A Randomized Controlled Clinical Trial on Efficacy and Safety of Electroacupuncture on Oral Oxycodone Hydrochloride Prolonged-Release Tablets Related Constipation

LI Xin (李 鑫), SUN Tao (孫 韜)

1. Shunyi Hospital, Beijing Traditional Chinese Medicine Hospital, Beijing 101300, China

2. Dongfang Hospital, Beijing University of Chinese Medicine, Beijing 100078, China

ABSTRACT Objective:To observe the efficacy and safety of electroacupuncture on oral oxycodone hydrochloride prolonged-release tablets related constipation in Qi (氣) deficiency syndrome. Methods:A randomized control trial was conducted in 44 participants, who were divided into the treatment group(electroacupuncture group) and the control group (western medicine group). Two groups were treated by electroacupuncture at Zusanli (ST36), Tianshu (ST25), Zhigou (SJ6) and Shangjuxu (ST37) acupoints every day for 20 mins for 14 consecutive days and lactulose oral solution 30 ml every day for 14 consecutive days respectively. The constipation symptoms, traditional Chinese medicine (TCM) symptoms, quality of life,physical condition before and after the treatments were observed, and the safety indicators were monitored.Results:The treatment group was better than the control group in improving constipation symptom score,improving TCM symptom score and improving quality of life score, and the difference was statistically significant. There was no significant difference between the two groups in improving physical condition score. No acupuncture related adverse events were observed in the treatment group. Two patients in the control group withdrew from the study due to taking emergency defecation therapy and mild diarrhea respectively. Conclusion:Electroacupuncture is better than lactulose in the treatment of Qi deficiency constipation related to oxycodone hydrochloride prolonged-release tablets. It can significantly improve the symptoms of constipation, improve the symptoms of TCM, improve the quality of life. It is safe and effective.

KEYWORDS Electroacupuncture; Opioids; Randomized controlled clinical trial; Constipation

BACKGROUND

Opioids is an important medicine in controlling the pain of cancer. However, opioid-induced constipation(OIC) is a common side effect caused by its clinical application. Study reported the incidence was at approximately 94%[1]. Furthermore, OIC often lasts in the whole process of medication, which affects the prolonged use of opioids and increases the suffering of patients. Therefore, it should be prevented and actively treated in whole process of cancer pain treatment.Currently, Laxatives are the first-line medicines for reducing OIC, but the high incidence of side effects[2]limits its application. Considering acupuncture has a long history in the treatment of constipation, with the advantages of quick effect, obvious curative effects,few adverse reactions and low price, we conducted a clinical study to observe the efficacy and safety of electroacupuncture on oral oxycodone hydrochloride prolonged-release tablets related constipation in Qi deficiency syndrome. The trial is reported as follows.

CLINICAL DATA

Participants and Recruitment

From June 2017 to June 2019, patients were recruited from Beijing Hospital of Traditional Chinese Medicine Shunyi Hospital. The subjects were randomly divided into the treatment group and control group for clinical research.

Inclusion Criteria

Patients were eligible for inclusion: ① They were confirmed with malignant tumors by histopathology or cytology; ② They were treated with oxycodone hydrochloride prolonged-release tablets to treat cancer pain; ③ They met the diagnostic criteria of OIC Rome IV; ④ They met the diagnostic criteria of Qi deficiency syndrome of constipation; ⑤ They were 18-85 years old; ⑥ The estimated survival time of the patients was more than 3 months; ⑦ Patients can correctly understand the content of the study and sign the informed consent.

Exclusion Criteria

Patients met one or more of the following were excluded: ① During radiotherapy and chemotherapy;② Other treatments affecting constipation are in progress; ③ There are intestinal obstruction or organic constipation caused by abnormal morphology of colon and rectum; ④ Pregnant and lactating women; ⑤ Patients with peptic ulcer and bleeding; ⑥ Patients who can't take medicine orally;⑦ Patients with severe dysfunction of heart, liver,kidney and hematopoietic system; ⑧ Patients were lactulose allergy.

Intervention and Control

Both groups received basic treatment of cancer. The intervention (treatment group) was conducted by selecting acupoints of Zusanli (ST36),Tianshu (ST25), Zhigou (SJ6) and Shangjuxu (ST37)and applying electroacupuncture for 14 days. The positioning standard was based on "acupoint name and positioning" (GB/T 12346-2006)[3]. Acupuncture was applied on one side of the body, alternately on the left or right in each time. Tianshu (ST25) and Zhigou (SJ6), and Shangjuxu (ST37) and Zusanli(ST36) were two acupoint groups connected to electroacupuncture therapy device with the sparse wave and dense wave at 2 Hz and 10 Hz. The stimulation intensity was between sensory threshold and pain threshold. Each treatment lasted 20 minutes. The control group was given lactulose oral liquid (approval number: National medicine permission number H20093524, manufacturer:Hunan Kelun Pharmaceutical Co., Ltd.), 30 mL, half an hour after breakfast each time for 14 days.

