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Table of Contents
ORIGINAL ARTICLE
Year : 2022  |  Volume : 8  |  Issue : 3  |  Page : 402-412

Systematic review and meta-analysis of acupuncture for pain caused by liver cancer


1 Shanghai Research Institute of Acupuncture and Meridian, Yueyang Hospital of Integrated Traditional Chinese and Western Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai, China
2 Shanghai Qigong Research Institute, Shanghai University of Traditional Chinese Medicine, Shanghai, China
3 Key Laboratory of Acupuncture and Immunological Effects, Shanghai University of Traditional Chinese Medicine, Shanghai, China
4 Shanghai Research Institute of Acupuncture and Meridian, Yueyang Hospital of Integrated Traditional Chinese and Western Medicine; Key Laboratory of Acupuncture and Immunological Effects, Shanghai University of Traditional Chinese Medicine, Shanghai, China
5 Liver and Immunology Research Center, Daejeon Oriental Hospital of Daejeon University, Korea
6 Shanghai Qigong Research Institute; Key Laboratory of Acupuncture and Immunological Effects, Shanghai University of Traditional Chinese Medicine, Shanghai, China

Date of Submission21-Jan-2021
Date of Acceptance13-Aug-2021
Date of Web Publication21-Jul-2022

Correspondence Address:
Lu-Yi Wu
Key Laboratory of Acupuncture and Immunological Effects, Shanghai University of Traditional Chinese Medicine, 650 South WanPing Road, Xu Hui District, Shanghai 200030
China
Rui Zhong
Shanghai Qigong Research Institute, Shanghai University of Traditional Chinese Medicine, 650 South WanPing Road, Xu Hui District, Shanghai 200030
China
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/2311-8571.351510

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  Abstract 


Objective: The objective of this study is to systematically review and analyze the efficacy of acupuncture for pain caused by primary liver cancer (PLC). Materials and Methods: We searched databases, including PubMed, Medline, Embase, Cochrane Library, Web of Science, China National Knowledge Infrastructure, Chinese Science and Technology Periodicals Database (VIP), Wanfang, and SinoMed/Chinese Biomedical Database (CBM), and retrieved randomized controlled trials (RCTs) that used acupuncture as the primary intervention to treat pain caused by PLC. Two investigators then screened the articles, extracted and pooled data, and evaluated the risk of bias of the included articles according to the Cochrane Handbook. RevMan5.3 was used for the meta-analysis of eligible RCTs. Results: A total of 145 articles were retrieved; after screening, 8 RCTs involving 496 patients were eventually included in this meta-analysis. The results showed that acupuncture effectively improved cancer pain and was superior to Western medicine. Moreover, acupuncture was fast-acting for pain relief, prolonged the relief, and prevented relapse. Its adverse reaction rate was also significantly lower than that of Western medicine. No significant difference was observed in Visual Analog Scale score between acupuncture and Western medicine. Conclusion: Acupuncture relieves pain caused by liver cancer and can be used as an adjunct and alternative therapy for drug treatment. The existing research evidence is not yet objective or comprehensive, and more rigorous clinical trials are needed to validate the results.

Keywords: Acupuncture, liver cancer, meta-analysis, pain, systematic review


How to cite this article:
Zhang XW, Gu YJ, Wu HG, Li KS, Zhong R, Qi Q, Wu P, Ji J, Liu HR, Huang Y, Son CG, Wu LY. Systematic review and meta-analysis of acupuncture for pain caused by liver cancer. World J Tradit Chin Med 2022;8:402-12

How to cite this URL:
Zhang XW, Gu YJ, Wu HG, Li KS, Zhong R, Qi Q, Wu P, Ji J, Liu HR, Huang Y, Son CG, Wu LY. Systematic review and meta-analysis of acupuncture for pain caused by liver cancer. World J Tradit Chin Med [serial online] 2022 [cited 2022 Dec 1];8:402-12. Available from: https://www.wjtcm.net/text.asp?2022/8/3/402/351510




