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. 2024 Feb 23;103(8):e37024. doi: 10.1097/MD.0000000000037024

External treatment of traditional Chinese medicine for cancer pain: A systematic review and network meta-analysis

Hong Jin a, Ji Liang a, Siqi Zhang a, Shuai Ma a, Hongyu Qin a, Dongxu Zhang a, Xueying Pang b, Miao Zhang c,*
PMCID: PMC11309619  PMID: 38394488

Abstract

Background:

Cancer pain is one of the most intolerable and frightening symptoms of cancer patients. However, the clinical effect of the three-step analgesic ladder method (TSAL) is not satisfactory. The combination of external treatment of traditional Chinese medicine (TCM) can improve the clinical effect.

Objective:

This study used network meta-analysis to compare the effects of different external treatment methods of TCM combined with TSAL on cancer pain.

Methods:

Databases searched by our team included Google Scholar, Web of Science, Scopus, Embase, PubMed, and Cochrane Library. Randomized controlled trials related to the external treatment of TCM combined with TSAL for cancer pain were screened from the establishment of the database till now. The above literature extracted clinical efficacy, NRS score, KPS score, analgesic onset time, and duration as the main results after the screening. The 95% confidence interval (95% CI) of OR value and SMD value was used as the effect index to compare the difference in efficacy of different interventions, and the ranking was conducted. STATA 17.0 software was used for the statistical analysis of the above data.

Results:

A total of 78 studies were included, including 8 interventions and 5742 participants. Based on ranking probability, the clinical effective rate of manual acupuncture combined with TSAL was the best when the intervention time was set at 4 weeks [OR = 5.42, 95% CI (1.99,14.81)], and the improvement effect on KPS score was also the best [SMD = 0.97, 95% CI (0.61, 1.33)]. Acupoint external application was the best intervention in reducing NRS score [SMD = −1.14, 95% CI (−1.90, −0.93)]. Acupoint moxibustion combined with TSAL was considered to be the most effective intervention to prolong the duration of analgesia [SMD = 1.69, 95% CI (0.84, 2.54)] and shortening the onset time of analgesia [SMD = −3.00, 95% CI (−4.54, −1.47)].

Conclusions:

TSAL combined with manual acupuncture is the best in terms of clinical efficacy and improvement of patients’ functional activity status. With the extension of treatment time, the intervention of this kind of treatment on the clinical effect is more pronounced. Acupoint external application also has a unique advantage in reducing the pain level of patients. From the point of view of analgesic duration and duration of analgesia, combined acupoint moxibustion has the best effect.

Keywords: analgesic, cancer pain, efficacy, External treatment of traditional Chinese medicine, network meta-analysis

1. Introduction

Cancer pain is a common symptom in cancer patients. Around 69% of cancer patients worldwide suffer from cancer pain.[1] The cause of cancer pain can be related to the tumor itself or its related treatment programs. Sometimes analgesic treatment is the only appeal of some patients to seek medical treatment. One systematic study has shown that more than half of patients experience pain during treatment, and 40 percent experience pain afterward.[2] Another study found that 64 percent of cancer patients experience pain in advanced or advanced stages of the disease.[3]

Unfortunately, the treatment and intervention methods of malignant tumors are increasing gradually, but the intervention of cancer pain lacks management in clinical practice. In 1986, the World Health Organization developed the three-step analgesic ladder method (TSAL), which initially guided medication based only on the three levels of cancer pain, then extended “Invasive and Minimally Invasive Treatments” to a fourth intervention when all drugs were ineffective.[4] Strictly regulated analgesia following this principle can bring relief to most patients. However, the adverse reactions caused by nonsteroidal anti-inflammatory drugs and opioids, such as liver and kidney function damage, addiction risk, drug resistance, gastrointestinal side effects, and respiratory depression, should not be ignored in clinical practice.[5] Due to the different economic levels, laws and regulations, and cultural backgrounds of various countries and regions, managing cancer pain is far more complicated than the guidelines, leading to the clinical effect of TSAL being unsatisfactory.[6] The synergistic effect of multiple treatment methods can reduce the problem of poor efficacy and side effects of TSAL alone. Therefore, comprehensive treatment has been paid more and more attention by clinicians.

Traditional Chinese medicine (TCM) external treatment includes acupuncture, electro-acupuncture, acupoint moxibustion, external application of TCM, acupoint external application, auricular acupuncture, acupoint catgut embedding and so on. Acupuncture refers to a treatment method in which needles are inserted into the patient’s body at a certain Angle to stimulate specific parts of the human body. Electro-acupuncture refers to the micro-current wave of human bioelectricity passed through on the basis of acupuncture after acupuncture gets qi. Acupoint moxibustion is to fumigate on certain acupoints on the body surface, and use heat stimulation to prevent and treat diseases. External application of TCM is a kind of TCM external treatment method that applies Chinese herbal medicine preparations to the skin, and acupoint external application is a treatment method that applies it to the acupoints. Auricular acupuncture is a kind of treatment to prevent and cure diseases by stimulating the points distributed on the auricle. Acupoint catgut embedding is a method to bury absorbable thread into the corresponding acupoint area to stimulate the acupoints for a long time and gently, so as to achieve the purpose of treating diseases.

