Abstract
Purpose
Bone cancer pain presents a clinical challenge with limitations of current treatments. Compound kushen injection (CKI) is a well-known traditional Chinese medicine (TCM) formulation in treatment of patients with bone cancer pain. The objective of this study is to assess the efficacy and safety of CKI for bone cancer pain.
Methods
A systematic literature search was conducted in nine databases until December 2012 to identify randomized controlled trials (RCTs) of CKI versus current western therapies for bone cancer pain. The primary outcome was total pain relief rate. The secondary outcomes were the quality of life and adverse events at the end of treatment course. The methodological quality of RCTs was assessed independently using six-item criteria according to the Cochrane Collaboration, and the level of evidence was assessed by the GRADE approach. All data were analyzed using Review Manager 5.1.0.
Results
Seven RCTs with 521 patients from 2010 to 2012 were identified. Compared with radiotherapy or bisphosphonates, seven RCTs showed significant effects of CKI for improving pain relief in patients with bone cancer pain (n = 521, risk ratio (RR) = 1.25, 95 % CI (95 % confidence intervals (CI)), 1.13 to 1.38, p < 0.0001)), three RCTs for improving Karnofsky scoring (KPS) increase rate (n = 305, RR = 1.62, 95 % CI, 1.32 to 1.99, p < 0.00001), 1 RCT for increasing KPS scores (n = 78, mean difference (MD) = 10.43, 95 % CI 4.76 to 16.10, p = 0.0003). 4 RCTs reported adverse effects in both the treatment and control groups. The patients treated with CKI achieved statistically significant reductions of incidences of leukopenia (n = 276, RR = 0.32, 95 % CI, 0.21 to 0.47, p < 0.00001) and nausea (n = 78, RR = 0.15, 95 % CI, 0.06 to 0.34, p < 0.00001). No severe adverse events were found and no treatment was stopped because of adverse events of CKI in the treatment groups. However, the studies were deemed to have a high risk of bias.
Conclusion
This systematic review showed positive but weak evidence of CKI for bone cancer pain because of the poor methodological quality and the small quantity of the included trials. Future rigorously designed RCTs are required.
Similar content being viewed by others
References
Thurlimann B, de Stoutz ND (1996) Causes and treatment of bone pain of malignant origin. Drugs 51:383–398
Peters CM, Ghilardi JR, Keyser CP, Kubota K, Lindsay TH, Luger NM, Mach DB, Schwei MJ, Sevcik MA, Mantyh PW (2005) Tumor-induced injury of primary afferent sensory nerve fibers in bone cancer pain. Exp Neurol 193:85–100
Portenoy RKFK, Lussier D, Hanks G (2004) Difficult pain problems: an integrated approach. Oxford University Press, Oxford
Colvin L, Fallon M (2008) Challenges in cancer pain management—bone pain. Eur J Cancer 44:1083–1090, Oxford, England: 1990
Mercadante S, Arcuri E (1998) Breakthrough pain in cancer patients: pathophysiology and treatment. Cancer Treat Rev 24:425–432
Laird BJ WJ, Murray G (2009) What is the key question in the assessment of cancer induced bone pain: results from a characterization study. British Pain Society, London
de Wit R, van Dam F, Loonstra S, Zandbelt L, van Buuren A, van der Heijden K, Leenhouts G, Huijer Abu-Saad H (2001) The Amsterdam Pain Management Index compared to eight frequently used outcome measures to evaluate the adequacy of pain treatment in cancer patients with chronic pain. Pain 91:339–349
Meuser T, Pietruck C, Radbruch L, Stute P, Lehmann KA, Grond S (2001) Symptoms during cancer pain treatment following WHO-guidelines: a longitudinal follow-up study of symptom prevalence, severity and etiology. Pain 93:247–257
Mercadante S (1997) Malignant bone pain: pathophysiology and treatment. Pain 69:1–18
Rubens RD (1998) Bone metastases—the clinical problem. Eur J Cancer 34:210–213, Oxford, England: 1990
Chow E, Zeng L, Salvo N, Dennis K, Tsao M, Lutz S (2012) Update on the systematic review of palliative radiotherapy trials for bone metastases. Clin Oncol 24:112–124
McQuay HJ, Collins SL, Carroll D, Moore RA (2000) Radiotherapy for the palliation of painful bone metastases. The Cochrane database of systematic reviews: CD001793
Bailey FFA (2006) Oral opioid drugs. Oxford University Press, Oxford
Portenoy RK, Payne D, Jacobsen P (1999) Breakthrough pain: characteristics and impact in patients with cancer pain. Pain 81:129–134
