitong gel on the basis of the control group and observed for one week.The primary outcome measures were the effectiveness of the most severe pain and average pain.Secondary indicators included changes in the most severe pain,average pain,minimum pain and breakout pain,changes in the impact of pain on daily living functions,changes in the demand for three-step analgesics,tolerance and adverse reactions of Xiaozheng Zhitong gel.In the study,we filled in the case report forms,established a database,and collected the information of patients’ general condition,medical history,medication,therapeutic effect,adverse reactions and so on.SPSS25 and Stata15 software were used for statistical analysis to evaluate the clinical efficacy and adverse reactions of Xiaozheng Zhitong gel in the treatment of pain from bone metastases.2.In the laboratory study,the mice were randomly divided into control group,pain from bone metastases group and Xiaozheng Zhitong gel group,and the femoral cancer pain model was established.Xiaozheng Zhitong gel group was treated with Xiaozheng Zhitong gel to the skin of mouse femur twice a day for 21 days.Mice were weighed every 3 days and PWL was tested to reflect changes in thermal pain sensitivity and PWT to reflect changes in mechanical pain sensitivity.The destruction of bone structure was detected by X-ray photography and micro-CT.The BMD and BMC of femur in mice were detected by dual energy X-ray absorptiometry.Bone tissue changes were detected by HE staining of femur.The expression levels of TNF-α and uPA in serum and bone tissue were detected by ELISA.The expressions of TNF-α,uPA and p-p65 in bone tissue were detected by immunohistochemical method.The relative RNA contents of PAR2,PKC y,PKA and TRPV1 in DRG were detected by PCR.The protein expression levels of TNF-α,TNFR1,TRADD,RIP,TRAF2,P-IKK β,IKKβ,P-P65,P65 in bone tissues and PAR2,PKC-y,PKA and TRPV1 in DRG were detected by Western blot.Results:1.A total of 103 patients were included in the clinical trial,52 cases in Xiaozheng Zhitong gel group,51 cases in the control group,and 3 shedding cases in each of the two groups.Under the condition of balanced baseline data such as demography,basic medical history,pain degree,the effect of pain on life function and breakout pain,whether combined with three-step analgesic or not,the effective rate of the most severe pain and the average pain of the patients with pain from bone metastases in Xiaozheng Zhitong gel group was significantly better than that in the control group,and the difference between the two groups was statistically significant(P<0.05).Moreover,the significant advantage in the most severe pain had nothing to do with the site of bone metastasis,gender,or age.The effective rate for the most severe pain in patients with pain from bone metastases such as stasis pain,phlegm-dampness pain and qi pain were significantly better in the Xiaozheng Zhitong gel group than in the control group.And the effective rate in the cold pain,heat pain,deficiency pain and wind pain in the Xiaozheng Zhitong gel group was also higher than that in the control group,but there was no significant difference between the two groups.In the Xiaozheng Zhitong gel group,the most severe pain of patients with different traditional Chinese medicine syndrome types,different metastatic sites,different ages and different genders showed satisfactory effective rate,and there was no statistical difference among groups with different traditional Chinese medicine syndrome types,gender and metastatic sites.However,older patients(≥65 years old)have more significant advantages than younger patients(<65 years old).There was no significant difference in the effectiveness of Xiaozheng Zhitong gel in treating the most severe or average pain degree of mild,moderate,and severe pain from bone metastases,whether or not combined with threestep analgesia.The change trend of the most severe pain,the average pain and the lightest pain also showed that the Xiaozheng Zhitong gel group had a good analgesic effect on pain from bone metastases.The effect of pain on living function in Xiaozheng Zhitong gel group was significantly reduced,which was significantly different from that in the control group.At the same time,Xiaozheng Zhitong gel can reduce the number and the intensity of breakout pain,reduce three-ladder analgesia and so on,but this advantage was not obvious,and there was no significant difference between the two groups.2.In the basic experiment,there was no significant difference in the weight among the three groups within 21 days.Compared with the control group,the PWL and PWT in the pain from bone metastases model group were significantly lower,while the PWL and PWT in the Xiaozheng Zhitong gel group were significantly higher than those in the pain from bone metastases group(P<0.05).X-ray photography and micro-CT showed that the distal femur of the mice in the pain from bone metastases model group had severe bone structure destruction,bone mineral density was obviously uneven,accompanied by cortical bone defect and swelling of surrounding muscles and soft tissues,and the bone destruction score was significantly increased,BV/TV and Conn.D values were significantly decreased.The bone structure damage was alleviated,the bone destruction score was significantly decreased,and the BV/TV and Conn.D values were significantly increased in the Xiaozheng Zhitong gel group.The difference between groups was statistically significant.The results of dual energy X-ray absorptiometry showed that the BMC in the pain from bone metastases group decreased significantly at about the 7th day and increased slowly from the 7th day to the 21st day,while the BMC in the Xiaozheng Zhitong gel group was higher than that in the pain from bone metastases group at all time points,and the BMD in the pain from bone metastases group decreased continuously from the 0th day to the 21st day,while the Xiaozheng Zhitong gel could significantly slow down the decrease of BMD.HE staining showed that the femur tissue structure of the control group was normal,while the bone tissue structure of the pain from bone metastases group was severely abnormal,the number of bone trabeculae in the bone marrow cavity decreased,and abundant cancer cells could be seen.Xiaozheng Zhitong gel alleviated this damage,and the number of cancer cells decreased.ELISA results showed that pain from bone metastases model mice could significantly increase the levels of TNF-α and uPA in serum and bone tissue,while Xiaozheng Zhitong gel could reduce this increasing trend.The results of immunohistochemistry showed that the presence of pain from bone metastases increased the expression of TNF-α,uPA and NF-κB/p-p65 in the femur tissue of mice,and Xiaozheng Zhitong gel could effectively inhibit this increasing trend.The results of PCR showed that the mRNA expression of PAR2,PKC-y,PKA and TRPV1 in DRG was significantly up-regulated in pain from bone metastases group,while Xiaozheng Zhitong gel inhibited this increasing trend.The results of Western blot showed that Xiaozheng Zhitong gel could inhibit the increase of TNF-α,TNFR1,TRADD,RIP,TRAF2,p-IKK β,p-p65,PAR2,PKC-y,PKA and TRPV1 protein expression induced by pain from bone metastases.Conclusion:1.Xiaozheng Zhitong gel alone or combined with three-step analgesia has a good analgesic effect in the treatment of pain from bone metastases.In clinical application,it is not necessary to be limited to the degree of pain,metastatic site,gender,age or traditional Chinese medicine syndrome type,which can achieve good efficiency,and may have more advantages for elderly patients.2.Xiaozheng Zhitong gel plays a role in the treatment of pain from bone metastases through TNF-α mediated NF-κB/uPA/PAR2 pathway,which can effectively reduce thermal pain sensitivity and mechanical pain sensitivity. |
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