The treatment of cancer pain in TCM is based on the syndrome differentiation theory. Some literature published in recent years has shown that external treatment of TCM combined with TSAL can improve clinical efficacy, improve patients’ quality of life, and reduce adverse reactions.[7,8] A systematic review and network meta-analysis analyzed the effectiveness of different TCM therapies combined with TSAL in the treatment of cancer pain, including oral TCM.[7] Another similar paper compared the clinical effectiveness and adverse reactions of different external treatment methods of TCM combined with TSAL for cancer pain.[8] In contrast, the present study added statistics on numerical descriptor scale (NRS) score, karnofsky performance status (KPS) score, analgesic onset time, and duration and evaluated clinical efficacy according to different intervention times to evaluate the advantages of different treatments more comprehensively. From another point of view, considering that the analgesic principle of acupoint injection and oral Chinese medicine is different from that of external treatment, this study did not include related trials. In addition, some newly published randomized controlled trials (RCTs) were not included in the previous study.[9–12] The sample size of these RCTs is relatively large, and the experimental idea is rigorous. Our team included these RCTs for a more comprehensive and systematic analysis.

Therefore, this systematic review and network meta-analysis mainly compared the effective rate of different time nodes and evaluated the comparison of NRS score, KPS score, and analgesic onset time and duration by different means, aiming to analyze the clinical efficacy of different external treatment methods of TCM combined with TSAL. The ultimate goal of this study is to provide a basis for comprehensive treatment of cancer pain patients.

2. Methods

2.1. Search strategy

The present systematic review and network meta-analysis were reported in accordance with the Preferred Reporting Items for Systematic Review and Meta-analyses extension statement for network meta-analyses.[13] This study has been registered with PROSPERO (CRD42023442170).

The main databases searched included the database of Google Scholar, Web of Science, Scopus, Embase, PubMed, and Cochrane Library, and we searched the relevant articles on the external treatment of TCM combined with TSAL since its inception. The keywords for the literature search were (“Cancerous pain” OR “Cancer-Associated Pain” OR “Cancer-Related Pains” OR “Neoplasm-Related Pain” OR “Neoplasm-Associated Pain” OR “Oncological Pain” OR “Tumor Related Pain”) AND (“acupuncture” OR “acusector” OR “point application therapy” OR “moxibustion” OR “external application of Chinese medicine” OR “auricular” OR “ear acupunctures” OR “acupoint catgut embedding”)

2.2. Inclusion and exclusion criteria

Studies in line with the following inclusion criteria were enrolled for this research:

  1. Study design: Consistent with RCT;

  2. Language restrictions: Chinese and English;

  3. Disease: Cancer pain caused by various types of malignant tumors;

  4. Intervention of the treatment group: External treatment of TCM, including manual acupuncture, electro-acupuncture, acupoint moxibustion, external application of TCM, acupoint external application, auricular acupuncture, acupoint catgut embedding combined with TSAL.

  5. Intervention of the control group: TSAL. The medication principle should be the same as that of the intervention group.

Studies that met the following criteria were also excluded:

  1. Combined with other analgesic treatments;

  2. Pain not caused by cancer;

  3. Animal studies, case reports, clinical experience and review articles;

  4. Similar and repeat studies.

2.3. Data extraction and quality assessment

Two groups of authors (H.J., H.Q., S.M., and S.Z.) reviewed the titles and abstracts of the retrieved RCTs, respectively. Then reviewed the total RCTs and assessed eligibility criteria for inclusion in the web meta-analysis. Differences between authors are discussed and resolved at the discretion of the third author (X.Y.P.). The following data were extracted from RCTs that passed the eligibility criteria, including year of publication, intervention, duration of intervention, number of patients, and outcome measures (Table 1).

Table 1.

Characteristics of RCTs Enrolled in this systematic review and network meta-analyses.

