The Chinese patent medicine Tongfengding capsule for gout in adults: a systematic review of safety and effectiveness

Abstract

Background  Gout is a common inflammatory arthritis caused by increased serum uric acid levels. Untreated or insufficiently treated gout can lead to deposition of monosodium urate crystals in joints, cartilage, and kidneys. Although Tongfengding capsules, a Chinese patent medicine, have long been used to treat gout, their effects and safety have not been reviewed systematically. This study evaluated its efficacy and safety for gout in adults.

Methods  Randomized controlled trials involving Tongfengding capsule for gout in adults were searched from PubMed, EMBASE, Cochrane Central Register of Controlled Trials, CBM, CNKI, and VIP databases, and analyzed using the Cochrane Handbook criteria. The primary outcome measures were the total effective rate. The secondary outcome measures including the blood uric acid (BUA), 24-h urinary total protein (24-h UTP), blood urea nitrogen (BUN), interleukin (IL)-6, IL-8, tumor necrosis factor-alpha (TNF-α) and adverse effects. The risk of bias was evaluated in all included studies. RevMan ver. 5.3.5 and GRADE profiler was used for data analysis and assessing the quality of evidence, respectively.

Results  Six studies (n = 607 Chinese participants) were included. Tongfengding capsules plus conventional treatment significantly increased the total effective rate (RR 1.21, 95% CI 1.11–1.33), while reducing the BUA (MD − 66.05 μmol/L, 95% CI − 81.26 to − 50.84), 24-h UTP (MD − 0.83 g/24 h, 95% CI − 0.96 to − 0.70), BUN (MD − 0.90 mmol/L, 95% CI − 1.60 to − 0.20), IL-6 (MD − 6.99 ng/L, 95% CI − 13.22 to − 0.75), IL-8 (MD − 12.17 ng/L, 95% CI − 18.07 to − 6.27), TNF-α (MD − 8.50 ng/L, 95% CI − 15.50 to − 1.51), and adverse effects (RR 0.21, 95% CI 0.04–0.95).

Conclusion  Tongfengding capsules plus conventional treatment is safe and beneficial for adults with gout compared with conventional treatment.

Keywords Chinese patent medicine; Tongfengding capsule; Gout; Randomized controlled trials; Systematic review

Introduction

Gout is a common type of inflammatory arthritis caused by increased serum levels of uric acid (UA) that exceed the limit of solubility of 7.0 mg/dL, leading to the deposition of monosodium urate crystals in joints, cartilage, and tissues [¹–³]. Its main clinical features including tophi deposition, specific recurring acute arthritis, chronic gouty arthritis, and deformed joints [⁴–⁶]. Gout usually affects the kidneys, causing the formation of uri-nary tract stones and chronic interstitial nephritis composed of UA [⁴, ⁷]. Gout caused by hyperuricemia is associated with rapid deterioration of renal function in patients with chronic kidney disease [³, ⁸]. The prevalence of gout is 3.9% in the US, affecting 8.3 million adults [⁹–¹²], 2.5% in the UK [¹³], and 5.2% in Australia [¹⁴]. In China, it is more commonly seen in the population over the age of 40 years [⁴]. Epidemiological evidence suggests that gout is becoming more prevalent over time [¹⁵, ¹⁶]. Acute gout causes short-term disability, which led to an average of five additional work days off each year and an estimated increase in medical care costs of US$3165 annually per affected person [¹⁷]. Untreated or insufficiently treated gout can lead to chronic manifestations of the disease, such as persistent inflammation, the development of tophi, and joint damage [¹⁸–²⁰].

