| Part Ⅰ Study on continuous low-dose dexmedetomidine combined with morphine controlled intravenous analgesia to treat cancer pain patients with opioid tolerance and difficulty eatingObjective: To evaluate the efficacy of treatment plan which use continuous low-dose dexmedetomidine combined with morphine controlled intravenous analgesia to treat cancer pain patients following opioid intolerance and difficulty eating.Methods: We choose 60 patients with moderate to severe cancer pain accompanied by oral medication difficulties and who had poor pain control admitted to our hospital rom January 2015 to June 2017.After Ethics committee review approval,the patients were randomly divided into two groups,30 patients in each group.Group M: morphine injection 200 mg,diluted with physiological saline to 200 ml,and then added the self controlled analgesia pump.Group DM: morphine injection 200mg& dexmedetomidine 600 μg,diluted with physiological saline to 200ml。Patients of two groups were added pain titration using intravenous PCIA(patient controlled intravenous analgesia)on the basis of the original narcotic analgesics.Application of electronic analgesic pump,using the "background infusion + patient control" model for infusion,locking time 15-20 minutes.Pain assessment was performed using NRS(numerical rating scale).Two groups of patients began to take small doses of titration to control pain,routine choice was background infusion0.5-1ml/h and patient controlled 0.5-1ml/h.Effective control interval was 15 min.Patients with severe pain and long-term using high dose of analgesics may be appropriate to increase the background infusion and control dose per hour,but the background infusion dose is generally not more than 5% of 24 hours dose previous,the total dose within 1 hours of not more than 20%.Pain control was assessed every two hours,if the pain is poorly controlled or the number of ineffective compressions per hour is excessive,the background infusion dose and the single controlled dosage are gradually increased until the patient is satisfied with pain control。 Comprehensive assessment of pain was performed at 24 hours and 72 hours.If the patients pain was controlled within 72 hours,the pain score is less than 3,the outbreak of pain is less than 3 times daily,and pain can quickly alleviate by patient-controlled analgesia,pain control of patients is considered successful,we can continue to maintain the dose of intravenous PCA for pain control.If the patient did not reach the goal of pain control or had adverse reactions(pain,nausea,vomiting,constipation,drowsiness or delirium)which can not be tolerated with 72 hours,then we consider the patients were not sensitive on pain control drugs,so we can use minimally invasive analgesia(such as spinal nerve damage,celiac plexus block,subarachnoid infusion pain etc.)for pain control.All patients were given nutritional support treatment,and symptomatic treatment.Efficacy evaluation: The dosage of morphine and dexmedetomidine,the degree of pain relief(NRS score)and patient satisfaction were recorded in the 2 groups before and after treatment following 1 day,3 days and 1 month,the curative effects of the 2 groups were compared.Adverse reaction evaluation: The adverse reactions such as constipation,nausea,vomiting,dysuria,hallucinations,pruritus,lethargy,respiratory depression,myoclonus,hypotension,hypertension and bradycardia were recorded before and after treatment following 1 day,3 days and 1 month,the incidence rates of the 2 groups were compared.Quality of life assessment: appetite,sleep,mental fatigue,daily life of patients were assessed by digital scoring,The score difference between the two groups was compared.Statistical analysis using SPSS19.0 statistical software,measurement data using (?)±s representation,Assessment the statistical difference in pain scores,quality of life,patient satisfaction before and after analgesia by repeated measures analysis of variance.Incidence of adverse reaction between two groups was compared using pearson chi square test or Fisher exact probability test,the difference was statistically significant with P < 0.05.Results: 1.Analgesic effect Of the 60 patients,55 achieved analgesia after 3 days,of which 51 patients achieved the analgesic target within 1 days,and the total effective rate was 91.7%.There were 5 patients who did not achieve analgesia,the pain was controlled satisfactorily by adding minimally invasive analgesia(3 cases of celiac plexus damage and 2 cases of subarachnoid space infusion).1 month after treatment,there were 3 patients died because of the progress of the disease,including 2 cases in group M and 1 cases in group DM,and 1 case was excluded because of intestinal obstruction in group DM.In the remaining 56 patients,51 patients received satisfactory results after patient-controlled analgesia,and 5 patients treated with minimally invasive methods were also satisfied with the pain control.Comparison intra-group: 3 days and 1 month after patient-controlled analgesia,the pain scores of the two groups were significantly lower,the quality of life and patient satisfaction were significantly improved,but the effective dose of morphine was also significantly higher,the difference was statistically significant(P<0.01)than before treatment.1 month after patient-controlled analgesia,The dosage of morphine consumption increased further,but the pain score increased slightly,and the difference was statistically