Chan FK (2006) Primer: managing NSAID-induced ulcer complications—balancing gastrointestinal and cardiovascular risks. Nat Clin Pract Gastroenterol Hepatol 3:563–573
Lapeyre-Mestre M, de Castro AM, Bareille MP, Del Pozo JG, Requejo AA, Arias LM, Montastruc JL, Carvajal A (2006) Non-steroidal anti-inflammatory drug-related hepatic damage in France and Spain: analysis from national spontaneous reporting systems. Fundam Clin Pharmacol 20:391–395
Schaffer D, Florin T, Eagle C, Marschner I, Singh G, Grobler M, Fenn C, Schou M, Curnow KM (2006) Risk of serious NSAID-related gastrointestinal events during long-term exposure: a systematic review. Med J Aust 185:501–506
Schneider V, Levesque LE, Zhang B, Hutchinson T, Brophy JM (2006) Association of selective and conventional nonsteroidal antiinflammatory drugs with acute renal failure: a population-based, nested case–control analysis. Am J Epidemiol 164:881–889
Michaelson MD, Smith MR (2005) Bisphosphonates for treatment and prevention of bone metastases. J Clin Oncol Off J Am Soc Clin Oncol 23:8219–8224
Wong R, Wiffen PJ (2002) Bisphosphonates for the relief of pain secondary to bone metastases. The Cochrane database of systematic reviews. CD002068
Chen YZLP (2005) Effectiveness and application of Chinese medicine for cancer pain. Clin J Tradit Chin Med 17:529–531
Tian JWW, Gao HM, Wang ZM (2007) Determination of matrine, sophoridine and oxymatrine in compound kushen injection by HPLC. Zhongguo Zhong Yao Za Zhi 32:222–224
Luo XYZX, Gao W (2001) Studies on site of analgesic action of matrine and its mechanism. Chin Tradit Herb Drugs 32:41–43
Cao WLBJ, Guo RY (2012) Radiotherapy combined with compound kushen injection in the treatment for 58 cases with malignant bone metastasis. Chin Remedies Clin 12:1217–1218
LA Chen G, Gu HG, Lu Y, Wang X, Zhang SK (2010) Clinical analysis of treating metastatic bone cancer with radiotherapy plus compound kushen injection. China Med Eng 18:48–50
Ge CZXY, Zhang DF (2011) Clinical observation of compound kushen injection combined with three-dimensional conformal radiotherapy for advanced metastatic bone pain. Shandong Med J 51:72–73
Ren FFY, Li SD, Lin MX, Wang HM, Li M (2012) Efficacy and safety of compound kushen injection combined with zoledronic acid for ostealgia in patients with malignant tumor and osseous metastases. Eval Anal Drug-Use Hosp China 12:246–248
Ren SPLJ, Zheng YS (2011) Radiotherapy combined with compound matrine injection in the treatment for 30 cases with malignant bone metastasis. J Chin Oncol 17:795–796
Wang RYM, Pan XY (2011) Clinical observation of compound matrine injection combined with radiotherapy for advanced metastatic bone pain. China Pharm 22:329–331
Zhang YKLB, Zhu XZ (2011) Clinical observation of compound kushen injection combined with radiotherapy for advanced metastatic bone pain. Shandong Med J 51:84–85
Chan K, Shaw D, Simmonds MS, Leon CJ, Xu Q, Lu A, Sutherland I, Ignatova S, Zhu YP, Verpoorte R, Williamson EM, Duez P (2012) Good practice in reviewing and publishing studies on herbal medicine, with special emphasis on traditional Chinese medicine and Chinese materia medica. J Ethnopharmacol 140:469–475
Moher D, Liberati A, Tetzlaff J, Altman DG, PRISMA Group (2009) Preferred reporting items for systematic reviews and meta-analyses: the PRISMA statement. PLoS Med 6:e1000097
WHO (1996) Cancer pain relief. 2nd edn. World Health Organization, Geneva, pp. 1–8
Balshem H, Helfand M, Schunemann HJ, Oxman AD, Kunz R, Brozek J, Vist GE, Falck-Ytter Y, Meerpohl J, Norris S, Guyatt GH (2011) GRADE guidelines: 3. Rating the quality of evidence. J Clin Epidemiol 64:401–406
Guyatt G, Oxman AD, Akl EA, Kunz R, Vist G, Brozek J, Norris S, Falck-Ytter Y, Glasziou P, DeBeer H, Jaeschke R, Rind D, Meerpohl J, Dahm P, Schunemann HJ (2011) GRADE guidelines: 1. Introduction-GRADE evidence profiles and summary of findings tables. J Clin Epidemiol 64:383–394
Guyatt GH, Oxman AD, Kunz R, Atkins D, Brozek J, Vist G, Alderson P, Glasziou P, Falck-Ytter Y, Schunemann HJ (2011) GRADE guidelines: 2. Framing the question and deciding on important outcomes. J Clin Epidemiol 64:395–400