The management of an acute gout includes treatment with colchicine, non-steroidal anti-inflammatory drugs (NSAIDs), adrenocorticotrophic hormones, and steroids. Uricosuric and diuretic drugs are used to prevent rebound gout in patients without kidney damage or a history of kidney stones [¹⁶]. The standard Western medicine therapy for the disease focuses on the therapy of the primary disease such as high UA levels [⁴]. Clinical guidelines recommend colchicine and NSAIDs as first-line therapy to treat acute gout [⁴, ²¹]. Corticosteroids are a potential first-line treatment to decrease joint inflammation in acute gout [⁴, ²², ²³]. However, many studies have reported that colchicine and NSAIDs increase the risk for gastrointestinal tract bleeding and reactions in the short term as well as cardiovascular adverse events in the longer term [²⁴–²⁶]. NSAIDs are contraindicated in patients with renal or liver dysfunction, bleeding disorders, and heart failure, hindering the use of these drugs in patients at higher risk for recurrent acute gout [²⁷]. Studies reported that corticosteroids have fewer clinical contraindications and drug side effects, particularly in people with chronic kidney disease [²⁷, ²⁸]. Although uricosuric drugs, allopurinol, and diuretic drugs are used to prevent rebound gout in patients without kidney impairment or a history of kidney stones [¹⁶, ²⁹, ³⁰], the potential of cardiovascular and gastrointestinal risks are well documented. Besides, patients with gastritis/ulcers, hypertension, congestive heart failure, or kidney insufficiency who suffer from gout have a high risk of side effects when taking the above drugs [¹⁶, ³¹, ³²]. Therefore, it is not surprising why patients with gout seek complementary and alternative therapies.

On the basis of the traditional Chinese medicine (TCM) theory, gout is an “impediment disease” (bi zheng: a group of diseases caused by the invasion of wind, dampness, cold, or heat pathogens on the meridian/channel involving sinews, muscles, bones, and joints, manifest by soreness, heaviness, local pain, or hotness, and even articular swelling, deformities and stiffness, also referred to as arthralgia). TCM theory holds that “stagnation leads to pain.” In TCM, the cause of gout involves dampness–heat and blood stasis pathogenic factors. In China, Chinese herbal medicine decoctions have a long history of being used to treat gout and have unique clinical effects [⁴]. In recent decades, an increasing number of studies have compared Chinese herbal medicine decoctions and traditional Western medicine for the therapy of gout. But, there are some disparities in the therapy methods and effect among these studies [³³], which affects the replicability and reliability of the conclusions and makes it difficult to appreciate the findings [³⁴].

Tongfengding capsules, a Chinese patent medicine, has long been used to treat gout. The capsules clear heat and eliminate dampness (qing re chu shi: a therapeutic method of treating dampness–heat in the middle and upper energizers by the combined use of heat-clearing and dampness-resolving medicinals), and activate blood to alleviate pain (huo xue zhi tong: a therapeutic method for treating painful conditions caused by blood stasis). Nevertheless, its effects and safety for the treatment of gout in adults have not been systematically reviewed. Therefore, this study was carried out to evaluate the efficacy and safety of Tongfengding capsule for treating gout in adults.

Methods

Criteria for included studies

Inclusion criteria

Type of studies: Only randomized controlled trials (RCTs) were included.

Types of participants: The selected studies included participants diagnosed with gout [³⁵] who were ≥ 18 years of age, of either sex, and had not received corticosteroids or nonsteroidal anti-inflammatory drugs (NSAIDs) within 24 h of disease onset before randomization.

The diagnostic criteria for gout in all studies included hyperuricemia, more than one attack of acute arthritis, joint redness, painful or swollen first metatarsophalangeal joint, unilateral attack involving the tarsal joint, asymmetric swelling within a joint on radiograph, subcritical cysts without erosions on radiograph, and/or joint fluid culture negative for organisms during an attack.

Exclusion criteria

Studies were excluded if the patients had accompanying debilitating conditions such as severe heart disease and liver or kidney failure, pregnant, or patients with joint deformities.