  Introduction Top


Primary liver cancer (PLC) is a common malignant tumor that can be histologically classified as hepatocellular carcinoma (HCC) or intrahepatic cholangiocarcinoma, where about 75%~85% of cases are HCC.[1],[2] By 2016, liver cancer was affecting 1 million individuals worldwide, which increased by 38% over the last decade, and the mortality rate was more than 80%.[3],[4] In addition, PLC is the sixth most commonly diagnosed cancer and the third leading cause of cancer death worldwide in 2020, with approximately 906,000 new cases and 830,000 deaths.[5] Both incidence and mortality of liver cancer are higher in men than in women (approximately 3:1) in most regions.[3],[4] According that, the number of patients with liver cancer in China accounts for more than half of the patients worldwide, which is one of the countries with the heaviest burden of liver cancer.[1] Liver cancer can occur in all age groups, although its incidence increases with age and is more common in men aged 60 years or above.[6]

Interdisciplinary research on the mechanism of liver cancer shows that liver cancer is closely related to chronic hepatitis (mainly hepatitis B and C), cirrhosis, nonalcoholic fatty liver, and alcohol intake.[3],[5] In China, hepatitis B is the most important pathogenic factor of liver cancer. Cancer pain is a common symptom of advanced cancer and occurs in more than 50% of patients.[4]

It may even cause insomnia, anorexia, and depression. With rapid tumor growth, the liver capsule is stretched and stimulated, causing upper-right-abdominal discomfort at first and then intermittent or persistent pain.[6] Cancer pain is unavoidable and mainly treated with drugs. With the principle of “three-step analgesia treatment of cancer pain” of the World Health Organization, different intensity of analgesic drugs are selected, mainly including nonsteroidal anti-inflammatory and analgesic drugs, opioids and auxiliary analgesics, according to the degree of pain of patients.[7] It still triggers a lot of thorny adverse reactions, which although the main treatment for cancer pain. Gastrointestinal reactions such as gastrointestinal bleeding, ulcer, and perforation are the most common in the use of nonsteroidal anti-inflammatory analgesics. The adverse reactions of opioids mainly include constipation, nausea and vomiting, lethargy, urinary retention, delirium, cognitive impairment, respiratory inhibition, etc. In addition, these drugs also have a certain degree of addiction. Auxiliary analgesics may cause dizziness, drowsiness, and peripheral edema.[8],[9] To some extent, these adverse reactions will affect patients' daily life, covering self-care ability, family and social communication ability, and overall quality of life. Therefore, it is important to look for effective, safe, nonaddictive alternative, or adjunct therapy to reduce pain.

As a treatment of traditional Chinese medicine, acupuncture has the advantages of rapid effect, simple operation, little adverse reaction, no dependence, and easy to be accepted by patients. With the wide application of traditional Chinese medicine and the development of modern medical treatment, theory of acupuncture is often involved in the combination with modern technology. Acupoint injection, electroacupuncture, bee acupuncture, auricular point, wrist-ankle acupuncture, and other treatments are made to enhance the effect of traditional acupuncture which are simple and effective in clinical operation with a widely spread in the treatment of cancer pain and good analgesic effect.[10],[11]

Modern studies show that acupuncture suppresses pain stimuli by increasing the production of monoamine transmitters, thereby increasing the pain threshold.[12] Moreover, acupuncture slows tumor progression by promoting the release of immune cells, enhancing the function of immune cells, and upregulating the level of immune response.[13] In the clinical study, Li Hui[14] observed some articles on acupuncture of cancer pain and found that acupuncture can effectively relieve cancer pain with an advance in safe and easy to operate, whether acupuncture alone compared with western medicine or acupuncture combined with western medicine compared with western medicine. It can significantly reduce the incidence of adverse reactions and improve the quality of life of patients to a certain extent as well. Liu Jie[15] used eight methods of intelligent turtle, Cai Yu[16] used TianYuan Acupuncture, while Hu Xia[17],[21] used wrist-ankle acupuncture to treat cancer pain, and they discovered that acupuncture could promote the release of β-endorphin in the human body and inhibit the production of substance P to achieve the effect of analgesic, which affirms the material basis of wrist-ankle acupuncture in the treatment of pain. However, no systematic review has been conducted on the effect of acupuncture for pain caused by liver cancer. In this study, we searched for and retrieved relevant randomized controlled trials (RCTs) to perform a systematic review and meta-analysis of acupuncture for pain caused by liver cancer, in order to provide empirical evidence for clinical treatment and research.


