A meta-analysis of Duhuo Jisheng decoction combined with non-operative therapy on lumbar disc herniation

Chen-Yang Zhang,Ling Li,Zhao-Yong Li,Xiao-Nan Wu,Shao-Feng Yang

1Hunan University of Traditional Chinese Medicine, Changsha, 410208, China. 2The First Hospital of Hunan University of Chinese Medicine,Changsha,410007,China.

Abstract Objective: To systematically evaluate the cllinical efficacy of Duhuo Jisheng decoction (DHJSD) combined with non-surgical therapy on lumbar disc herniation(LDH).Methods:China Science and Technology Journal Database(VIP), Chinese National Knowledge Infrastructure (CNKI), WanFang Data, PubMed were searched and eligible randomized controlled clinical trials (RCTs) were included. Two reviewers evaluated the quality of the included RCTs and extracted data independently. Then, data analysis was performed with RevMetn 4.2 software. Results:A total of 18 RCTs were enrolled, including 1682 patients. Meta-analysis results showed that the overall response rate of DHJSD combined with non-operative therapy group (treatment group) in the treatment of LDH was better than that of the non-operative therapy group (control group) [OR = 4.29, 95% CI (3.19, 5.76), P ＜0.001]. JOA score of the treatment group was significantly higher than that of control group [OR=3.96,95%CI(3.4,4.52),P＜0.001]. VAS score was dramatically lower in the treatment group than the control group [OR = -1.58, 95% CI(-1.97, -1.18), P ＜0.001]. Conclusion: The clinical efficacy of DHJSD combined with non-surgical therapy is better than that of non-surgical therapy alone. However, due to the low quality of the included literatures,large-scale and high-quality RCTs are still needed for further confirmation.

Keywords: Duhuo Jisheng decoction (DHJSD), Lumbar disc herniation (LDH), Meta-Analysis, Randomized controlled trials(RCTs).

Introduction

LDH is an injury to the intervertebral disc on the basis of, degeneration usually caused by excessive strain or trauma to the lumbar vertebra. It may result in lumbar-leg pain due to the pressure on sinus nerves and nerve roots [1]. In traditional Chinese medicine(TCM), LDH can be included into the scope of"backache", "bone arthralgia " and "tendons wilting"[2]. Most of the patients with LDH are treated with non-surgical therapy, and about 80% ～90% of them can be relieved or even cured [3]. Non-surgical treatment includes bed rest,nonsteroidal anti-inflammatory drugs(NSAID),traction,physiotherapy, TCM, etc. TCM has been paid more and more attention in clinical treatment of LDH by virtue of its advantages such as little side effects,obvious effects and good compliance. DHJSD, which originated from Sun Simiao'sBeiji Qianjin Yao Fang,has the effects of dispelling wind and dampness,preventing arthralgia, benefiting liver and kidney,replenishing Qi and blood, and dredging the channel.According to modern pharmacological studies [4],DHJSD can significantly inhibit the NLRP3/ NF-κ B signal pathway and regulate the levels of the signal pathway related factors in patients, thereby achieving therapeutic effects. In addition, DHJSD has anti-inflammatory, analgesic and immunomodulatory effects[5].

In recent years, there have been many studies on LDH treated with DHJSD combined with non-surgical therapy. However, the quality of these researches is uneven and poorly regulated, making the research results difficult to be recognized by the international medical community. Meta-analysis is a statistical analysis that combines the results of multiple scientific studies [6]. It is mainly used for the comprehensive analysis of clinical RCT results, truly reflecting the clinical efficacy of the drugs studied. Therefore, based on a comprehensive understanding of the quality of relevant researches, this paper intends to make an objective evaluation of the effectiveness of DHJSD combined with non-surgical treatment for LDH by applying Meta-analysis.

Materials and methods

Literature search

Taking "Duhuo Jisheng decoction", "lumbar disc herniation" as key words, we searched VIP database,CNKI database, Wanfang database, PubMed and other electronic databases, and at the same time manually searched relevant magazines, professional materials and online information.The articles on the treatment of LDH by DHJSD combined with non-operative therapy were screened. The retrieval period was from January 1,2012 to December 31,2018.

Inclusion criteria

(1) All the involved participants were diagnosed as LDH according to the diagnostic criteria [7]: ①a history of lumbar trauma, chronic strain or cold and wet, and a history of chronic lumbar pain before onset in most patients; ② lumbar pain radiates to the buttocks and lower extremities, and get worse when abdominal pressure is increased (such as coughing and sneezing); ③ scoliosis, disappearance of lumbar physiological radians, tenderness beside the vertebra with radiation to the lower limbs, and limitation of lumbar activity; ④the lower extremity affected nerve innervation area has the sense hypersensitivity or the dullness, and the patients with long duration may appear the muscle atrophy; ⑤straight leg elevation or reinforcement test positive, the patellar and achilles tendon reflexes decreased or disappeared, and the extensor strength of hallux decreased. (2) The intervention measures of the control group were non-surgical therapy, and the treatment group was DHJSD combined with non-surgical therapy. (3)Outcomes include overall response rate (ORR), VAS score and JOA score. (4)All included literatures were published RCTs. (5) The equilibrium between groups was good and comparable.