Types of interventions

The interventions included the Chinese patent medicine, Tongfengding capsules alone versus no treatment, placebo, or conventional treatment (e.g., colchicines, NSAIDs, other urate-lowering drugs, or/and symptomatic treatment); Tongfengding capsules plus conventional treatment versus placebo plus conventional treatment; and Tongfengding capsules plus conventional treatment versus conventional treatment.

The China Food and Drug Administration assesses Chinese patent medicines according to a strict drug evaluation process.

Outcome measures

The primary outcome measures included all-cause mortality and total effective rate (cure: total absence of the signs and symptoms of gout, including redness, swelling, heat, and joint pain, and erythrocyte sedimentation rate [ESR], blood uric acid [BUA], and C-reactive protein [CRP] levels in the normal range; markedly effective: substantially improved [≥ 50%] signs and symptoms including redness, swelling, heat, and joint pain, and reduced ESR, BUA and CRP levels, but remaining above normal range; effective: partially improved [≥ 30%] signs and symptoms including redness, swelling, heat, and joint pain with lower ESR, BUA, and CRP levels, but remaining above the normal range).

The secondary outcome measures included BUA, CRP, ESR, interleukin-6 (IL-6), interleukin-8 (IL-8), tumor necrosis factor alpha (TNF-α), serum creatinine (SCr), blood urea nitrogen (BUN), and 24-h urinary total protein (24-h UTP) levels, relapse rate, traditional Chinese medicine (TCM) tongue and pulse assessment (tongue coating and pulse), economic index, withdrawal, and adverse effects.

Search methods used to identify studies

The following electronic databases and series of associative terms were searched, and all searches were completed on May 31, 2019: the Cochrane Central Register of Controlled Trials (to May 2019), Embase (1967–May 2019), PubMed (1966–May 2019), the Chinese National Knowledge Internet (1979–May 2019), the Chinese Biomedicine Database (1978–May 2019), and the VIP Chinese Science and Technology Periodical Database (1989–May 2019). The included trials were assessed using the Cochrane Handbook criteria [³⁶].

We used the following search terms for the review: (traditional Chinese and Western medicine OR integrated Chinese and Western medicine OR Chinese medicine OR traditional Chinese medicine OR traditional Chinese pharmacy OR Chinese patent medicine OR Chinese patent drugs OR Chinese traditional patent medicine OR Chinese traditional herb OR Chinese medicinal herb OR Chinese herbal medicine OR Tongfengding capsule OR Tong-Feng-Ding-Jiao-Nang) AND (gout OR pain paralysis OR hyperuricemia OR Bi Zheng). We manually investigated the Journal of Guangzhou University of Traditional Chinese Medicine. We attempted to contact all of the original authors to clarify the protocols for each study.

Data collection and analysis

Study selection

Two authors (QH and XL) independently browsed the titles and abstracts of all of the papers identified in the literature search. We assessed the abstracts retrieved in the initial search independently to identify studies that met the inclusion criteria. Uncertainties were resolved by consultation or discussion with a third author (QY). who independently determined whether the studies met the inclusion criteria. In this review, we telephoned the original authors of the trials to confirm the randomization procedure and other methodological procedures to ensure that only RCTs were included in our analysis. Studies were excluded if the inclusion criteria were not met.

Data extraction and management

We extracted the data using a pretested data extraction form and according to the study characteristics including methods, participants, interventions, and outcomes. No disagreements arose among the authors. We extracted the Chinese patent medicine content from the included studies, and the names of the Chinese herbal medicines are shown in Chinese, Latin, and English in Table 1.