  Materials and Methods Top


Inclusion criteria

Subjects

Participants met the diagnostic criteria of PLC. The diagnostic criteria could be any one of the following criteria: the Criteria for the Clinical Diagnosis and Staging of PLC developed by the Professional Committee of the Chinese Anti-Cancer Association,[18] the diagnostics criteria for PLC from Internal Medicine (Ed 6; People's Health Publishing House)/the International Union Against Cancer (UICC), the diagnostic criteria for PLC from Internal Medicine (Ed 5), the diagnostic criteria for liver cancer developed at the 2001 Conference in Guangzhou, China.

Types of articles included

The articles could be written in Chinese or English.

Interventions

The treatment group received acupuncture as the primary intervention. If acupuncture was the only intervention in the treatment group, the control group could receive conventional Western medicine, traditional Chinese medicine, or mock acupuncture. If the treatment group received acupuncture combined with Western medicine or traditional Chinese medicine, the control group had to receive the same Western medicine or traditional Chinese medicine. If the treatment group received acupuncture followed by moxibustion combined with Western medicine or traditional Chinese medicine, the control group had to receive moxibustion combined with the same Western medicine or traditional Chinese medicine.

Outcome measures

The primary outcome measures were clinical response rate/pain relief rate, significant response rate, overall response rate, Visual Analog Scale (VAS) score, relapse rate, and the time to relapse. Moreover, the time to pain relief, the duration of pain relief, and the level of plasma β-endorphin and substance P (SP) before and after treatment were used as secondary outcome measures.

Exclusion criteria

Articles that met any of the following criteria were excluded:

  1. Articles that focused on PLC accompanied by other underlying diseases, which complicated with severe pain caused by liver rupture and bleeding and serious primary diseases such as cardiocerebrovascular, kidney, lung, hematopoietic system, or mental diseases
  2. Articles that focused on intervention-induced pain caused by liver cancer
  3. Articles that were missing critical data, such as subject data and interventions
  4. Articles with unrealistic or unanalyzable data
  5. Duplicate articles.


Search strategy

We searched Chinese databases, including China National Knowledge Infrastructure, VIP, SinoMed/CBM, and Wanfang, with these Chinese keywords: “肝癌” (liver cancer), “肝恶性肿瘤” (malignant hepatoma), “原发性肝细胞癌” (primary hepatocellular carcinoma), “肝脏恶性肿瘤” (malignant hepatoma), “肝腺癌” (liver adenocarcinoma), “肝肿瘤” (hepatoma), “肝细胞癌” (hepatocellular carcinoma), “针灸” (acupuncture and moxibustion), “针刺” (acupuncture), “针” (needle), and “温针灸” (warm acupuncture). We searched English databases, including PubMed, Medline, Embase, Cochrane Library, and Web of Science, with these English keywords: “HCC,” “hepatocellular carcinoma,” “hepatoma”, “liver cancer,” “liver neoplasms,” “acupuncture,” “auricular needle,” “acupuncture and moxibustion,” “acupuncture-moxibustion,” and “pain.” The specific retrieval strategies of PubMed is presented as follows: (“hepatocellular carcinoma” [Title/Abstract] OR “hepatoma” [Title/Abstract] OR “liver cancer” [Title/Abstract] OR “liver neoplasms”[Title/Abstract]) AND (“acupuncture” [Title/Abstract] OR “auricular needle” [Title/Abstract] OR “acupuncture and moxibustion” [Title/Abstract] OR “acupuncture-moxibustion” [Title/Abstract] OR “scalp acupuncture” [Title/Abstract] OR “tongue acupuncture” [Title/Abstract] OR “wrist-ankle acupuncture” [Title/Abstract]) AND (“RCT” [Title/Abstract] OR “rct” [Title/Abstract] OR “randomized controlled trials” [Title/Abstract] OR “randomized” [Title/Abstract]) AND (“pain”[All Fields]). Articles published before May 28, 2021 were retrieved. We also screened the references of these articles to identify reviews and look for additional studies.

Data compilation

Data screening

The search strategy was developed according to the predetermined inclusion criteria. The articles searched were imported into EndNote version X9.1 by two investigators (Yun-Jia Gu and Xiao-Wen Zhang) independently. They read the titles and abstracts to exclude irrelevant articles. Next, they downloaded and read the entire remaining articles to determine their eligibility. In case of any discrepancy, the investigators discussed the results, and if needed, a third investigator (Rui Zhong) was consulted for resolution.