Author Year Interventions Duration Outcomes
C Sample size T Sample size
Miaoguo Cai[14] 2020 1 50 1 + 6 50 2 wk ④
Run Chen[15] 2021 1 50 1 + 7 50 4 wk ⑤
Xuezhang Chen[16] 2020 1 49 1 + 5 49 10 d ④
Yan Chen[17] 2020 1 42 1 + 5 42 1 wk ①
Yuwen Chen[18] 2017 1 30 1 + 7 30 1 wk ①
Yi Deng[19] 2015 1 42 1 + 2 42 4 wk ③、⑤
Rui Gao[20] 2018 1 50 1 + 5 50 10 d ⑤
Xingcai Guo[9] 2022 1 35 1 + 2 35 Unclear ⑤
Yun He[10] 2022 1 40 1 + 2 40 4 wk ⑥、⑦
Shenlin Hu 2017 1 30 1 + 8 30 1 wk ①、④
Jianrong Hui[22] 2019 1 40 1 + 2 40 2 wk ②、④、⑦
Bin Jiang[20] 2020 1 29 1 + 2 25 12 d ④
Dan Li 2020 1 30 1 + 2 30 2 wk ②、⑤
Dehui Li[24] 2021 1 20 1 + 2 20 20 d ⑤
Dehui Li[25] 2017 1 30 1 + 2 30 1 wk ①
Yingdong Li[11] 2022 1 75 1 + 2 75 2 wk ②、⑤
Jietao Lin[26] 2011 1 29 1 + 8 31 1 wk ④
Xinping Liu[27] 2011 1 34 1 + 5 34 4 wk ③
Jiheng Ma[28] 2018 1 33 1 + 5 54 4 wk ④
Jie Peng[29] 2012 1 24 1 + 3 23 1 wk ⑥
Daiping Qiao[30] 2008 1 30 1 + 2 33 1 wk ①
Fumin Shi[31] 2021 1 41 1 + 2 41 1 wk ①
Ruirui Sun[32] 2017 1 30 1 + 2 30 2 wk ②、⑤
Can Wang[33] 2019 1 40 1 + 3 40 2 wk ④
Daojun Wang[34] 2019 1 35 1 + 2 35 2 wk ②、④
Jing Wang[35] 2015 1 30 1 + 7 30 Unclear ⑤
Qingquan Wang[36] 2016 1 60 1 + 7 60 1 wk ⑤
Jinchai Xu[37] 2018 1 32 1 + 5 32 Unclear ⑤
Na Xue[12] 2022 1 57 1 + 2 57 2 wk ②、④
Jingtao Yan[38] 2017 1 50 1 + 5 50 2 wk ②、④
Liya Yang[42] 2019 1 34 1 + 6 34 1 wk ①
Yimei Yu[43] 2021 1 22 1 + 2 22 1 wk ④
Yajing Zhang[44] 2014 1 18 1 + 5 27 5 d ⑥、⑦
Kai Zheng[45] 2015 1 14 1 + 2 15 2 wk ②
Minyu Zhong[46] 2012 1 50 1 + 7 50 1 wk ①
Deqi Zhou[47] 2016 1 33 1 + 6 32 2 wk ②
Qunqin Zhou[48] 2022 1 42 1 + 2 42 2 wk ②
Li Feng[40] 2021 1 40 1 + 6 40 4 wk ③
Xingyu Chen[39] 2017 1 56 1 + 6 57 4 wk ③
Xiao Wang[41] 2017 1 30 1 + 5 30 2 wk ②
Dianrong Lu[52] 2016 1 34 1 + 5 35 10 d ④、⑤
Meixian Jiang[51] 2019 1 40 1 + 6 40 4 wk ③
Qiaotong Huang[50] 2014 1 50 1 + 4 50 1 wk ⑥、⑦
Xingyu Chen[49] 2018 1 56 1 + 6 57 4 wk ③
Wei Luo[53] 2020 1 43 1 + 5 43 20 d ④
Yanfang Mo[54] 2008 1 43 1 + 6 44 2 wk ②
Yunxia Rong[55] 2021 1 35 1 + 5 35 4 wk ③、④
Zongbing Guo[56] 2015 1 32 1 + 2 32 8 wk ④
Lin Song[61] 2018 1 45 1 + 5 45 3 mo ⑥
Qi Li[58] 2016 1 39 1 + 5 40 4 wk ④
Aihua Rao[60] 2015 1 24 1 + 5 24 2 wk ②
Guangwei Sun[62] 2020 1 48 1 + 5 48 2 wk ②
Ping Lv[59] 2019 1 30 1 + 6 30 20 d ④
Minling You[63] 2020 1 30 1 + 2 30 2 wk ②、④
Yanwen Yu[64] 2013 1 18 1 + 5 18 1 mo ⑥、⑦
Yanju Bao[57] 2009 1 60 1 + 5 64 24 d ⑤、⑦
Hua Chen[65] 2002 1 31 1 + 2 31 6 h ⑦
Jingjing He[66] 2020 1 30 1 + 5 30 1 wk ①、④、⑤
Gongjin Hou[67] 2019 1 30 1 + 5 30 2 wk ⑤
Xiu Huang[68] 2011 1 40 1 + 5 40 1 wk ①、⑥、⑦
Jie Liu[69] 2011 1 30 1 + 2 30 4 wk ③、⑥、⑦
An Luo 2019 1 40 1 + 5 40 1 mo ⑤、⑦
Ting Luo[71] 2019 1 31 1 + 6 31 1 wk ①、④
Liqiong Lv[72] 2021 1 30 1 + 4 30 1 wk ⑥、⑦
Ting Su[73] 2012 1 17 1 + 5 17 1 wk ⑤
Ying Wang[74] 2016 1 30 1 + 3 30 2 wk ④、⑥
Sa Xi[75] 2018 1 30 1 + 2 30 1 wk ①、⑥、⑦
Xiaoming Xiao[76] 2008 1 20 1 + 5 20 1 wk ①、⑥、⑦
Yanhong Xuan[78] 2021 1 48 1 + 6 48 6 d ④
Chundi Yang[79] 2016 1 40 1 + 5 40 2 wk ②
Jie Yu[80] 2015 1 35 1 + 5 35 2 wk ⑤
Guodong Zang[81] 2021 1 39 1 + 8 41 1 wk ①、④
Weijian Zhang[82] 2014 1 30 1 + 2 30 1 wk ①、⑦
Manyu Zhao[83] 2018 1 39 1 + 5 39 2 wk ④、⑤
Weixuan Zhao[84] 2017 1 17 1 + 6 17 1 wk ④
Xing Zhong[85] 2009 1 30 1 + 5 31 1 wk ①、⑤
Lin Zhou[86] 2019 1 30 1 + 2 30 2 wk ②、⑤、⑥、⑦
Xianghong Wei[77] 2021 1 50 1 + 2 50 4 wk ③
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① Clinical efficacy at the intervention time of 1w; ② Clinical efficacy at the intervention time of 2w; ③ Clinical efficacy at the intervention time of 4w; ④ NRS scores; ⑤ KPS scores; ⑥ Analgesic onset time; ⑦ Duration of analgesia. T: Treatment group; C: Control group.