Outcomes

The outcomes include constipation symptoms,traditional Chinese medicine (TCM) symptoms,quality of life, physical condition and treatment efficacy. Constipation symptoms were evaluated according to the constipation symptom score table[4]formulated by the anorectal surgery group of Chinese Medical Association. TCM symptoms were assessed according to the guiding principles for clinical research of new drugs of TCM[5,6]. Quality of life (QOL) and physical condition were scored according to QOL of tumor patients[7]and ECOG score standard[8]. The efficacy was assessed by the efficacy evaluation formula and efficacy grading standard. They were formulated according to the consensus opinion of TCM diagnosis and treatment experts on constipation[9]published by spleen and stomach disease branch of Chinese Traditional Medicine Association. Adverse events related to laxatives and acupuncture were observed. Blood routine, liver and kidney function, fecal routine and ECG were monitored.

Efficacy Evaluation Formula

Efficacy index=(score of constipation symptoms before treatment–score of constipation symptoms after treatment)/(score of constipation symptoms before treatment)×100%.

Efficacy Grading Standard

① Cured: The main symptoms and signs disappeared or basically disappeared, and the efficacy index95%. ② Markedly effective: The main symptoms and signs were significantly improved, 70% efficacy index ＜ 95%. ③Effective: The main symptoms and signs improved significantly, 30% efficacy index ＜ 70%. ④Ineffective: The main symptoms and signs were not significantly improved or even aggravated, and the efficacy index＜30%.

Total effective rate=(cured cases+markedly effective cases+effective cases)/(total cases in this group)×100%.

Statistical Analysis

SPSS26.0 software was applied for statistical analysis. Continues variables were tested for normality and described by (means±standard)deviation. According to the data of normal distribution, the differences within the group before and after treatment were compared by paired t-test,and the differences between the two groups were compared by independentt-test. Non-parametric test was used to analyze the variables were not in normal distribution and nominal and ordinal variables. The nominal and ordinal variables were described by frequency (constituent ratio).χ2test or Fisher exact probability method were used to compare the differences within or between groups. Using two-sided test, the test standard with statistical difference was: α=0.05, β=90%,P＜0.05.

RESULTS

General Information

According to the inclusion criteria, a total of 44 hospitalized patients were included in this study. One participant in the control group withdrew from this study due to the use of other defecation treatment, and one participant in the control group withdrew from this study due to diarrhea. A total of 2 cases dropped out, which was lower than the estimated 20% drop out rate. There were 42 cases completed 14 days clinical observation, including 22 cases in the treatment group and 20 cases in the control group. The average age of the treatment group was (68.86±8.725) years old, and that of the control group was (67.00±10.331) years old.There was no significant difference between the two groups (t=0.633,P=0.530＞0.05). There were 11 males and 11 females in the treatment group and 9 males and 11 females in the control group. There was no significant gender difference between the two groups (χ2=0.105,P=0.746＞0.05). A total 11 cases of lung cancer, 4 cases of pancreatic cancer,3 cases of breast cancer, 3 cases of ovarian cancer and 1 case of prostate cancer were included in the treatment group. As well as 13 cases of lung cancer,2 cases of pancreatic cancer, 3 cases of breast cancer and 2 cases of ovarian cancer were in the control group. There was no significant difference in the distribution of primary tumor between the two groups (P=0.862＞0.05).

Constipation Symptoms

On the 7th day of treatment, there was no significant difference in the improvement of constipation symptoms between the two groups(χ2=1.061,P=0.303＞0.05), as shown in Table 1.

On the 14th day of treatment, there was a significant difference in the improvement of constipation symptoms between the two groups(χ2=13.476,P=0.009＜0.05). The treatment group was significantly higher than the control group in the total effective rate, as shown in Table 2.

TCM Symptoms

Before treatment, there was no significant difference in TCM symptom scores between the two groups (P＞0.05). On the 7th and 14th day of treatment, there were significant differences in TCM symptom scores between the two groups (P＜0.05).The effect of improving the scores of TCM symptom in the treatment group was better than that in the control group, as shown in Table 3.

Quality of Life

Before treatment, there was no significant difference in the scores of quality of life between the two groups (P＞0.05). On the 7th day of treatment,there was no significant difference in the scores of quality of life between the two groups (P＞0.05). On the 14th day of treatment, there was significant difference in the scores of quality of life between the two groups(P＜0.05). The effect of improving the scores of qualityof life in the treatment group was better than that in the control group, as shown in Table 4.

Table 1. Improvement of Constipation Symptoms in the Two Groups on the 7th Day of Treatment

Table 2. Improvement of Constipation Symptoms in the Two Groups on the 14th Day of Treatment

Table 3. Comparison of TCM Symptom Scores Between Groups (Point)

Table 4. Comparison of Quality of Life Scores Between Groups (Point)

Table 5. Physical Condition Scores Between Groups (Point)

Physical Condition

Before treatment, on the 7th day and the 14th day of treatment, there was no significant difference in the physical condition scores between the two groups (P＞0.05), as shown in Table 5.