Exclusion criteria

(1) Literature review, experience summary, theoretical elaboration or repeated publication;(2)studies without randomized control or with semi-randomized control;(3) animal experiments, adverse reaction reports,pharmacology,pharmacokinetics and other non-clinical efficacy studies; (4) literature without clear outcome indicators; (5) clinical trials with poor intergroup balance and incomparability; (6)the control group received surgical treatment; (7) other traditional prescription in the treatment group.

Quality evaluation

The methodological bias risk of all studies was evaluated by using the Cochrane evaluation handbook of RCTs. The bias risk indices were the random sequence generation, the allocation concealment, the blinding of participants and personal, the blinding of outcome assessment, data integrity, the selective reporting and the other bias. Each item was judged on three levels such as low risk of bias, high risk of bias and unclear risk of bias.

Data extraction and analysis

Using the unified quality evaluation form, two researchers extracted and cross-checked the data of each document that met the inclusion criteria independently. If the data in the study was not clear,we would call the author of the original literature to obtain relevant information. The meta-analysis was performed using Review Manager (RevMan) 4.2.7.This study used ORR for evaluation, which belonged to the counting data. So odds ratio (OR) and 95%confidence intervals (CI) was used in the results. The chi-square test was applied to evaluate heterogeneity among studies, and I2was used to show the magnitude of this heterogeneity. Results ofP≥0.1 and I2≤50%suggested a lack of significant heterogeneity; the fixed-effect model was used accordingly. For cases withP＜0.1 and I2 ＞50%, the random-effect model was adopted. Funnel plots were used to reveal the potential publication bias.

Results

Search results

Initially, 1470 potentially relevant articles were retrieved, including 627 from CNKI, 391 from VIP,452 from Wanfang databases and 12 from Pubmed.After initial screening, 290 studies met the inclusion criteria. After careful reading of the full text and excluding the duplication and non-compliance with the inclusion criteria, a total of 18 RCTs, including 1682 patients,were enrolled for this meta-analysis.The flow chart of literature search is shown in Figure 1. The general characteristics of the 18 literatures are shown in Table 1.The methodological quality of the included studies is shown in Figure 2.

Outcomes

Overall response rate

The efficacy evaluation criteria of included studies mainly adoptStandards for Diagnosis and Curative Effect of Chinese Medical SymptomandGuidelines for the Clinical Research of Chinese Medicine New Drugs.There are 15 articles [8-10,12-13,15-17,19-25]reference theStandards for Diagnosis and Curative Effect of Chinese Medical Symptom.Meta-analysis was performed in the included studies and the results showed that the OR of overall response rate between the treatment group and the control group was 4.29 and 95% CI was [3.19, 5.76]. The overall response rate of the treatment group was better than that of the control group, and the difference was highly statistically significant (P＜0.00001). It indicates that DHJSD combined with non-surgical therapy has a better effect in the treatment of LDH than the non-surgical therapy alone(Figure 3).

Figure 1 Flow chart of literature search

Table 1 The basic characteristics of the included studies

Shuai-shuai Guo[21]2016 64(32/32)DHJSD plus or minus+control group drug Dexamethasone sodium phosphate injection+ibuprofen slow release-1m Standards for Diagnosis and Curative Effect of Chinese Medical Symptom ORR Jie Li[22]2016 240(120/120)DHJSD plus or minus+control group drug Breviscapine injection+mannitol+dexamethasone Standards for Diagnosis and Curative Effect of Chinese Medical Symptom 3w Standards for Diagnosis and Curative Effect of Chinese Medical Symptom ORR,VAS score Jian-xing Pan[23]2017 94(47/47)DHJSD plus or minus+control group drug Dexamethasone+mannitol Standards for Diagnosis and Curative Effect of Chinese Medical Symptom 14d Standards for Diagnosis and Curative Effect of Chinese Medical Symptom ORR,VAS score Pei-hong Lu[24]2015 48(24/24)DHJSD plus or minus+control group drug Deer and melon polypeptide injection+mannitol+meroxicillin Standards for Diagnosis and Curative Effect of Chinese Medical Symptom 7d Standards for Diagnosis and Curative Effect of Chinese Medical Symptom ORR,JOA score Yu-wen Hou[25]2018 120(60/60)DHJSD plus or minus+control group drug Sodium dichlorophenate enteric-coated tablet Guidelines for the Clinical Research of Chinese Medicine New Drugs 3w Standards for Diagnosis and Curative Effect of Chinese Medical Symptom ORR