Guyatt GH, Oxman AD, Vist G, Kunz R, Brozek J, Alonso-Coello P, Montori V, Akl EA, Djulbegovic B, Falck-Ytter Y, Norris SL, Williams JW Jr, Atkins D, Meerpohl J, Schunemann HJ (2011) GRADE guidelines: 4. Rating the quality of evidence–study limitations (risk of bias). J Clin Epidemiol 64:407–415
Review Manager (RevMan) [Computer program] VfW (2008). In: Editor (ed)^(eds) Book. The Nordic Cochrane Centre, City
Chen A, Muzzio IA, Malleret G, Bartsch D, Verbitsky M, Pavlidis P, Yonan AL, Vronskaya S, Grody MB, Cepeda I, Gilliam TC, Kandel ER (2003) Inducible enhancement of memory storage and synaptic plasticity in transgenic mice expressing an inhibitor of ATF4 (CREB-2) and C/EBP proteins. Neuron 39:655–669
Wang LN, Yao M, Yang JP, Peng J, Peng Y, Li CF, Zhang YB, Ji FH, Cheng H, Xu QN, Wang XY, Zuo JL (2011) Cancer-induced bone pain sequentially activates the ERK/MAPK pathway in different cell types in the rat spinal cord. Mol Pain 7:48
Song XS, Cao JL, Xu YB, He JH, Zhang LC, Zeng YM (2005) Activation of ERK/CREB pathway in spinal cord contributes to chronic constrictive injury-induced neuropathic pain in rats. Acta Pharmacol Sin 26:789–798
Zhang K, Li YJ, Yang Q, Gerile O, Yang L, Li XB, Guo YY, Zhang N, Feng B, Liu SB, Zhao MG (2013) Neuroprotective effects of oxymatrine against excitotoxicity partially through down-regulation of NR2B-containing NMDA receptors. Phytomedicine Int J Phytother Phytopharmacol 20:343–350
Wang H, Li Y, Dun L, Xu Y, Jin S, Du J, Ma L, Li J, Zhou R, He X, Sun T, Yu J (2013) Antinociceptive effects of oxymatrine from Sophora flavescens, through regulation of NR2B-containing NMDA receptor-ERK/CREB signaling in a mice model of neuropathic pain. Phytomedicine : Int J Phytother Phytopharmacol 20:1039–1045
De Angelis C, Drazen JM, Frizelle FA, Haug C, Hoey J, Horton R, Kotzin S, Laine C, Marusic A, Overbeke AJ, Schroeder TV, Sox HC, Van Der Weyden MB, International Committee of Medical Journal Editors (2004) Clinical trial registration: a statement from the International Committee of Medical Journal Editors. New England J Med 351:1250–1251
Ernst E, Lee MS (2008) A trial design that generates only ''positive'' results. J Postgrad Med 54:214–216
De Smet PA (2002) Herbal remedies. New England J Med 347:2046–2056
Vickers A, Goyal N, Harland R, Rees R (1998) Do certain countries produce only positive results? A systematic review of controlled trials. Control Clin trials 19:159–166
Caraceni A, Brunelli C, Martini C, Zecca E, De Conno F (2005) Cancer pain assessment in clinical trials. A review of the literature (1999–2002). J Pain Sympt Manag 29:507–519
Carr DB, Goudas LC, Balk EM, Bloch R, Ioannidis JP, Lau J (2004) Evidence report on the treatment of pain in cancer patients. J Natl Cancer Inst Monogr 23–31
Kaasa S (2008) Palliative care research: time to intensify international collaboration. Palliat Med 22:301–302
Schulz KF, Altman DG, Moher D, CONSORT Group (2010) CONSORT 2010 statement: updated guidelines for reporting parallel group randomised trials. PLoS Med 7:e1000251
Calvert M, Blazeby J, Altman DG, Revicki DA, Moher D, Brundage MD, CONSORT PRO Group (2013) Reporting of patient-reported outcomes in randomized trials: the CONSORT PRO extension. JAMA : J Am Med Assoc 309:814–822
Flower A, Witt C, Liu JP, Ulrich-Merzenich G, Yu H, Lewith G (2012) Guidelines for randomised controlled trials investigating Chinese herbal medicine. J Ethnopharmacol 140:550–554
Bian Z, Liu B, Moher D, Wu T, Li Y, Shang H, Cheng C (2011) Consolidated standards of reporting trials (CONSORT) for traditional Chinese medicine: current situation and future development. Front Med 5:171–177
Acknowledgments
The current work was partially supported by the National Natural Science Foundation Project of China (no. 81273718 and no. 81302961). The funder had no role in study design, data collection and analysis, decision to publish, or preparation of the paper. The authors declare no conflict of interest.
Author information
Authors and Affiliations
Corresponding authors
Rights and permissions
About this article
Cite this article
Yanju, B., Yang, L., Hua, B. et al. A systematic review and meta-analysis on the use of traditional Chinese medicine compound kushen injection for bone cancer pain. Support Care Cancer 22, 825–836 (2014). https://doi.org/10.1007/s00520-013-2063-5
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s00520-013-2063-5