Table 1
Contents of the Chinese patent medicine (in three languages) used in the included studies

Study ID	Herbs (composition) in three languages	Administration methods
Tang [40]	Tongfengding capsules (national drug approval number Z10970025, Sichuan Shenghe Pharmaceutical Co., Ltd.): Huangbai (Cortex Phellodendri/amur cork-tree bark), Qinjiao (Radix Gentianae Macrophyllae/large leaf gentian root or straw-colored gentian root), Chishao (Radix Paeoniae Rubra/red peony root)	Oral administration
Gao et al. [41]	Tongfengding capsules (national drug approval number Z10970025, Sichuan Shenghe Pharmaceutical Co., Ltd.): Huangbai (Cortex Phellodendri/amur cork-tree bark), Qinjiao (Radix Gentianae Macrophyllae/large leaf gentian root or straw-colored gentian root), Chishao (Radix Paeoniae Rubra/red peony root)	Oral administration
Chi and Li [42]	Tongfengding capsules (national drug approval number Z10970025, Sichuan Shenghe Pharmaceutical Co., Ltd.): Huangbai (Cortex Phellodendri/amur cork-tree bark), Qinjiao (Radix Gentianae Macrophyllae/large leaf gentian root or straw-colored gentian root), Chishao (Radix Paeoniae Rubra/red peony root)	Oral administration
Tang [43]	Tongfengding capsules (national drug approval number Z10970025, Sichuan Shenghe Pharmaceutical Co., Ltd.): Huangbai (Cortex Phellodendri/amur cork-tree bark), Qinjiao (Radix Gentianae Macrophyllae/large leaf gentian root or straw-colored gentian root), Chishao (Radix Paeoniae Rubra/red peony root)	Oral administration
Ao [44]	Tongfengding capsules (national drug approval number Z10970025, Sichuan Shenghe Pharmaceutical Co., Ltd.): Huangbai (Cortex Phellodendri/amur cork-tree bark), Qinjiao (Radix Gentianae Macrophyllae/large leaf gentian root or straw-colored gentian root), Chishao (Radix Paeoniae Rubra/red peony root)	Oral administration
Wang et al. [45]	Tongfengding capsules (national drug approval number Z10970025 Sichuan Shenghe Pharmaceutical Co., Ltd.): Huangbai (Cortex Phellodendri/amur cork-tree bark), Qinjiao (Radix Gentianae Macrophyllae/large leaf gentian root or straw-colored gentian root), Chishao (Radix Paeoniae Rubra/red peony root)	Oral administration

Assessment of risk of bias in the included studies

We used a risk of bias assessment tool to assess the following items [³⁶]: sequence generation (selection bias), allocation concealment (selection bias), blinding of the intervention allocations (including participants, personnel, and outcome assessors), handling of incomplete outcome data (attrition bias), alternative outcome reporting (reporting bias), and other potential biases.

Assessment of treatment effect

All statistical analyses were performed using the Cochrane Collaboration RevMan software ver. 5.3.5. Dichotomous (all-cause mortality, total effective rate, relapse rate, and adverse effects) and continuous (BUA, CRP, erythrocyte ESR, IL-6, IL-8, 24-h UTP, SCr, BUN, and TNF-α levels) variables were assessed. The data are expressed as risk ratios (RR) and 95% confidence intervals (CI).

The quality of evidence was assessed using GRADE profiler [³⁷]. GRADE was divided into four levels of evidence: high, moderate, low, and very low [³⁸].

Dealing with missing data

If necessary, the original authors were contacted by telephone to obtain required information. We carefully assessed all of the data, including screened and randomized participants as well as the as-treated, intention-to-treat, and per-protocol populations. Additionally, attrition rates (including losses to follow-up, dropouts, and withdrawals) were assessed. Problems that arose due to missing data and the attributed methods used were critically evaluated [³⁶]. The original authors were contacted by telephone to clarify missing information. The primary authors of the included studies were contacted by telephone to obtain missing information.

Assessment of heterogeneity

Heterogeneity was assessed using the chi-squared test with n − 1 degrees of freedom and an alpha of 0.05 for statistical significance, and with the I² test values of 25%, 50%, and 75% corresponding to low, medium, and high levels of heterogeneity, respectively [³⁹].

Assessment of reporting biases

We planned to use a funnel plot to assess reporting bias.