Data extraction and management

The investigators (Qin Qi and Pin Wu) extracted valid data from all eligible articles, including basic information of the study (authors and publication date), basic characteristics of the subjects (sample size, sex, age, and duration of disease), interventions (method, frequency, dose, and time), course of treatment, primary outcome measures and data, follow-up data, and adverse events. The two investigators independently sorted and verified all the data and then entered the data on a standardized form. In case of any discrepancy, the investigators resolved it by discussion. A third investigator (Lu-Yi Wu) was consulted as needed. In the case of incomplete or unknown data, the investigators attempted to contact the original author(s) to obtain additional information.

Evaluation of article quality

The Chinese version of the Cochrane Handbook (2014) was used to evaluate the risk of bias of the articles included. We evaluated seven items on study design: the generation of random sequences, allocation concealment, patient and investigator blinding, outcome evaluator blinding, integrity of outcome data, selective reporting, and other biases. We evaluated and rated the quality of the articles as having low risk of bias, high risk of bias, or unknown risk of bias.

Statistical analysis

RevMan5.3 was used for meta-analysis. The continuous variables are expressed as the mean difference (MD) with 95% confidence interval (CI). The categorical variables are expressed as odds ratio (OR) with 95% CI. I2 was calculated to test for heterogeneity. RCTs with high heterogeneity (P ≤ 0.10 and/or I2 ≥ 50%) were analyzed with a random-effect model for combined effects. RCTs with low heterogeneity (P > 0.10 and I2 < 50%) were analyzed with a fixed-effect model. P < 0.05 was considered statistically significant. If many RCTs were included in the meta-analysis (n ≥ 10), RevMan would be used to perform funnel plot analysis and evaluate the publication bias. Following the Cochrane Handbook, mean change and standard deviation (SD) from before to after treatment were calculated as follows: Meanchange = Mean1-Mean2; SDchange = √SD2 + SD2 – 2 × Corr × SD1 × SD2, where the Corr coefficient is 0.3–0.8 (0.4 was used in this study as per convention); Mean1 is the endpoint mean; Mean2 is the baseline mean; SD1 is the endpoint SD; and SD2 is the baseline SD.


  Results Top


Literature search and retrieval

Based on the predetermined search strategy, 20 English articles and 125 Chinese articles were retrieved from major English and Chinese databases. The titles were exported to Excel. After exclusion of 54 duplicate articles, the investigators read the titles and abstracts of the other 91 articles and excluded 50 irrelevant articles, such as animal studies, case reports, literature reviews and meta-analyses, noninterventional basic research, nonclinical controlled trials, and studies unrelated to pain caused by liver cancer. Next, the investigators downloaded and read the full text of the remaining 41 articles to exclude non-RCTs, studies with unknown diagnostic criteria, and studies with ineligible interventions. In the end, 8 RCTs were included in this study,[16],[17],[18],[19],[20],[21],[22],[23] all of which were written in Chinese. See [Figure 1] for the inclusion flow chart.
Figure 1: Flow Chart

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Basic characteristics of included randomized controlled trials

Eight RCTs involving 496 patients were included in this study. One RCT provided no information of the number of male and female patients and was thus excluded from further analysis of gender. Of the remaining 416 patients, 334 (80.3%) were men and 82 (19.7%) were women, they were aged 18–73 years, and they had a duration of disease of 1 month to 3 years. One RCT[15] based their diagnoses on the Criteria for the Clinical Diagnosis and Staging of PLC developed by the Professional Committee of the Chinese Anti-Cancer Association. 2 RCTs[16],[19] used the diagnostic criteria for PLC from Internal Medicine (editor-in-chief, Rengao Ye). 3 RCTs[17],[20],[22],[23] used the UICC diagnostic criteria for PLC. 1 RCT[21] used the diagnostic criteria for liver cancer developed at the 2001 Conference in Guangzhou, China.

