| Objectives:To evaluate the efficacy and safety of acupuncture in treatment of Chemotherapy induced peripheral neuropathy.Background:Chemotherapy induced peripheral neuropathy(CIPN)is one of the most common dose limiting adverse events of chemotherapeutic agents and is described as injury to the peripheral nervous system due to neurotoxic chemotherapeutic agents such as platinium compounds,taxanes,vinca alkaloids,bortezomib and thalidomide.The incidence rate of toxicity due to chemotherapy is estimated to be more than 60%.The overall incidence rate of CIPN in patients,who treated with multiple agents has been reported to be 38%,although this percentage is different according to chemotherapy regimens,duration of therapy and assessment methods.According to the type and intensity of sensory,motor and autonomic nerves that are influenced,symptoms of CIPN are different,but most symptoms of CIPN are sensory and contain numbness,tingling,shooting and burning pain in the toes and fingers,that can progress proximally in a glove and stocking type distribution.CIPN has two significant aspects,it can cause to decrease quality of life and deterioration in function and also lead to dose reduction or early termination of treatment.The pathophysiological mechanism of CIPN hasn’t been totally discovered.Usually,neurotoxic drugs can induce axonal poly neuropathy in different ways,by damaging microtubules,by interfering with microtubule-related axonal transport,by causing disability of mitochondrial,by making changes in release of pain mediators such as growth factors,cytokines,and ion channels,and also with cytotoxic effects on DNA.Pathogenesis of CIPN according to TCM is deficiency of qi and blood,qi stagnation and blood stasis that lead to malnourishment of tendon and vessel and also stasis in channels and collaterals.Although chemotherapy induced nausea,vomiting and neutropenia have been treated because of improvement in cancer supportive care,but treatment of CIPN is remained as a challenge.The first step for the non-pharmacologic treatment of CIPN is dose and treatment timing reduction,although this method is effective in reducing the severity of CIPN but can affect the treatment and cause disease aggravation.Improvement of pain and paresthesia are the purpose of current treatment of CIPN.Tricyclic antidepressants(TCA)and membrane stabilizing drugs like carbamazepine and gabapentin are relatively effective.These drugs not only have severe side effects such as dry mouth,cardiac complication,postural hypotension and sedation but also symptoms recur after discontinuation of treatment.The efficacy of new treatment such as neurotrophic growth factors,insulin-like growth factor,glutamate and alpha-lipoic acid hasn’t been proven.Acupuncture has been used as an effective treatment for chemotherapy induced nausea and vomiting,fatigue,anxiety,depression and insomnia.Moreover,it has also been used for treatment of diabetic peripheral neuropathy and HIV related peripheral neuropathy.The possible effect of acupuncture on treatment of CIPN has been increasing in recent years with some researches,but they reported different findings about the effectiveness of acupuncture in treatment of CIPN and its efficacy had not been proven yet with the comprehensive study.Moreover,treatment of CIPN is often a significant problem in the management of patients with cancer.Although,there are different therapeutic methods for peripheral neuropathy due to chemotherapy but their effect,application mode and availability are different.The aim of current study is to evaluate the efficacy and safety of acupuncture in treatment of CIPN.Methods:Setting:The study is a pilot randomized controlled trial,that was conducted with cooperation between Beijing University of Chinese Medicine(BUCM),China and Tehran University of Medical Science(TUMS),Iran,from March 2017 until March 2018.Patients:Patients with CIPN were chosen in Imam Khomeini hospital in Iran and Dongzhimen hospital in China.After the initial screening evaluation,patients were enrolled in the study if they met all of the inclusion criteria and were excluded if they had any of exclusion criteria.The number of 46 patients were recruited in this study.Three patients were excluded due to history of diabetes,1 due to multiple sclerosis,2 due to have symptoms of CIPN less than 3 months.Finally,40 patients were enrolled in this study.Inclusion criteria of this study included patients with age between 18 and 70 years,who have received neurotoxic chemotherapy(at least one complete course)and have experienced symptoms of chemotherapy induced peripheral neuropathy for more than three months and peripheral neuropathy