RCT = randomized controlled trial.

Two groups of investigators (H.J., H.Q., S.M., and S.Z.) will conduct an independent review of the included studies by using Cochrane’s tools. Since the included trials in this study complied with the randomization principle, the Cochrane Risk of Bias Tool (2.0) for RCTs was adopted. The evaluation measures included six items: a selection of the reported result, measurement of the outcome, missing outcome data, deviations from intended interventions, randomization process, and overall bias. Each project was assessed as “low risk,” “high risk,” or “some concerns.” Any objection in the evaluation process will be discussed by the researchers and ultimately judged by PANG Xueying.

2.4. Outcome

In this study, the primary outcome measure was defined as clinical efficacy. Effective response was defined as complete, partial, and mild. Secondary outcome measures were defined as the NRS Score, KPS score, analgesic onset time, and analgesic duration before and after treatment. The NRS score is a numerical grading method for pain intensity. The pain degree is represented by 11 numbers ranging from 0 to 10, with 0 representing no pain and 10 representing the most pain. Subjects are asked to mark one of the numbers according to their personal pain experience. Karnofsky scoring standard is adopted in KPS scoring. The onset time of analgesia was the time from the beginning of treatment to the beginning of pain relief, and the analgesic duration was the time when the pain level returned to the pretreatment level.

2.5. Statistical analyses

The network and mvmeta packages in Stata17.0 software were used for statistical analysis. Based on the above data, the network, funnel, and assessment publication bias diagrams among various interventions were also drawn. Since there is no closed loop in this study, the consistency model is adopted. At last, the surface under the cumulative ranking curve (SUCRA) of various intervention measures was obtained by iterative calculation. Cluster analysis of outcome indexes was conducted based on SUCRA value to obtain the best intervention measures. All effect sizes had 95% confidence intervals (CIs). For the joint effect size, standardized mean difference (SMD) was used for measurement data, and odds ratios (OR) were used for counting data.

3. Results

3.1. Description of selected randomized controlled trials

The preferred reporting items for systematic reviews and meta-analyses flow chart found in this study was shown in Figure 1. Through the search strategy, 4490 related articles were found in the database, of which 900 duplicated articles were found. After reading the title and abstract, 645 articles were obtained. Finally, 78 randomized controlled trials met the inclusion criteria after the full-text evaluation of the above articles.[9–12,14–86] These RCTs use one or more clinical efficacy, NRS score, KPS score, time of onset, and duration of analgesia as outcome measures. The intervention time of clinical efficacy was limited to 1 week, 2 weeks, and 4 weeks, respectively. 78 randomized studies were included, involving 5742 patients and 8 interventions. Intervention methods include TSAL,

Figure 1.

Figure 1.

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Flow chart of all enrolled RCTs. RCT = randomized controlled trial.

Manual acupuncture + TSAL, Electro-acupuncture + TSAL, Acupoint moxibustion + TSAL, External application of TCM + TSAL, Acupoint external application + TSAL, Auricular acupuncture + TSAL, Acupoint catgut embedding + TSAL.

3.2. Quality assessment of included studies

Selection of the reported result, measurement of the outcome, and missing outcome data from 78 studies were assessed as low risk. 66 (84.6%) studies had a low risk of deviating from the intended intervention, and 12 (15.4%) studies were assessed as some concern. 74 (94.9%) studies adequately described the randomization process, 3 (3.8%) studies were classified as high-risk studies, and 1 (1.3%) had an unclear risk of bias. Of the overall bias of all 78 studies, 63 (80.8%) were rated as low risk, 13 (16.7%) as unclear risk bias, and 2 (2.6%) as high risk. Detailed risk bias risk assessment information was reported in Figure 2 and Figure S1, Supplemental Digital Content, http://links.lww.com/MD/L393.

Figure 2.

Figure 2.

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Risk of bias summary.

3.3. Clinical effect

Clinical efficacy was reported in 42 pieces of literature within a limited intervention time. Among them, 16 studies with intervention duration of 1 week involved 1080 participants with 6 interventions, 17 studies with 2 weeks involved 1303 participants with 4 interventions, and 9 studies with 4 weeks involved 768 participants. The network relationships among the various interventions were shown in Figure 3.