Safety Evaluation

In the course of this study, the vital signs of the two groups were relatively stable. One participant in the control group withdrew from this study due to the use of other defecation treatment, and one participant in the control group withdrew from this study due to diarrhea. There were no acupuncture related adverse events such as vertigo, needle bending or breaking, abnormal bleeding and so on in the treatment group. There were no significant changes in blood routine, liver and kidney function,fecal routine and ECG, and no other serious adverse events in the two groups.

DISCUSSION

Constipation of Qi deficiency syndrome is the most common type of OIC in cancer patients. The occurrence of tumor is due to the long-term effect of six pathogens, seven emotions, diet and other factors on the human body based on the deficiency of vital Qi, as a result of the imbalance between Yin (陰) and Yang (陽), the rise of pathogen and the decline of vital Qi. As stated inPlain Questions-Treatise Discussing Heat Disease(《素問?評(píng)熱病論篇》), for pathogen to encroach, Qi must be vacuous. YU Ting-hong, a doctor in the late Qing Dynasty, said in the collection of medical records of external syndrome: "deficiency of vital Qi leads to cancer", which directly pointed out that deficiency of vital Qi is the fundamental cause of cancer. HE Ren[10], a master of TCM, believes that cancer patients undergoing surgery, chemotherapy and radiotherapy can lead to severe consumption of Qi and blood, therefore it is essential to pay attention to support the vital Qi. MA Qian[11]analyzed the type of TCM syndrome of 122 patients with lung cancer after chemotherapy, and found that the deficiency syndrome became more obvious after chemotherapy, especially the deficiency of both Qi and blood. This suggested that chemotherapy may cause Qi and blood consumption injury. Similarly,XU Yan[12]analyzed the TCM syndrome types of 161 patients undergone NSCLC chemotherapy, and reported after chemotherapy, the number of patients with Qi and Yin deficiency syndrome increased, and chemotherapy drugs may severely consume Qi and Yin and cause the deficiency. Consistently, other studies also showed HE Ren's view that surgery,chemotherapy and radiotherapy can lead to the damage of vital Qi. For example[13-18], the number of cases of Qi and blood deficiency syndrome after chemotherapy of advanced gastric cancer increased. The number of cases of deficiency syndrome after chemotherapy or operation of colorectal cancer increased. The number of cases of Qi deficiency syndrome, Yin deficiency syndrome and Yang deficiency syndrome increased after concurrent radiotherapy and chemotherapy of advanced cervical cancer. The number of cases of Qi deficiency syndrome and Yin deficiency syndrome increased after thoracic radiotherapy.

Considering cancer patients with OIC are prone to Qi deficiency syndrome, the treatment should be benefiting vital Qi and moving Qi. The acupoints of Foot-Yangming (足陽明) meridian were mainly selected. Clinical observation showed that electroacupuncture stimulation of Zusanli (ST36),Tianshu (ST25), Zhigou (SJ6) and Shangjuxu (ST37)could achieve good medical effect. The selection of acupoints is based on the theory that "the large intestine and small intestine belong to the stomach","the stomach is the root of the five organs" and "the stomach governs free downflow" recorded inInner Canon of Huangdi(《黃帝內(nèi)經(jīng)》). Modern physician KE Chuan-hao noted in the treatment formula of acupuncture and moxibustion at 14 meridians:"Tianshu (ST25), Zhongji (RN3), Fujie (SP14),Daheng (SP15), Dachangshu (BL25), Zhigou (SJ6),Zusanli (ST36), and Dadun (LR1) points are selected for the treatment of deficiency constipation". This study included Tianshu (ST25), Zhigou (SJ6) and Zusanli (ST36) acupoints. Zusanli (ST36)can boost Qi. Tianshu (ST25), Shangjuxu (ST37) and Zhigou(SJ6) have the function of rectifying Qi and moving stabilization. The combination of four acupoints has the effect of supplementing Qi, promoting Qi and relieving constipation. Thus, it has a significant effect on Qi deficiency syndrome of cancer patients with OIC.

Acupuncture has the function of dredging meridians, regulating Qi and blood, and treating diseases. Current stimulation therapy belongs to modern physical therapy, which is able to affect the bioelectricity of cells, activate tissue cells, cause local muscle contraction, and induce nerve cell conduction impulse. The combination of acupuncture and electrical stimulation can further enhance the effect. The mechanism of electroacupuncture in the treatment of constipation might relate to the effect of electroacupuncture on autonomic nervous system and intestinal nervous system.The potential influence of rlectroacupuncture on autonomic nervous system could be the peripheral nerves transmit nerve impulse to nerve center and nerve center integrates nerve impulse caused by the stimulation. This effect regulates sympathetic nerve and parasympathetic nerve excitability, which maintain the balance between them and restore the normal movement and gland secretion of intestine through prevertebral ganglion receiving information from the central nervous system and regulates the intestinal nervous system.

CONCLUSION

This study showed that compared with the firstline treatment drug lactulose, electroacupuncture in the treatment of cancer patients with OIC can not only improve the symptoms of constipation, but also improve the symptoms of TCM and the quality of life. Because of the the advantages of quick effect,obvious curative effect, less adverse effect and low price, it could be considered into the clinical practice.