Acupuncture was the main treatment in the treatment group, either alone with variation in techniques and acupoints (4 RCTs[16],[17],[19],[23]), alone or in combination with Western medicine (2 RCTs[21],[22]), or always in combination with Western medicine (2 RCTs[15],[20]). Among the RCTs included, acupuncture was mostly administered for 20–30 min, once a day. In 3 RCTs,[21],[22],[23] a needle was left in the ankle for 10–12 h. One RCT[20] used auricular acupuncture, followed by auricular acupressure with small seeds. The patients were then instructed to press the seeds daily for approximately 10 min. As the control group, two RCTs[16],[19] used the three-step analgesic ladder. Patients with Grade I pain took indomethacin capsules 30 mg i. m. t. i. d.; patients with Grade II pain received bucinnazine hydrochloride injection 50–100 mg i. m. t. i. d.; patients with grade III pain received pethidine hydrochloride injection 50–100 mg i. m. 4–6 times a day. The pain symptoms were evaluated with the VAS as follows: VAS score ≤3, Grade I; VAS score 3–6, Grade II; and VAS score >6, Grade III. In 1 RCT,[17] patients with mild pain took drugs such as indomethacin 25–35 mg i. m. t. i. d. 4 RCTs[17],[21],[22],[23] used differential therapy, where patients with moderate pain received weak opioids such as codeine 30 mg t. i. d., and patients with severe pain received morphine with an initial dose of 10/30 mg b. i. d., which could be increased for aggravating pain. The pain was graded using a Verbal Rating Scale (VRS) as follows: VRS score of 0, no pain; VRS score of 1–3, mild pain; VRS score of 4–6, moderate pain; VRS score of 7–10, severe pain. In 1 RCT,[15] patients took tramadol hydrochloride 100 mg q12 h. In another RCT,[20] patients took morphine sulfate sustained-release tablets 30 mg b. i. d., and the dose may be adjusted based on patient condition with the treatment target of no pain. Course of the treatment varied from 10 days[17],[21],[22],[23] to 2 months.[16]

Various outcome measures were used in the RCTs. Two RCTs[16],[19] observed VAS score before and after treatment; 2 RCTs[15],[19] observed the effective rate (significant response rate + response rate) after treatment. Six RCTs[16],[17],[20],[21],[22],[23] observed the pain relief rate (basic relief rate + significant relief rate) and overall response rate (basic relief rate + significant relief rate + mild relief rate). Two RCTs[21],[22] observed the time to relapse and relapse rate. Three RCTs[15],[17],[22] observed the time to pain relief and the duration of pain relief, with means provided in 2 RCTs[15],[22] and the time range provided in 1 RCT.[17] Other RCTs[15],[21],[22] observed significant response rate, the level of β-endorphin and SP before and after treatment, and the mean duration of pain relief See [Table 1].
Table 1: Basic characteristics of included randomized controlled trials

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Evaluation of the risk of bias in the included randomised controlled trials

The risk of bias in the included RCTs was evaluated according to the criteria in the Cochrane Handbook. For the generation of random sequences (a type of selection bias), 3 RCTs[15],[16],[20] used a random number table and were thus deemed to have low risk of bias; 1 RCT[17] used the layered random method and were deemed to have low risk of bias; 4 RCTs[19],[21],[22],[23] mentioned randomization without detailed information of how the random sequence was generated and was thus deemed to have unknown risk of bias. For allocation concealment, 1 RCT[15] used sequentially numbered, opaque, sealed envelopes for allocation concealment and were deemed to have low risk of bias; 7 RCTs[16],[17],[19],[20],[21],[22],[23] provided no information on allocation concealment and were deemed to have unknown risk of bias. For blinding, 1 RCT[15] implemented triple blinding of the operator for randomization, patients, and outcome statisticians and evaluators; these individuals had no communications with each other and were blinded to randomization. Thus, this RCT was deemed to have low risk of bias. The remaining RCTs provided no information on blinding and were deemed to have unknown risk of bias. More details of the RCTs were presented in [Figure 2] and [Figure 3] based on the above evaluations.
Figure 2: Risk of bias graph

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Figure 3: Risk of bias summary

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Meta-analysis

Given various outcome measures used in the included RCTs, we used VAS score, pain relief rate, overall response rate, the time to relapse, relapse rate, the time to pain relief, and the duration of pain relief as primary measures for meta-analysis. We also used significant response rate and the mean duration of pain relief as secondary measures.

