East Asian Herbal Medicine to Reduce Primary Pain and Adverse Events in Cancer Patients : A Systematic Review and Meta-Analysis With Association Rule Mining to Identify Core Herb Combination

Objective: Cancer pain is an important factor in cancer management that affects a patient’s quality of life and survival-related outcomes. The aim of this review was to systematically evaluate the efficacy and safety of oral administration of East Asian herbal medicine (EAHM) for primary cancer pain and to explore core herb patterns based on the collected data. Methods: A comprehensive literature search was conducted in 11 electronic databases, namely, PubMed, Cochrane Library, Cumulative Index to Nursing & Allied Health Literature, EMBASE, Korean Studies Information Service System, Research Information Service System, Oriental Medicine Advanced Searching Integrated System, Korea Citation Index, Chinese National Knowledge Infrastructure Database (CNKI), Wanfang Data, and CiNii for randomized controlled trials from their inception until August 19, 2021. Statistical analysis was performed in R version 4.1.1 and R studio program using the default settings of the meta-package. When heterogeneity in studies was detected, the cause was identified through meta-regression and subgroup analysis. Methodological quality was independently assessed using the revised tool for risk of bias in randomized trials (Rob 2.0). Results: A total of 38 trials with 3,434 cancer pain patients met the selection criteria. Meta-analysis favored EAHM-combined conventional medicine on response rate (risk ratio: 1.06; 95% CI: 1.04 to 1.09, p < 0.0001), continuous pain intensity (standardized mean difference: −1.74; 95% CI: −2.17 to −1.30, p < 0.0001), duration of pain relief (standardized mean difference: 0.96, 95% CI: 0.69 to 1.22, p < 0.0001), performance status (weighted mean difference: 10.71; 95% CI: 4.89 to 16.53, p = 0.0003), and opioid usage (weighted mean difference: −20.66 mg/day; 95% CI: −30.22 to −11.10, p < 0.0001). No significant difference was observed between EAHM and conventional medicine on response rate and other outcomes. Patients treated with EAHM had significantly reduced adverse event (AE) incidence rates. In addition, based on the ingredients of herb data in this meta-analysis, four combinations of herb pairs, which were frequently used together for cancer pain, were derived. Conclusion: EAHM monotherapy can decrease adverse events associated with pain management in cancer patients. Additionally, EAHM-combined conventional medicine therapy may be beneficial for patients with cancer pain in increasing the response rate, relieving pain intensity, improving pain-related performance status, and regulating opioid usage. However, the efficacy and safety of EAHM monotherapy are difficult to conclude due to the lack of methodological quality and quantity of studies. More well-designed, multicenter, double-blind, and placebo-controlled randomized clinical trials are needed in the future. In terms of the core herb combination patterns derived from the present review, four combinations of herb pairs might be promising for cancer pain because they have been often distinctly used for cancer patients in East Asia. Thus, they are considered to be worth a follow-up study to elucidate their actions and effects. Systematic Review Registration: https://www.crd.york.ac.uk/prospero/, identifier CRD42021265804