confirmed by Nerve Conduction Study(NCS)and had scores>4 on 10 on Numerical Rating Scale(NRS)and accepted and signed an informed consent form.Patients also should not use medication like Tricyclic antidepressants(TCA),calcium channel blocker and membrane stabilizing drugs for prevention or treatment of the neuropathy at least for one month before enrollment,and exclusion criteria included history of disease that cause neuropathy such as diabetes,multiple sclerosis,HIV,Parkinson,the presence of peripheral neuropathy or history of peripheral neuropathy because of any cause except of chemotherapy,severe dysfunction of heart,kidneys and liver,alcohol abuser,pregnancy,psychologic disease,currently neurotoxic drug use except of chemotherapy,and unwilling to complete this study because of any reason.The clinical trial followed the ethical principles and approval obtained from the human research ethics committee in Iran and China.All participants should be signed an informed consent form before enrollment and could exit from this study at any time.Randomization:Forty patients were randomly divided into 2 groups(acupuncture group and vit B1 and gabapentin group)by block randomization with ’blockrand’ package in R software(Version 3.3.3)by a blind statistician who hadn’t involved in the intervention phase of the study.Interventions:In acupuncture group,treatment was done three times per week for four weeks.Two groups point was used including local points and general points:Qihai(CV 6),Baihui(GV 20),Bilateral Zusanli(ST 36),Sanyinjiao(SP 6),Hegu(LI 4),Quchi(LI 11),Taichong(LR 3)as general points and bilateral Bafeng(EX-LE10)and Baxie(EX-UE9)as local points.In patients with CIPN symptoms,in lower extremities only Bafeng,and in upper extremities only Baxie were used and patients with CIPN symptoms in the upper and lower extremities were treated with the combination of these two points.Additional individualized points were used,if needed according to patient symptoms,including Tianshu(ST 25),Waiguan(SJ 5)and Zhaohai(KI 6)for constipation,Neiguan(PC 6)and Zhongwan(CV 12)for vomiting,Sishencong(EX-HN1)and Shenmen(HE 7)for insomnia.In general points,reinforcing technique was used for Qihai(CV 6),Zusanli(ST 36),Sanyinjiao(SP 6),Baihui(GV 20),reducing technique for Hegu(LI 4),Quchi(LI 11)and even technique for Taichong(LV 3),and for local point reducing technique only was used.After using alcohol for local skin sterilization,disposable streel filiform needles(0.25×0.40 mm)were inserted perpendicularly with proper needling manipulation to induced de qi(arrival of qi),after de qi the needles were retained for 20 minutes.In control group,the treatment consisted of one tablet vit B1 300 mg and three capsule gabapentin 300 mg per day for four weeks.Outcome measures:To determine efficacy,patients were evaluated according to both subjective and objective outcome measurements.The primary outcome measure was Numerical Rating Scale,which were evaluated at baseline,at 10th days of treatment,at the end of treatment and four weeks after the end of treatment.The secondary outcome measurements were National Cancer Institute-Common Toxicity Criteria for Adverse Events(NCI-CTCAE)neuropathy grading scale,NCS and patient global satisfaction of treatment.Patients were evaluated at baseline,at 10th day,at the end of treatment and 4 weeks after the end of treatment with NCI-CTCAE neuropathy grading scale.NCS is a non-invasive,objective and quantitative parameter of peripheral nerve function,which is used for neurophysiological assessment of CIPN and was carried out before and after treatment.Patient global satisfaction of treatment was done at the end of treatment and four weeks after the end of treatment.For safety,in acupuncture group all patients were assessed for signs and/or reports of excessive bruising,local persistent pain and evidence of bleeding after each acupuncture session,and all adverse events that were reported by patients and researchers were recorded in both groups and monitored till its resolution.Subjective and objective evaluation were performed by blinded specialists who were not aware of the allocation of patients.Statistical analysis:Statistical analysis was performed by using SPSS statistical software(Version 20.0,IBM)by statistician,who was blinded from the allocation of groups.Baseline demographic and clinical characteristics of participants were shown as mean and standard deviation for numerical variables and as frequencies and percentages for categorical variables.Independent samples and Chi-Square tests were used for analyzing the baseline data.The normal distribution of data and equality of variances were investigated