Figure 2 Methodological quality of included trials

Table 2 shows that the curative effect of the treatment group is better than that of the control group,no matter it is combined with sacral canal injection or other therapies such as non-steroidal anti-inflammatory drugs + neurotrophic drugs. 5 articles [8-12] about the efficacy of DHJSD combined with sacral canal injection therapy and the control group, showed that DHJSD combined with sacral canal injection therapy had better efficacy than the sacral canal injection therapy alone(P＜0.0001,RR[95%CI]=4.88[2.51,9.50]). 4 articles study [16-19] on the efficacy of DHJSD combined with NSAID+neurotrophic drugs,showing that DHJSD combined with sacral canal injection has better efficacy than NSAID +neurotrophic drugs (P＜0.0001,RR[95%CI]=5.17[2.6,10.28]). 2 articles study [14-15] on the efficacy of DHJSD combined with NSAID + hormone +dehydration therapy , showing that the efficacy of DHJSD combined with NSAID + hormone +dehydration therapy has better efficacy than that of NSAID + hormone + dehydration therapy (P=0.0004,RR[95%CI]=6.44[2.30,18.02]).

JOA scores

A total of 6 studies compared the effect of the DHJSD combined with non-operative therapy and non-operative therapy alone in the JOA score. We made heterogeneity test and found that there was statistical heterogeneity among the 6 trials (P＜0.00001). Therefore, the random-effect model was Adopted. The combined effect size OR = 3.96, 95%CI [3.4,4.52], and the combined effect size test Z=13.9 (P＜0.00001). The results suggest that the treatment group could significantly improve the JOA score of patients(Figure 4).

VAS scores

7 studies reported VAS scores after treatment.There was statistical heterogeneity among the above 7 trials (P＜0.00001) and the random-effect model was performed. The combined effect size OR =-1.58,95%Cl[-1.97,-1.18],and the combined effect size test Z = 7.72 (P＜0.00001), suggesting that the VAS score could be significantly reduced in the treatment group(Figure 5).

Publication bias

Funnel plots was made in the overall response rate of DHJSD combined with non-surgical treatment for LDH. The distribution of the study results was skewed, indicating there was a certain degree of publication bias(Figure 6).

Adverse reactions

In the included studies, 5 literatures [17, 18, 20, 23,25] reported adverse reactions. In the study of Yu-wen Hou [25], 3 patients in the control group presented gastrointestinal reactions, accounting for 5.0%, which were all relieved after targeted treatment. There was no statistical difference in the incidence of adverse reactions between the two groups, and no adverse reactions were recorded in the other studies.

Discussion

Figure 3 Forest plot of overall response rate

Table 2 Overall response rates

Figure 4 Forest plot of JOA scores

Figure 5 Forest plot of VAS scores

LDH belongs to the categories of"backache", "bone arthralgia"and"tendon weakening"in TCM.Su Wen Mai Yao Jing Wei Lunpoints out " The waist, the house of the kidney, can not be shaken, the kidney will be exhausted". It shows the main characteristics of kidney deficiency and backache.Dan Xi Xin Fapoints out that the causes of lumbago are "heat and deficiency, blood stasis, demoralization and phlegm accumulation", and emphasizes the important role of kidney deficiency in the occurrence of lumbago.DHJSD is composed ofRadix Angelicae Pubescentis,HerbaTaxilli,CortexEucommiae,Radix Acanthopanacis Bidentatae,Herba Asari,Radix Gentianae Macrophyllae,Poria,Cinnamon Heart,Radix Saposhnikoviae,Rhizoma,Radix Ginseng,Radix Glycyrrhizae,Radix Angelicae Sinensis,Peony,Dry Rehmannia Root. It mainly cures syndrome of chronic arthralgia, deficiency of liver and kidney,insufficiency of Qi and blood. In the prescription,Radix Angelicae Pubescentisis acrid,bitter and mild,having the effect of dispelling wind and dehumidification,dispersing arthralgia and analgesic.Herba Taxillitastes bitter and sweet, flat, and has the effect of tonifying liver and kidney, making muscles and bones strong, dispelling wind and dampness,dredging meridian. BothRadix Angelicae PubescentisandHerba Taxilliact as sovereign drugs.Herba Asari,Radix Saposhnikoviae,Radix Gentianae MacrophyllaeandCinnamomi Heartare minister drugs.Herba Asaritastes acrid, and can dispel wind,relieve pain, and dispel the exterior cold companied withRadix Saposhnikoviae.CinnamomiHearthas the efficacy of dispelling cold and relieving pain in warmth,asShen Nong Ben Caosaid"acrid and warm, in charge of dozens of diseases,nourish the spirit,pleasant countenance,benefit joint,invigorating spleen-stomach and replenishing Qi".Radix Gentianae Macrophyllaecan dispel wind and dampness, clear dampness and heat, prevent arthralgia pain, good at treating tendon and vein constriction and aching pain of joints.Cortex EucommiaeandRadix Acanthopanacis Bidentataecan be used to supplement liver and kidney,strengthen muscles and bones. In addition,Rhizoma Chuanxiongcan induce the blood downward, which can effectively treat the symptoms of lumbago.Lumbago disease can be caused by blood stasis blocking collaterals, that is, the so-called "stagnation leading to pain". Lumbago with a long time can hurt essence and blood, soRadix Angelicae Sinensisis used to raise blood and activate blood.Peonyrelieve tendon and pain.However,the deficiency of body Qi yin, can also lead to the occurrence of lumbago disease,soPoriaandRadix Ginsengare added in the prescription to invigorate spleen and supplement Qi.Dry Rehmannia Rootnourishing yin andRadix Glycyrrhizaereconcile the drugs.The combination of these drugs can effectively improve clinical symptoms. TCM theory thinks, "The waist is the home of the kidney", "Kidney holds bone and give birth to marrow", "The liver and the kidney have a common source". So, LDH lesions are in the liver and kidney,can choose DHJSD to treat.

