Should eighteen incompatibilities be used? A systematic review and meta-analysis of the analgesic effect of pinellia and aconitum used externally for cancer pain

Many clinical formulas containing the couplet Chinese medicines pinellia and aconitum (CMPA) have been recognized and demonstrated analgesic efficacy. However, CMPA belongs to the "eighteen incompatibilities" of traditional Chinese medicine theory, which is considered prohibited and dangerous by some medical practitioners. Whether CMPA can truly be used safely and without concern in the clinic urgently requires a more cohesive evaluation of the evidence. This review aims to evaluate the effectiveness and safety of CMPA for external use in the treatment of cancer pain. We searched PubMed, Embase, Cochrane Library, CNKI, Wanfang, VIP, and Sinomed databases to collect randomized controlled trials (RCTs) comparing CMPA with conventional medicines for the treatment of cancer pain from their inception to December 31, 2023. Meta-analysis was conducted using RevMan 5.4 software. The modified Cochrane risk of bias tool was used to assess the quality of the included studies, and the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) evidence profile was constructed to illustrate the certainty of evidence. A total of 1083 patients were enrolled in 14 RCTs. The results of the meta-analysis showed that the numerical rating scale (NRS) pain score [MD=-0.84, 95 % CI (-1.21, -0.47), P < 0.00001, moderate certainty], duration of continuous analgesia [MD=1.45 h, 95 % CI (1.13, 1.77), P < 0.00001, low certainty], and Karnofsky performance status (KPS) quality of life score [MD=7.25, 95 % CI (5.01, 9.48), P < 0.00001, low certainty] of patients after external administration of CMPA-containing prescriptions in combination with conventional medicine therapy were better than those with the conventional medicine therapy. The incidence of total adverse reactions [RR=0.69, 95 % CI (0.58, 0.83), P < 0.0001, moderate certainty] and constipation [RR=0.43, 95 % CI (0.19, 0.97), P = 0.04, moderate certainty] of patients after external administration of CMPA-containing prescriptions in combination with conventional medicine therapy were lower than those with the conventional medicine therapy. No statistically significant differences were found regarding the effectiveness or safety of CMPA-containing prescriptions compared to conventional medicine therapy (low or very low certainty evidence). The external use of CMPA-containing prescriptions, when combined with conventional medicine therapy, is safer and more effective for cancer pain than conventional medicine therapy. However, higher-level evidence is still warranted. PROSPERO registration number: CRD42023400792.