Figure 3.

Figure 3.

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Network plots for clinical efficacy at different intervention time.

When the intervention time was set for 1 week to compare the clinical efficacy, we found that, compared with the control group, manual acupuncture + TSAL [OR = 2.94, 95% CI (1.41, 6.12)], external application of TCM + TSAL [OR = 4.44, 95% CI (1.87, 10.58)] and acupoint external application + TSAL [OR = 5.61, 95% CI (1.12, 28.01)] were better than the control group, and the difference was statistically significant (P < .05). There was no significant difference between other intervention methods and TSAL. In addition, the comparison results of all components were not statistically significant (P > .05), as shown in Table 2. According to SUCRA value, the clinical treatment of 5 intervention methods in the control group was ranked as follows: acupoint external application + TSAL (79.6%) > external application of TCM + TSAL (77.4%) > manual acupuncture + TSAL (56.6%) > acupoint catgut embedding + TSAL (41.1%) > auricular acupuncture + TSAL (40.9%) (Fig. 4A). The risk of bias is shown by funnel plot in Figure S2, Supplemental Digital Content, http://links.lww.com/MD/L394.

Table 2.

League table of clinical effect (The lower left intervention time is 1w, and the upper right intervention time is 2 weeks).

Manual acupuncture + TSAL 1.56 (0.62, 3.96) 0.76 (0.20, 2.86) 4.41 (2.27, 8.57)
0.66 (0.21, 2.06) External application of CTM + TSAL 0.49 (0.13, 1.82) 2.82 (1.47, 5.42)
0.52 (0.09, 3.07) 0.79 (0.13, 4.93) Acupoint external application + TSAL 5.82 (1.85, 18.32)
1.41 (0.29, 7.00) 2.13 (0.40, 11.29) 2.69 (0.31, 23.06) Acupoint catgut embedding + TSAL
1.36 (0.44, 4.22) 2.05 (0.60, 6.98) 2.59 (0.42, 16.07) 0.96 (0.18, 5.08) Acupoint catgut embedding + TSAL
2.94 (1.41, 6.12) 4.44 (1.87, 10.58) 5.61 (1.12, 28.01) 2.08 (0.50, 8.63) 2.17 (0.91, 5.14) TSAL
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Figure 4.

Figure 4.

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(A) Bayesian ranking of clinical efficacy at the intervention time of 1 week. (B) Bayesian ranking of clinical efficacy at the intervention time of 2 weeks. (C) Bayesian ranking of clinical efficacy at the intervention time of 4 weeks.

When the intervention time was set at 2w, compared with the control group using TSAL alone, manual acupuncture + TSAL [OR = 4.41, 95% CI (2.27, 8.57)], external application of TCM + TSAL [OR = 2.82, 95% CI (1.47, 5.42)], acupoint external application + TSAL [OR = 5.82, 95% CI (1.85, 18.32)] had better clinical efficacy. The difference was statistically significant (P < .05). Comparison results of components showed no statistical significance (P > .05), as shown in Table 2. According to the SUCRA value, the clinical treatment of the 3 intervention methods in the control group was ranked as follows: acupoint external application + TSAL (83.6%) > manual acupuncture + TSAL (72.3%) > external application of TCM + TSAL (44%) (Fig. 4B). The risk of bias is shown by funnel plot in Figure S3, Supplemental Digital Content, http://links.lww.com/MD/L395.

When the intervention time was limited to 4w, compared with the control group, manual acupuncture + TSAL [OR = 5.42, 95% CI (1.99, 14.81)], external application of TCM + TSAL [OR = 3.38, 95% CI (1.55, 7.34)] and acupoint external application + TSAL [OR = 4.52, 95% CI (2.21, 9.26)] were better than the control group. The difference was statistically significant (P < .05). As shown in Table 3., there was no statistical significance in the comparison results of all components (P > .05). According to the SUCRA value, the clinical treatment of the 3 intervention methods in the control group was ranked as follows: manual acupuncture + TSAL (79.3%) > acupoint external application + TSAL (69.5%) > external application of TCM + TSAL (51.1%) (Fig. 4C). The risk of bias is shown by funnel plot in Figure S4, Supplemental Digital Content, http://links.lww.com/MD/L397.

Table 3.

League table of clinical effect and NRS scores (The lower left is the NRS score, and the upper right is the clinical effect of the intervention time of 4 weeks).