by using Kolmogorov-Smirnov Z and Box’s tests respectively.P value more than 0.01 was considered as normal distribution or equality of variances.Paired samples test was used for assessment of data in each group and independent samples test and analysis of covariance were used for evaluation of data between 2 groups.Non-parametric Wilcoxon and Mann-Whitney U tests were used for the data that have not normally distributed.P value lower than 0.05 was considered as statistically significant in this study.Results:A total of 40 patients,who met the eligibility criteria were randomized into 2 groups.Two patients stopped treatment during this study for the following reasons:One patient in vit B1 and gabapentin group due to side effect of gabapentin including somnolence and dizziness and one patient in acupuncture group for individual reasons.Therefore,data of 38 patients who completed the treatment and evaluation were included in the analysis.Among 38 patients who completed study,there were 23(60.5%)female and 15(39.5%)male,with the mean age of 57.95±10.39 years old in acupuncture group and 58.79±8.36 years old in vit B1 and gabapentin group.According to cancer type 18(47.4%)patients had breast cancer,16(42.2%)colorectal cancer,1(2.6%)lung cancer,1(2.6%)ovarian cancer and 2(5.3%)prostate cancer.Twenty(52.7%)patients had been treated with Taxanes,16(42.1%)with platinum compounds and 2(5.3%)with combination of taxanes and platinum compounds.The mean duration since neuropathy onset was 7.32±6.17 months and the mean number of chemotherapy courses was 7.50±2.30.Most common symptoms of CIPN were paresthesia(100%),numbness(94.7%),pain(71.1%)and subjective impairment in walking(13.2%).The mean of initial NRS and neuropathy grade were 6.89±1.48 and 2.13±0.34 respectively.There was no significant difference between 2 groups about baseline characteristics of randomized subjects(P>0.05).Reduction of NRS indicates reduction of symptoms severity and relieving CIPN.Within-group comparison showed that NRS significantly decreased from 7.00±1.53 at baseline to 5.37±1.64 at 10th day of treatment and to 3.47±1.61 at the end of treatment in acupuncture group(P<0.001);and from 6.79±1.47 at baseline to 6.32±1.38 at 10th day of treatment and to 5.16±1.26 at the end of treatment in vit B1 and gabapentin group(P<0.05).Compare to vit B1 and gabapentin,acupuncture was significantly more effective to decrease NRS after 10 days of treatment(5.37±1.64 vs 6.32±1.38,P<0.001)and 4 weeks of treatment(3.47±1.61 vs 5.16±1.26,P<0.001).Within-group comparison showed that NRS significantly increased from 3.47±1.61 at the end of treatment to 3.68±1.67 one month after the end of treatment in acupuncture group(P<0.05)and from 5.16 ±1.26 at the end of treatment to 5.79±1.32 one month after the end of treatment in vit B1 and gabapentin group(P<0.001).However,between-group comparison showed that there was significant difference between acupuncture group and vit B1 and gabapentin group about NRS between after treatment and 1 month after the end of treatment(P<0.05),indicating worsening the symptoms was more significant in vit B1 and gabapentin group.Reduction of NCI-CTCAE neuropathy grade indicates reduction of CIPN severity.Within-group comparison showed that the NCI-CTCAE neuropathy grade was significantly decreased from 2.16±0.37 at baseline to 1.84±0.60 at 10th day of treatment and to 1.37±0.68 at the end of treatment in acupuncture group(P<0.05 and P<0.001,respectively);and from 2.11±0.32 at baseline to 1.84±0.60 at the end of treatment in vit B1 and gabapentin group(P<0.05),but there was no significant difference after 10 days of treatment compare to before treatment in vit B1 and gabapentin group(2.05±0.40 vs 2.11 ±0.32,P>0.05).Between-group comparison showed that there were significant differences between acupuncture group and vit B1 and gabapentin group about NCI-CTCAE neuropathy grade after 10 days of treatment(1.84±0.60 vs 2.05±0.40,P=0.039)and 4 weeks of treatment(1.37±0.68 vs 1.84±0.60,P=0.003),indicating acupuncture is more effective than vit B1 and gabapentin to decrease NCI-CTCAE neuropathy grade after 10 days and 4 weeks of treatment.Within-group comparison showed that there were no any significant changes in the NCI-CTCAE neuropathy grade between after treatment and 1 month after the end of treatment in acupuncture group(1.37±0.68 vs 1.42±0.69,P=0.317)and in vit Bland gabapentin group(1.84±0.60 vs 2.00±0.47,P=0.083).Between group comparison also showed that the difference of NCI-CTCAE neuropathy grade between after treatment and one month after the end of treatment between 2 groups was not significantly different(P>0.05),indicating both