Figure 6 The funnel plots of the meta-analysis

This Meta-analysis found that the effective rate of DHJSD combined with non-surgical therapy was better than that of non-surgical therapy alone (OR=4.29:95%CI [3.19, 5.76] (P＜ 0.001). Through subgroup analysis, it was found that the effective rate of DHJSD combined with sacral canal injection,DHJSD combined with NSAID anti-inflammatory drugs + nutritional nerve drugs, DHJSD combined with NSAID anti-inflammatory drugs + hormone +dehydration therapy, and DHJST combined with other non-surgical therapies were all superior to that of non-surgical therapy alone. Meta-analysis showed that JOA scores of patients in the treatment group were significantly improved compared with those in the control group. The difference was highly statistically significant (P＜0.001), as can be seen from Figure 3:Meta-analysis showed that VAS scores of patients in the treatment group could be significantly reduced compared with those in the control group. The difference was highly statistically significant (P＜0.001). However, due to the small number of included studies and the insufficient sample size of each study,the results may be biased to some extent,which needed to be verified by more clinical studies. The literatures included in the evaluation of this system were all Chinese literatures, and the quality is generally not high from the perspective of methodology. 50% (9/18)of the literature studies only mentioned "random grouping" in their articles; 50% (9/18) of the studies described the randomization method; neither the concealment of random allocation schemes nor the use of blind methods have been mentioned. Therefore, the reliability and accuracy of the evidence of this system evaluation were affected.

The inverted funnel plot analysis of 18 RCTs showed that the graph presented in the form of skewed distribution, indicating that the research results had publication bias to some extent and the meta-analysis results may be affected by publication bias. There are two possible causes: researchers are more likely to publish positive results than negative ones; the editors of newspapers and magazines are also more likely to report positive results [26].The above two reasons can influence the reliability of the evaluation conclusion of the meta-analysis. Therefore, given to the above limitations,the conclusion of the paper should be more cautious to use. In order to obtain more accurate evaluation and reliable conclusions, high-quality RCTs should be included.

Based on the above analysis,DHJSD combined with non-surgical treatment for LDH has significant advantages in improving JOA score and lowering VAS score. However, due to the differences in design,randomization method and efficacy evaluation of randomized trials, the Jadad score of selected literature belongs to low-quality trials. This study does not provide a strong gist for evidence-based medicine.Nevertheless, we can still see from the results of this analysis that the advantages of traditional Chinese and western medicine in the treatment of LDH are complementary and organic combination, and the comprehensive application of the two treatments can achieve satisfactory results.

In the treatment of LDH, the combined use of DHJSD and NSAID anti-inflammatory drugs,hormones or neurotrophic drugs is better than the single use of NSAID anti-inflammatory drugs,hormones and neurotrophic drugs.However,due to the low quality of the included literatures and the possibility of bias, large-scale and high-quality RCTs are still needed for further confirmation.

Abbreviations

DHJSD, Du-Huo-Ji-Sheng-Tang; CNKI, China Knowledge Network; LDH, Lumbar disc herniation;RCTs, Randomized controlled trials; TCM, traditional Chinese medicine; NSAID, non-steroidal; OR, odds ratio; CI, confidence intervals; ORR, overall response rate.

Acknowledgments

None.

Competing interests

The authors declare that there is no conflict of interests regarding the publication of this paper.