Manual acupuncture + TSAL 1.61 (0.45, 5.72) 1.20 (0.35, 4.12) 5.42(1.99, 14.81)
−0.08 (−0.92, 0.75) Electro-acupuncture + TSAL
−0.20 (−0.73, 0.32) −0.12 (−0.93, 0.69) External application of CTM + TSAL 0.75 (0.26, 2.15) 3.38 (1.55, 7.34)
0.68 (0.05, 1.30) 0.76 (−0.12, 1.64) 0.88 (0.29, 1.48) Acupoint external application + TSAL 4.52 (2.21, 9.26)
−0.57 (−1.29, 0.15) −0.49 (−1.44, 0.46) −0.37 (−1.06, 0.32) −1.25 (−2.02, −0.48) Acupoint catgut embedding + TSAL
−0.74 (−1.13, −0.34) −0.65 (−1.39, 0.08) −0.53 (−0.87, −0.19) −1.41 (−1.90, −0.93) −0.16 (−0.76, 0.44) TSAL
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3.4. NRS score

A total of 26 kinds of literature have reported on NRS scores, involving 6 intervention means and 1905 participants. The network relationships among the various interventions are shown in Figure 5A. Compared with control group, manual acupuncture + TSAL [SMD = −0.74, 95% CI (−1.13, −0.34)], electro−acupuncture + TSAL [SMD = −0.65, 95% CI (−1.39, −0.08)], external application of TCM + TSAL [SMD = −0.53, 95% CI (−0.87, −0.19)], acupoint external application + TSAL [SMD = −1.14, 95% CI (−1.90, −0.93)], acupoint catgut embedding + TSAL [SMD = −0.16, 95% CI (−0.76, 0.44)] were better than the control group, and the difference was statistically significant (P < .05). As shown in Table 3, except for the difference between external application + TSAL, manual acupuncture + TSAL, Electro-acupuncture + TSAL and external application of TCM + TSAL, there were statistical differences between the other intervention methods (P < .05). According to the SUCRA value, the 5 intervention methods in the control group were ranked as follows: acupoint external application + TSAL (98.8%) > manual acupuncture + TSAL (66.3%) > electro-acupuncture + TSAL (57.5%) > external application of TCM + TSAL (49.3%) > acupoint catgut embedding + TSAL (21.4%) (Fig. 5B). The risk of bias is shown by funnel plot in Figure S5, Supplemental Digital Content, http://links.lww.com/MD/L400.

Figure 5.

Figure 5.

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(A) Network plots for NRS score. (B) Bayesian ranking of NRS score. NRS = Numerical Descriptor Scale.

3.5. KPS score

A total of 21 kinds of literature reported KPS scores, involving 1604 participants using 4 intervention means. The network relationships among the various interventions are shown in Figure 6A. Compared with control group, external application of TCM + TSAL [SMD = 0.39, 95% CI (0.11, 0.68)] was better than the control group, the difference was statistically significant (P < .05). Except for the difference between Manual acupuncture + TSAL and External application of TCM + TSAL, there were statistical differences between the other intervention methods (P < .05), as shown in Table 4. The SUCRA values of the 3 intervention methods in the control group were ranked according to SUCRA value, as follows: manual acupuncture + TSAL（94.2%）> auricular acupuncture + TSAL（65.3%) > external application of TCM + TSAL（40.2%） (Fig. 6B). The risk of bias is shown by funnel plot in Figure S6, Supplemental Digital Content, http://links.lww.com/MD/L403.

Figure 6.

Figure 6.

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(A) Network plots for KPS score. (B) Bayesian ranking of KPS score. KPS = Karnofsky Performance Status.

Table 4.

League table of KPS scores.

Manual acupuncture + TSAL
0.58 (0.12, 1.04) External application of CTM + TSAL
0.32 (−0.32, 0.96) −0.26 (−0.86, 0.34) Auricular acupuncture + TSAL
0.97 (0.61, 1.33) 0.39 (0.11, 0.68) 0.65 (0.12, 1.18) TSAL
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3.6. Analgesic onset time

Time to onset of analgesia was reported in 13 studies involving 818 participants from four interventions. The network relationships among the various interventions are shown in Figure 7A. Compared with the control group, manual acupuncture + TSAL [SMD = −0.82, 95% CI (−1.89, −0.24)], electro-acupuncture + TSAL [SMD = −1.04, 95% CI (−2.55, 0.48)], acupoint moxibustion + TSAL [SMD = −3.00, 95% CI (−4.54, −1.47)], external application of TCM + TSAL [SMD = −1.16, 95% CI (−2.13, −0.19)] was better than the control group, and the difference was statistically significant (P < .05). As shown in Table 5, there were statistical differences between external application of TCM + TSAL and Manual acupuncture + TSAL (P < .05). According to the SUCRA value, the four intervention methods in the control group were ranked as follows: acupoint moxibustion + TSAL (98.4%) > external application of TCM + TSAL (55.7%) > electro-acupuncture + TSAL (49.8%) > manual acupuncture + TSAL (41.8%) (Fig. 7B). The risk of bias is shown by funnel plot in Figure S7, Supplemental Digital Content, http://links.lww.com/MD/L406.

Figure 7.

Figure 7.

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(A) Network plots for analgesic onset time. (B) Bayesian ranking of analgesic onset time.

Table 5.

League table of analgesic onset time and duration of analgesia (The lower left is analgesic onset time, and the upper right is duration of analgesia).