method had long-term effect on NCI-CTCAE neuropathy grade.Reduction of onset latency in NCS indicates positive treatment result with improvement of changes in myelin sheaths.Within-group comparison showed that onset latency of sensory and motor nerves(except sural nerve)significantly decreased after treatment compare to before treatment in acupuncture group(P<0.05),while there was no obvious change in vit B1 and gabapentin group(P>0.05).Between group comparison showed that there was significant difference in onset latency of bilateral median and ulnar sensory and motor nerves between acupuncture group and vit B1 and gabapentin group after 4 weeks of treatment(0.05),but there was no significant difference in onset latency of bilateral sural sensory nerve and bilateral peroneal and tibial motor nerves after 4 weeks of treatment between 2 groups(P>0.05),indicating acupuncture is more effective than vit B1 and gabapentin to decrease only onset latency of bilateral median and ulnar sensory and motor nerves.Increase of amplitude in NCS indicates positive treatment result with improvement of axonal damage.Within-group comparison showed that amplitude of bilateral sural,median and ulnar sensory nerves and peroneal,tibial,median and ulnar motor nerves increased significantly after treatment compare to before treatment in acupuncture group(P<0.05),while there were no significant changes in vit B1 and gabapentin group(P>0.05).Between-group comparison showed that the effect of 2 therapeutic methods on the amount of amplitude of the bilateral sural,ulnar and median sensory nerves and bilateral median,ulnar and tibial motor nerves was significantly different after 4 weeks of treatment(P<0.05),indicating acupuncture was significantly more effective than vit B1 and gabapentin group to increase amplitude of sensory and motor nerves(except peroneal nerve)after 4 weeks of treatment.Increase of NCV indicates positive treatment result with improvement of myelin sheaths injury.Within-group comparison showed that the NCV of bilateral sural,median,ulnar,peroneal and tibial nerves significantly improved after treatment compare to before treatment in acupuncture group(P<0.05),while there were no significant changes in vit B1 and gabapentin group(P>0.05).Compare to vit B1 and gabapentin,acupuncture showed better effects of improvement of bilateral median,ulnar,peroneal and tibial NCV after 4 weeks of treatment(P<0.05),but there was no significant difference between 2 groups in NCV of bilateral Sural nerve after 4 weeks of treatment(P>0.05),indicating acupuncture was significantly more effective than vit B1 and gabapentin to increase NCV of sensory and motor nerves(except sural nerve)after 4 weeks of treatment.Higher patient global satisfaction of treatment indicates positive treatment result on CIPN.Between-group comparison showed that there were significant differences between acupuncture group and vit B1 and gabapentin group about patient global satisfaction of treatment at the end of treatment(3.31±0.82 vs 2.47±0.96,P=0.006)and 1 month after the end of treatment(3.21±0.85 vs 2.10±0.87,P=0.000),indicating satisfaction of treatment in acupuncture group was higher than vit BI and gabapentin group in each time point.Within-group comparison showed that there was no significant difference in patient global satisfaction of treatment 1 month after the end of treatment compare to after treatment in acupuncture group(3.21±0.85 vs 3.31 ±0.82,P=0.163),while patient global satisfaction of treatment significantly decreased 1 month after the end of treatment compare to after treatment in vit B1 and gabapentin group(2.10±0.87 vs 2.47±0.96,P=0.005).There were no adverse events related to acupuncture treatment during this study.But 1 patient in vit B1 and gabapentin left the study due to side effect of gabapentin including somnolence and dizziness.Therefore,acupuncture is a safe way in treatment of CIPN.Conclusion:Our study revealed that acupuncture as a kind of Traditional Chinese therapeutic method is significantly effective and safe in treatment of CIPN,moreover acupuncture is more effective than gabapentin and vit B1 as the conventional treatment.According to our results,acupuncture had effects shortly after starting the treatment and quicker than gabapentin and vit B1,and also provide a longer term effect than gabapentin and vit B1 for treatment of CIPN after the treatment sessions was over.Further large randomized controlled trials with long-tenn follow up,in the future are needed,to validate beneficial effect of acupuncture in treatment of CIPN and find whether the effect are persistence. |
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