significant,(P<0.05)than 3 days after patient-controlled analgesia.Comparison between groups: There was no significant difference in pain score,quality of life and patient satisfaction between the two groups,P>0.05,before and 3 days and 1 month after patient-controlled analgesia.The effective dose of morphine between the two groups was not statistically significant before treatment,but 3 days and 1 month after patient-controlled analgesia,the effective doses were of morphine were(178±47)VS(141±36)mg and(235±54)VS(187±41)mg between group M and group DM,and the effective dose of morphine in group DM was significantly lower than that in group M,and the difference was statistically significant(P<0.01).2.Incidence of adverse reaction Comparison intra-group:In group M,the number of drowsiness cases and the number of constipation cases increased significantly after 3 days and 1 month of PCA treatment than before PCA treatment,the difference was statistically significant(P<0.05).In group DM,the number of somnolence cases increased obviously after 3 days and 1 month of PCA treatment than before PCA treatment,the difference was statistically significant(P<0.05).After PCA treatment,although the number of cases has increased with adverse reactions such as nausea,vomiting,drowsiness,itching,and hallucinations,myoclonus and other complication than before PCA treatment,but the difference was not statistically significant difference(P>0.05).Comparison between groups: there was no statistically significant differences(P>0.05)in adverse effects such as constipation,nausea,vomiting,dysuria,somnolence,hallucinations,and myoclonus between M and DM groups.However,the number of patients with somnolence after PCA treatment in group M was relatively less than that in group DM,and the patients with constipation,nausea,hallucination and myoclonus were more than those in group DM.There were no hyperalgesia,respiratory depression,and blood pressure changes in the two groups.Conclusions: 1.Intravenous self-controled analgesia can be used on cancer pain patients with opioid tolerance and oral medication difficulties,which can not only relieve the patients with persistent pain,also can well control the outbreak of pain,improve the life quality of patients,and patients with sleep,appetite,mental state and daily life were improved obviously.2.Long term continuous low-dose dexmedetomidine combined with morphine can reduce the dosage of morphineini in cancer pain patients with opioid tolerance,.It can reduce incidence of hallucinations,myoclonus and other adverse reactions in the patients without increasing the associated adverse reactions.Part Ⅱ Study on the effect of continuous low dose intrathecal injection using dexmedetomidine on cancer pain patients with opioid tolerance using intrathecal analgesiaObjective: To investigate the effect of intrathecal analgesia by continuous low dose intrathecal injection using dexmedetomidine on morphine tolerance in patients with cancer pain,evaluate the safety and efficacy of long time intrathecal application of dexmedetomidine,looking for better treatment options for the treatment of pain in patients with opioid tolerance.Methods: We choose 60 patients into the study who underwent intrathecal analgesia with intractable cancer pain in our hospital from January 2014 to June 2016,the study protocol was approved by the medical ethics committee of Henan Cancer Hospital agreed.Establish intravenous administration rout preoperative,using intrathecal analgesic system from the French SOPHYSA company.Patients were randomly divided into two groups,30 patients in each group,100mg/100 ml morphine in group M,,300 ug dexmedetomidine & 100mg/100 ml morphine group DM for analgesia.The initial analgesia was single injection of 0.5ml,and the interval was 30 min.If the daily dose is greater than 2.5ml,the continuous dose is 0.1ml/h and 0.5ml the single injection,the interval was also 30 min.The use of opioids in the spinal canal began with 50% doses,gradually decreased,and ceased to be applied at last.The dose of oral morphine was recorded before analgesia and after 7 days& 1 month using intrathecal analgesia,the dose of intrathecal morphine and dexmedetomidine,pain score,quality of life score and patient satisfaction were recorded on the same time.The curative effect was compared between the two groups before and after treatment.Simultaneous,to monitor and record adverse events and types of adverse events and comparing incidence of adverse reactions before and after treatment in the two groups and in each group.Statistical analysis using SPSS19.0 statistical software,measurement data using (?)±s representation,Assessment the statistical difference in pain scores,quality of life,patient satisfaction before and after intrathecal analgesia by repeated measures analysis of variance.Incidence of adverse reaction between two groups was compared using pearson chi square test or Fisher exact probability test,the difference was statistically significant with P < 0.05.Results: 1.The analgesic effect: Comparison between groups: There was no significant difference in pain score,quality of life and patient satisfaction between the two groups before operation and after 7 days&1 month operation(P>0.05).There was no significant difference in the effective dose of morphine between the two groups before operation.However,the effective dose of morphine in the DM group was significantly lower than that in the D group after 