Manual acupuncture + TSAL −0.96 (−1.92, 0.01) 0.31 (−0.36, 0.98) 0.73 (0.28, 1.18)
0.22 (−1.63, 2.07) Electro-acupuncture + TSAL
2.18 (0.32, 4.04) 1.96 (−0.19, 4.12) Acupoint moxibustion + TSAL 1.27 (0.28, 2.25) 1.69 (0.84, 2.54)
0.33 (−1.10, 1.77) 0.12 (−1.68, 1.92) −1.85 (−3.66, −0.03) External application of CTM + TSAL 0.42 (−0.08, 0.92)
−0.82 (−1.89, 0.24) −1.04 (−2.55, 0.48) −3.00 (−4.54, −1.47) −1.16 (−2.13, −0.19) TSAL
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3.7. Duration of analgesia

A total of 15 kinds of literature were reported on the duration of analgesia, involving 1027 participants in 4 intervention methods. The network relationships among the various interventions are shown in Figure 8A. Compared with the control group, External application of TCM + TSAL [SMD = 0.42, 95% CI (−0.08, 0.92)] was better than the control group, the difference was statistically significant (P < .05), There were statistical differences between manual acupuncture + TSAL and external application of TCM + TSAL and the comparison results between manual acupuncture + TSAL and acupoint moxibustion + TSAL was statistically significant (P < .05), as shown in Table 5. According to SUCRA value, the three intervention methods in the control group were ranked as follows: acupoint moxibustion + TSAL (98.9%) > manual acupuncture + TSAL (61.4%) > external application of TCM + TSAL (37.8%) (Fig. 8B). The risk of bias is shown by funnel plot in Figure S8, Supplemental Digital Content, http://links.lww.com/MD/L409.

Figure 8.

Figure 8.

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(A) Network plots for duration of analgesia. (B) Bayesian ranking of duration of analgesia.

4. Discussion

For the first time, our team compared the clinical efficacy of TCM external treatment combined with TSAL at different time nodes and added NRS scores, KPS scores, analgesia onset time, and duration of analgesia to evaluate this combination therapy comprehensively.78 clinical trials with a total of 5742 participants were included in this systematic review. Among them, 2850 participants used TSAL alone, and 2892 participants used the external treatment of TCM combined with TSAL.

In the evaluation of clinical efficacy, the SUCRA of manual acupuncture ranked third, second, and first at the intervention time of 1 week, 2 weeks, and 4 weeks, respectively. Therefore, we know that with the passage of time, the effect of manual acupuncture combined with TSAL will become better and better, and at 4 weeks, it is the best treatment. When the intervention time was less than or equal to 2 weeks, the best solution was acupoint external application combined with TSAL. The results of NRS score shows that acupoint external application combined with TSAL is the best form of intervention. In the evaluation of KPS score, manual acupuncture intervention had the best effect. In terms of the onset time and duration of analgesia, we found that acupoint moxibustion combined with TSAL had a shorter effective time. It is worth noting that this comprehensive treatment can also maximize the duration of analgesia.

TSAL is considered as the gold standard for cancer pain.[87,88] However, long-term use of this method will cause some inevitable side effects. Long-term use of nonsteroidal anti-inflammatory drugs in combination with opioids for moderate pain may cause gastrointestinal dysfunction and renal insufficiency,[89] while mild and strong opioids may cause constipation, drowsiness, and nausea.[90] Due to these unavoidable side effects, the use of TSAL has been limited to a certain extent.

National Comprehensive Cancer Network recommends non-pharmacological interventions, such as acupuncture, for managing cancer pain.[91] Although combination therapy is not included in world health organization criteria, neutralization should be considered in any step of pain management, as interventions provided early in the disease may be more beneficial than when the pain is difficult to control.[92] Pain management based on TCM theory requires systematic evaluation based on the patient’s history and symptoms, and individualized guidance, which had shown good effects.[93]

The cancer pain system is complex, and many factors, such as the central mechanism and peripheral mechanism, can cause pain.[94] External treatment of TCM combined with TSAL can improve the clinical symptoms and reduce the degree of cancer pain in patients, which may be related to inhibiting the activation of spinal cord glial cells, recombinant toll like receptor 4/nuclear factor kappa-B signal expression, inhibiting the expression of inflammatory factors in the spinal cord and serum,[95] increasing levels of the nociceptive receptor β-endorphins in the brain and spinal cord, decreasing the production of nociceptive transmitter P.[96] Some scholars have found that acupoint external application can relieve cancer pain by reducing interleukin-1β and tumor necrosis factor-α levels. The principle of acupuncture analgesia is complicated. Some studies have shown that the mechanism of acupuncture analgesia may be mediated by local purine signals adenosine and A1 receptors, and many purine signals are involved together.[97] Other scholars believe that the analgesic effect of acupuncture is related to the regulation of the mitogen-activated protein kinase Mitogen-activated Protein Kinase signaling pathway and transmission fibers.[98] The mechanism of moxibustion and electroacupuncture involved in analgesia may be related to the cationic channels acid-sensing ion channel 3, purinergic receptor P2X, ligand gated ion channel 3 and purinergic receptor P2X, ligand gated ion channel 7, mediating the induction of acid and purine.[99] Electroacupuncture blocks pain by activating a variety of bioactive chemicals through peripheral, spinal, and supraspinal mechanisms[100] and has been shown to affect endogenous opioid release. The operation of the auricular needle is easier to learn and manage in the clinically.[101] Due to the limited experiments on the intervention of external treatment of TCM in cancer pain, the deep mechanism of action at the molecular level still needs to be further explored.