Acupuncture versus Western medicine

Two RCTs[15],[19] investigated effective rate after treatment. A random-effect model was used due to significant heterogeneity (P = 0.13, I2 = 56%). Meta-analysis showed that effective rate was higher in the acupuncture group than in the Western medicine group, but the difference did not reach statistical significance (OR = 1.77, 95% CI [0.22, 14.11], P = 0.59), as shown in [Figure 4].
Figure 4: acupuncture vs drug in Effective Rate

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Two RCTs[15],[22] investigated the time to pain relief. A fixed-effect model was used due to low heterogeneity (P = 0.39, I2 = 0%). Meta-analysis showed a significant between-group difference in the time to pain relief that favored acupuncture (MD = −21.14, 95% CI [−25.22, −17.07], P < 0.00001), as shown in [Figure 5].
Figure 5: acupuncture vs drug in Time to Pain Relief

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Two RCTs[15],[22] investigated the duration of pain relief. A random-effect model was used due to significant heterogeneity (P < 0.00001, I2 = 99%). Meta-analysis showed that acupuncture extended the duration of pain relief relative to Western medicine, but the difference did not reach significant difference (MD = 11.62, 95% CI [−5.27, 28.50], P = 0.18). See [Figure 6].
Figure 6: acupuncture vs drug in Duration of Pain Relief

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Two RCTs[21],[22] investigated the time to relapse. A fixed-effect model was used due to low heterogeneity (P = 0.69, I2 = 0%). Meta-analysis showed a significant between-group difference in the time to relapse that favoured acupuncture (MD = 25.66, 95% CI [21.63, 29.69], P < 0.00001). See [Figure 7].
Figure 7: acupuncture vs drug in Time to Relapse

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Moreover, these RCTs investigated the relapse rate. A fixed-effect model was used due to low heterogeneity (P = 0.86, I2 = 0%). Meta-analysis showed a significant between-group difference in the relapse rate that favoured acupuncture (OR = 0.01, 95% CI [0.00, 0.09], P < 0.0001). See [Figure 8].
Figure 8: acupuncture vs drug in Relapse Rate

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Two RCTs[16],[19] investigated the VAS scores before and after treatment. A random-effect model was used due to significant heterogeneity (P < 0.00001, I2 = 97%). Meta-analysis showed no significant between-group difference in the VAS score (MD = 1.32, 95% CI [−4.03, 6.67], P = 0.63). See [Figure 9].
Figure 9: acupuncture vs drug in VAS

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One RCT[15] investigated the significant response rate and found that the rate was significantly higher in the acupuncture group than in the Western medicine group (OR = 6.57, 95% CI [2.11, 20.48], P = 0.001).

One RCT[22] investigated the mean duration of pain relief and found that acupuncture significantly extended the mean duration of pain relief over Western medicine (MD = −60.63, 95% CI [−67.38, −53.88], P < 0.00001).

Acupuncture alone/acupuncture + Western medicine versus Western medicine alone

Four RCTs[16],[20],[22],[23] investigated the pain relief rate. A fixed-effect model was used due to low heterogeneity (P = 0.53, I2 = 0%). Meta-analysis showed that the pain relief rate was significantly higher in the acupuncture group than in the Western medicine group (OR = 1.94, 95% CI [1.15, 3.28], P = 0.01). See [Figure 10].
Figure 10: acupuncture (+drug) vs drug in Pain Relief Rate

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Six RCTs[16],[17],[20],[21],[22],[23] investigated the overall response rate. A fixed-effect model was used due to low heterogeneity (P = 0.76, I2 = 0%). Meta-analysis showed that the overall response rate was higher in the acupuncture group than in the Western medicine group, but the difference did not reach statistical significance (OR = 1.35, 95% CI [0.69, 2.63], P = 0.37). See [Figure 11].
Figure 11: acupuncture (+drug) vs drug in Overall Response Rate

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Adverse events

Seven RCTs[15],[16],[17],[19],[21],[22],[23] reported and described adverse reactions, which occurred in all study groups. Two RCTs[21],[22] reported a lower incidence of adverse reactions in the acupuncture group than in the Western medicine (alone) group.