7 days&1 month operation(P<0.01).Comparison intra-group: the pain scores of the two groups were significantly decreased and the quality of life and patient satisfaction improved significantly.The effective dose of morphine was significantly lower than that before the operation(P<0.01).2.The incidence of adverse reactions Comparison intra-group: The incidence of adverse events was constipation(73%),followed by nausea(47%),vomiting(33%),lethargy(20%),dysuria(13%),and hallucinations(10%)before the operation.The incidence of constipation,nausea and vomiting in two groups was significantly lower after 7 days&1 month operation than that before operation(P<0.05),there were no statistically significant differences in hallucination and sleepiness before and after operation(P>0.05),but the number of cases was lower than that before operation,and the number of drowsiness in group M was less.The incidence of dysuria was not significantly reduced(P>0.05).Although the skin pruritus was unprecedented increase in the number,but the difference was not statistically significant(P>0.05);There were 1 cases with mild myoclonus and no myoclonic in MD group M before operation.Some patients had myoclonus in the M group and the MD group,and the symptoms were severe after operation.Comparison between groups: At the same time,the M and MD groups had no statistically significant differences in adverse events such as constipation,nausea,vomiting,dysuria,somnolence,hallucinations,and myoclonus(P>0.05),but the patients with somnolence in group M were less than those in group MD,and the patients with constipation and myoclonus were more than those in group MD.There were no hyperalgesia,respiratory depression,and marked changes in blood pressure in the two groups.Conclusions:1.Intrathecal analgesia can effectively control pain and reduce adverse reactions in patients with morphine tolerance and poor analgesic efficacy or intolerable adverse reactions;2.Continuous low-dose intrathecal dexmedetomidine can reduce the dose of intrathecal morphine,and reducing the serious adverse effects associated with excessive use of intrathecal morphine.Part Ⅲ Study on opioid related gene polymorphisms in cancer pain patients with opioid tolerance using high dose opioidObjective: To investigate the relationship between opioid related gene polymorphisms and opioid tolerance in cancer pain patients using high dose opioid.Methods:20 cases of cancer pain patients with opioid tolerance as the experimental group(opioid tolerance and using high dose opioid group,A group)who were hospitalized in Henan Cancer Hospital and were treated with high doses of opioid drugs from June 2016 to June 2017.In the same period,30 patients with stage IV tumors who were treated with chemotherapy without pain in Henan Cancer Hospital were selected as control group(B group).Peripheral blood DNA extraction of Two groups of patients and detection gene SNP polymorphism of nine opioid receptor gene which most likely related to opioid tolerance and using high dose opioid of cancer patients,SNP sites detected were rs1799971,rs754891060,rs200637194,rs1045642 rs7439366,rs2242480,rs7438135,rs1080985,rs529520,rs581111,rs2234918,rs4680,rs6276,rs3732765,and rs9859538,which located in gene OPRM1、ABCB1、UGT2B7、CYP3A4、CYP2D6、OPRD1、COMT、DRD2 and P2RY12.Statistical analysis using SPSS19.0 statistical software and EXCEL,measurement data using (?)±s representation,The statistical difference in the distribution of demographic characteristic between two groupss,such as age,sex,and location of primary tumor was analyzed by using two independent samples t-test,pearson chi square test and Fisher exact probability test.The statistical difference of genotype frequency distribution between the pain group and the control group was analyzed by using chi square test and Fisher exact probability test.The association of different genotypes of SNP loci with pain risk in cancer patients was evaluated using single-factor non-conditional logistic regression analysis(OR&95%CI),the difference was statistically significant with P < 0.05.Results: 1.The different genotypes of rs7438135 loci in UGT2B7 gene were statistically different between the opioid tolerance with high dose opioid group and the control group(P=0.004).2.The different genotypes of the rs3732765 locus of P2RY12 gene in the opioid tolerance with high dose opioid group were different from those in the control group,and were statistically significant(P=0.05).3.Related SNP locus association analysis showed that carrying rs7438135 GA genotype in cancer patients is 6.19 times of carrying AA genotype with the risk of opioid tolerance with high dose opioid group.Conclusions: 1.rs7438135 polymorphism of UGT2B7 gene may be closely related to opioid tolerance in cancer pain patients using high doses of opioid.Cancer patients with the rs7438135 genotype of the GA locus are 6.19 times more likely to develop into opioid tolerance with high doses of opioid than those carrying AA genotypes.2.The relationship between the rs3732765 locus of P2RY12 gene polymorphisms and opioid tolerance in cancer pain patients using high doses of opioid is uncertain.We needed further studies to investigate.3.13 SNP loci polymorphism from OPRM1,ABCB1,CYP3A4,CYP2D6,OPRD1,COMT,and DRD2 gene,may be unassociated with opioid tolerance in cancer pain patients using high doses of opioid.The conclusion needs further study. |
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