External treatment of TCM has the advantages of simple operation, apparent curative effect, and economical benefits. This study has proved the clinical effectiveness and advantages of TCM external treatment combined with TSAL, and compared different TCM external treatment methods, providing the specific clinical basis for the comprehensive treatment of cancer pain patients. It is hoped that this treatment plan can be widely promoted in clinical practice to ultimately benefit patients suffering from cancer pain.

5. Limitation

There are still limitations to this study. Firstly, in terms of literature quality, some studies need to indicate the method of randomization, and we cannot contact the authors for confirmation. Most of the included studies were not registered and did not describe assignment concealment and blinding, limiting the reliability of the results to some extent. Secondly, due to the limitation of the number of literatures, the outcome indicators set in this study did not involve every intervention mode. Additionally, in the observation of clinical efficacy, although the analysis of node method at different times has obtained the conclusion that manual acupuncture combined with the three-step analgesic ladder method has the best effect at 4w, however, due to the limitation of the number of literatures, the efficacy of intervention with longer duration has not been evaluated. The effect of acupoint external application in this study is generally better than that of external application of TCM. Although it proves the advantage of acupoint selection, the type and dose of external use of TCM are not restricted in this study, so the specific mechanism needs to be further explored. Finally, the acupoint selection method in this study was not defined, so the external treatment of TCM described in this study refers to a general concept rather than a fixed treatment method.

6. Conclusions

At present, there is evidence that manual acupuncture combined with TSAL has a significant effect, and it gradually becomes prominent with the extension of treatment time. Acupoint moxibustion combined with TSAL has the best effect on shortening the onset time and prolonging the duration of analgesia. However, due to the poor methodological quality of the included RCTs, these results should be interpreted with great caution. In addition, well-designed studies are needed to confirm these results.

Acknowledgments

All the authors of this article would like to express their gratitude to all the members of Acupuncture and Moxibustion Consulting Room No. 10 in the Second Affiliated Hospital of Heilongjiang University of Traditional Chinese Medicine.

Author contributions

Conceptualization: Hong Jin, Ji Liang, Miao Zhang.

Data curation: Hong Jin, Ji Liang, Siqi Zhang, Shuai Ma, Hongyu Qin, Dongxu Zhang, Miao Zhang.

Formal analysis: Hongyu Qin.

Supervision: Xueying Pang, Miao Zhang.

Writing – original draft: Hong Jin, Siqi Zhang.

Writing – review & editing: Ji Liang, Xueying Pang, Miao Zhang.

Supplementary Material

medi-103-e37024-s001.tiff (188.4KB, tiff)
medi-103-e37024-s002.tiff (875.6KB, tiff)
medi-103-e37024-s003.tiff (71.4KB, tiff)
medi-103-e37024-s004.tiff (875.6KB, tiff)
medi-103-e37024-s005.tiff (875.6KB, tiff)
medi-103-e37024-s006.tiff (875.6KB, tiff)
medi-103-e37024-s007.tiff (875.6KB, tiff)
medi-103-e37024-s008.tiff (70.8KB, tiff)

Abbreviations:

CI
confidence intervals
KPS
karnofsky performance status
NRS
numerical descriptor scale
OR
odds ratios
RCT
randomized controlled trial
SMD
standardized mean difference
SUCRA
Surface Under The Cumulative Ranking Curve
TCM
traditional Chinese medicine
TSAL
three-step nalgesic ladder method

The research of our article was funded by High-level Key Disciplines of Traditional Chinese Medicine (no. 14061230010).

This is a systematic review and meta-analysis, ethics approval and consent to participate are not applicable.

Not applicable. This study does not involve human participants.

The authors have no conflicts of interest to disclose.

Data sharing not applicable to this article as no datasets were generated or analyzed during the current study.

Supplemental Digital Content is available for this article.

How to cite this article: Jin H, Liang J, Zhang S, Ma S, Qin H, Zhang D, Pang X, Zhang M. External treatment of traditional Chinese medicine for cancer pain: A systematic review and network meta-analysis. Medicine 2024;103:8(e37024).

Contributor Information

Hong Jin, Email: jinhong517kh@163.com.

Ji Liang, Email: hljucm_lj@126.com.

Siqi Zhang, Email: 13845088833@139.com.

Shuai Ma, Email: m18245119455@163.com.

Hongyu Qin, Email: qinhongyu0503@163.com.

Dongxu Zhang, Email: 13845088833@139.com.

Xueying Pang, Email: pangxueying11@163.com.

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Supplementary Materials

medi-103-e37024-s001.tiff (188.4KB, tiff)
medi-103-e37024-s002.tiff (875.6KB, tiff)
medi-103-e37024-s003.tiff (71.4KB, tiff)
medi-103-e37024-s004.tiff (875.6KB, tiff)
medi-103-e37024-s005.tiff (875.6KB, tiff)
medi-103-e37024-s006.tiff (875.6KB, tiff)
medi-103-e37024-s007.tiff (875.6KB, tiff)
medi-103-e37024-s008.tiff (70.8KB, tiff)

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