Five RCTs[15],[16],[17],[19],[23] provided analysable data. A random-effect model was used due to significant heterogeneity (P = 0.007, I2 = 72%). Meta-analysis showed that the incidence of adverse reactions was significantly lower in the acupuncture group than in the Western medicine group (OR = 0.08, 95% CI [0.02, 0.29], P = 0.0001). See [Figure 12].
Figure 12: acupuncture (+drug) vs drug in Adverse Reactions

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The remaining RCTs did not describe or report any adverse reactions or side effects.

Test of sensitivity

As for the overall response rate of Acupuncture alone/acupuncture + Western medicine versus Western medicine alone, we found that after excluding 3 articles,[18],[21],[23] the heterogeneity of meta analysis results decreased: OR = 1.82, 95% CI (0.84, 3.93), I2 = 0%. As for the Adverse events of all RCTs, we found that after excluding 3 articles,[16],[17] the heterogeneity of meta analysis results decreased: OR = 0.02, 95% CI (0.01, 0.07), I2 = 0%.


  Discussion Top


Liver cancer belongs to the categories of “accumulation”, “ruffian fullness”, “bulging”, “jaundice”, “hypochondriac pain”, “Fei qi” and so on.[24] The description of pain of liver cancer in ancient literature can be found in “Key Points for Treatment and Syndrome”: “Lumps accumulate in the gastric cavity, which is as big as a cup covered, and the lumps are blocked, so back pain and heartache.”[25] The pathogenesis of pain of liver cancer can be roughly divided into two types, called pain without access and pain without nutrition. In different stages of its development, the pathogenesis is also different. Clinically, it is often characterized by original deficiency and the excess with a mixed situation. Pain is predominant, in the early and middle stages of liver cancer, it is mainly manifested as real pain, and in the late stage, it mainly manifests as deficiency pain or both deficiency and excess.

Acupuncture can activate qi and blood, dredge collaterals and relieve pain. It can stimulate partial blood circulation while stimulating acupoints, which can effectively improve the pain of liver cancer and improve the quality of life of patients.[26] This method makes the general principle painless, the glory is not painful, and obtains the ideal curative effect in clinical practice. At the same time, it avoids the side effects of western analgesic medicine as a good supplementary and alternative therapy.[27],[28] Some scholars have evaluated the acupoint selection of acupuncture in the treatment of cancer pain and found that ST36, RN12, LI4, PC6, SP6 and Ashi acupoints are the most frequently used. Among them, Ashi acupoints are the important points for the treatment of symptoms, which can promote blood circulation, remove blood stasis, promote qi and relieve pain.[29] Through stimulation, it can increase the secretion of endorphins in the brain, inhibit the excitation of parafascicular nucleus and spinal dorsal horn, and correspondingly improve the pain threshold of the body to analgesic.[30] ST36 is the acupoint of the stomach meridian with more qi and blood which can significantly increase the blood lysin, opsonin, and leukocyte phagocytic index in blood cross excitation,[31] reduce the spinal dorsal horn pain and the expression of substance P for alleviating cancer pain.[32] After that, the corresponding acupoints of Beishu and meridians are selected according to the type of cancer. Therefore, for liver cancer, ST36, BL18, LR14 and Ashi points are generally selected, and most of which belong to the liver meridian, gallbladder meridian, and stomach meridian.[33]

Acupuncture at acupoints promotes tissue repair and suppresses pain.[34] Tumor compression, invasion of tissue structure, and triggering of certain chemical changes directly cause nerve damage. The release of tumor cells and the production of proinflammatory cytokines indirectly cause nerve damage.[35] Tumor-secreted endothelin-1 mediates and leads to cancer pain after activating the endothelin-A receptor. Acupuncture reduces cancer pain by regulating the release of opioid peptides in the body and inhibiting their interaction with high-density secreted receptors.[33],[36],[37] In addition, acupuncture promotes the production of interleukin-2, a T-cell– secreted lymphokine that enhances the killing capacity of killer cells and stimulates the immune cells to secrete a variety of lymphokines, thereby enhancing the immunity and self-repair of cancer patients with an analgesic effect.[38]

Previous meta-analysis of the effect of acupuncture and moxibustion combined with acupoint injection for pain caused by liver cancer have directed attention to the effect of Western medicine or traditional Chinese medicine combined with acupuncture. The present study indicated that acupuncture may be an effective alternative therapy for pain caused by liver cancer. 8 RCTs were included in this study. Meta-analysis showed that acupuncture was superior to Western medicine in the pain relief rate and significant response rate, with no significant between-group difference in the overall response rate or VAS scores. Acupuncture took effect faster, prolonged the pain relief, and effectively reduced pain. Acupuncture significantly extended the time to relapse and reduced relapse, thereby significantly improving the quality of life. 7 RCTs reported adverse reactions. Overall, the incidence of adverse reactions was significantly lower in the acupuncture group than in the Western medicine group for patients with pain caused by liver cancer.