Data synthesis

We used a random effects model under the hypothesis that the effects being evaluative were not identical throughout, but followed certain assignment patterns, and a fixed-effects model to assure the stability of the model susceptibility and choice of outliers with a pooled data analysis of the included studies.

Subgroup analyses

Subgroup analyses were performed according to Tongfengding capsules and relieve pain drugs types (e.g., colchicines, indomethacin, or NSAIDs).

Sensitivity analysis

The sensitivity analysis was performed by excluding low-quality studies (based on allocation concealment, randomization, double-blinded or blinded assessment of outcomes, and analyses/descriptions of dropouts and withdrawals) followed by comparisons of the pooled data from the random- and fixed-effects models.

Results

Search results

Our search strategy identified 217 records, one of which was in an English language database. After removing 51 duplicates, 166 papers were included initially, 153 of which were subsequently excluded because they did not meet the inclusion criteria (not an RCT, n = 41; animal studies, n = 37; wrong intervention, n = 23; and wrong disease, n = 52). Of the 13 potentially eligible studies, six were excluded from further assessment; in one of these, the comparator was a Chinese herbal medicine that lacked sufficient evidence of effect, two studies assessed the wrong intervention, the exclusion criteria were unclear in two studies, and the remaining study had unclear inclusion and exclusion criteria. The missing information in one study could not be obtained and it is awaiting assessment. Therefore, our review includes six studies (607 Chinese participants; Fig. 1).

Fig. 1
Summary of the search results in a flow diagram

Included studies

Participants

Six studies [⁴⁰–⁴⁵] were included comprising 607 adults with gout. The trial populations were small, ranging from 64 to 180 Chinese participants (average: 101.17 participants). All of the studies were conducted in China. The ratio of male to female participants in five of the trials was 345/180 [⁴⁰, ⁴¹, ⁴³–⁴⁵]. Participant ages ranged from 30 to 87 years. The disease duration was not reported in two of the studies [⁴⁰, ⁴²]. In total, 607 adults with gout were included in six studies, and all of the participants were from China.

Interventions

The primary intervention was oral administration of the Chinese patent medicine Tongfengding capsule. The therapy duration ranged from 7 days to 12 weeks. The follow-up duration was 6 months in two studies [⁴¹, ⁴⁵], three studies mentioned follow-up but did not specify the duration [⁴²–⁴⁴], and the remaining study did not mention follow-up [⁴⁰]. All six studies compared Tongfengding capsule plus conventional treatment versus conventional treatment alone. NSAIDs, urate-lowering drugs, and symptomatic treatment were the main conventional treatments for gout in adults. The medication used in these studies including NSAIDs (diclofenac sodium dual release enteric-coated capsules [⁴⁴] and diclofenac sodium enteric-coated sustained release capsules + indomethacin [⁴⁵]), xanthine oxidase inhibitor (allopurinol [⁴⁰] and Febuxostat tablets [⁴³]), xanthine oxidase inhibitor (Benzbromarone capsules) + indomethacin [⁴¹], and colchicine + xanthine oxidase inhibitor (allopurinol) [⁴²].

Outcomes

The total effective rate was reported in four studies [⁴¹–⁴⁴], BUA concentration was reported in four studies [⁴⁰, ⁴¹, ⁴³, ⁴⁵], CRP and ESR were reported in one study [⁴⁰], Il-6, Il-8, and TNF-α levels were reported in two studies [⁴⁰, ⁴³], 24-h UTP was reported in one study [⁴⁰]; SCr and BUN were reported in one study [⁴³]; the relapse rate and adverse effects were reported in two studies [⁴¹, ⁴⁵], and the withdrawal rate was reported in one study [⁴²]. However, none of the studies reported all-cause mortality, economic index, or TCM tongue and pulse assessment (tongue coating and pulse). The characteristics of the included studies are shown in Table 2.