Pain is personal and subjective and may be associated with potential injury. Quantitative evaluation tools for the intensity of cancer pain include VRS, Numerical Rating Scale (NRS), VAS, integrated pain score, pain rating index (developed by Italian researchers),[39] and Brief Pain Inventory (BPI).[40] VRS is simple, with good compliance, and is suitable for patients with low educational level or difficulties in comprehension or communication. NRS is straightforward, accurate, and sensitive, making it a popular tool worldwide.[41] VAS is simple and easy to perform but less accurate. In this study, 2 RCTs[16],[19] used VAS, and 1 RCT[17] used NRS; both scales are objective, especially when they were combined with clinical response rate. In addition, 1 RCT[20] used BPI to evaluate pain relief and quality of life. This study also showed that acupuncture reduced the level of plasma β-endorphin and SP and hindered the transmission of pain stimuli.[21],[42] In summary, acupuncture reduces pain through multiple mechanisms.

This study still has some limitations. There were variations in study design, and the sample size was not large. In addition, there are some problems such as inconsistent acupoint selection and treatment time, especially the significant differences in the course of intervention, which have a great impact on the results. In the future, proper randomization, generation of random sequences, and allocation concealment should be used in RCTs on acupuncture for pain caused by liver cancer. For blinding, acupuncture requires physician-patient cooperation, making it difficult to implement blinding of operators. However, subject blinding should be performed when possible. Moreover, it is important to implement proper blinding during data measurements and analysis. Further research is needed to investigate the course of treatment. The effect of acupuncture is cumulative and requires sufficient treatment time. In addition, clinical efficacy should be evaluated based on quantitative criteria to ensure accuracy and objectivity. Furthermore, proper follow-up can help researchers to obtain information on long-term efficacy to provide a better guidance for clinical treatment.


  Conclusion Top


For pain caused by liver cancer, acupuncture is superior to Western medicine in improving the pain relief rate, reducing the time to pain relief, prolonging the pain relief, preventing relapse, and reducing patient suffering. Moreover, acupuncture prevents adverse reactions associated with Western medicine and improves the quality of life. Acupuncture is comparable to Western medicine in improving the overall response rate and VAS score. These data indicate that acupuncture is effective for pain caused by liver cancer and is a good adjunct or alternative therapy. Nevertheless, further research is needed to reach more objective conclusions. In the future, large, multi-center, high-quality RCTs with rigorous design are needed for validation. Moreover, scales other than VAS may be used to evaluate clinical efficacy. The same objective outcome measures should be used to ensure more accurate evaluation of the effect of acupuncture for pain caused by liver cancer.

Acknowledgments

This research was supported by Key Project of Chinese National Programs for Fundamental Research and Development (973 Program) (No. 2009CB522900, No. 2015CB554501), the Project of Three-Year Action Plan for development of traditional Chinese medicine in Shanghai (No. ZY (2018-2020)-CCCX-2004-01) and Shanghai Clinical Research Center for Acupuncture and Moxibustion (No. 20MC1920500). We thank to the three programs which provided some time for us to carry out this work.

Ethical statement

All authors including myself have seen and approved this manuscript for publication. This manuscript has not been submitted to any other journals for publication.

Financial support and sponsorship

This study was financially supported by Key Project of Chinese National Programs for Fundamental Research and Development (973 Program)(No. 2009CB522900, No. 2015CB554501), the Project of Three-Year Action Plan for development of traditional Chinese medicine in Shanghai (No.ZY (2018- 2020)-CCCX-2004-01) and Shanghai Clinical Research Center for Acupuncture and Moxibustion (No. 20MC1920500).

Conflicts of interest

There are no conflicts of interest.



 
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