Table 2
Characteristics of the included studies

Tang [40]
	Methods	Randomized controlled trial (RCT): randomization described in detail
		Allocation concealment: not mentioned; however, the randomization method would have prevented participants/investigators
		from knowing or influencing the treatment group before eligible participants were enrolled in the study
		Follow-up: not mentioned
		Study duration: 30 days
		Parallel/factorial/crossover RCT: parallel RCT
		Randomization method: a random number table was used
		Blinding: no details were provided
		Intention to treat (ITT): not mentioned
	Participants	Setting: Chinese patients of hospital, but did not mention if inpatients or outpatients
		Country: China
		Number (randomized/analyzed): Treatment group (90/90); control group (90/90)
		Treatment group: 52 males (57.8%) and 38 females (42.2%), age 30–35 (43.7 ± 4.6) years, disease duration: not mentioned
		Control group: 54 males (60%) and 36 females (40%), age 30–55 (42.9 ± 4.8) years, disease duration: not mentioned
	Interventions	Treatment group: Chinese patent medicine Tongfengding capsules plus conventional treatment
		Tongfengding capsules containing Huangbai, Qinjiao, and Chishao; the Chinese medicine dose was not mentioned. Tongfengding capsules: three capsules orally taken three times daily (tid) for 30 days
		Conventional treatment was the same as that used in the control group
		Control group: conventional treatment: Allopurinol tablets (50 mg) orally taken twice daily (bid), extra water, low purine foods, and alcohol consumption prohibited for 30 days
	Outcomes	1. BUA
		2.CRP
		3. ESR
		4. Il-6, Il-8, and TNF-α
		5. 24-h UTP
	Notes	3. Economic index: not mentioned
		4. TCM tongue and pulse assessment (tongue coating and pulse): not mentioned
		5. Adverse effects (rash, diarrhea, and gastrointestinal discomfort): not mentioned
		5. Source of funding: Project support, Project Number: Sichuan Technological Innovation Funding Project, 2015GF01299
		6. Relapse rate: not mentioned
		7. Withdrawals: not mentioned; however, the full text suggested that there were no withdrawals
		8. The study was approved by the ethics committee and participants provided informed consent
		9. Overall, the participant demographic data were similar between groups
Gao et al. [41]
	Methods	Randomized controlled trial (RCT): randomization described in detail
		Allocation concealment: not mentioned; however, the randomization method would have prevented participants/investigators from knowing or influencing the treatment group before eligible participants were enrolled in the study
		Follow-up: 6 months
		Study duration: 4 weeks
		Parallel/crossover/factorial RCT: parallel RCT
		Randomization method: a random number table was used
		Blinding: no details were provided
		Intention to treat (ITT): not mentioned
	Participants	Setting: outpatients
		Country: China
		Number (randomized/analyzed): Treatment group (41/41); control group (40/40)
		Treatment group: 38 males (92.7%) and 3 females (7.3%), age 41.6 ± 2.8 years, disease duration: 7.8 ± 5.2 years
		Control group: 38 males (95%) and 2 females (5%), age 40.2 ± 2.7 years, disease duration: 7.6 ± 6.4 years
	Interventions	Treatment group: Tongfengding capsules plus conventional treatment
		Tongfengding capsules containing Huangbai, Qinjiao, and Chishao, the dose was not mentioned. Tongfengding capsules four capsules orally tid for 4 weeks
		Conventional treatment was the same as that used in the control group
		Control group: conventional treatment: benzbromarone capsules, 50 mg orally once daily (qd), taken after breakfast; sodium bicarbonate tablets and dipyridamole tablets 0.5 g orally tid; Indomethacin tablets 25 mg orally tid, continuously for 3 days; a high purine diet was prohibited during the study period
	Outcomes	1. Total effective rate
		2. BUA
		3. Relapse rate
		4. Adverse effects (rash, diarrhea, and gastrointestinal discomfort)
	Notes	1. All-cause mortality: not mentioned
		2. CRP: not mentioned
		3. ESR: not mentioned
		4. Il-6, Il-8, and TNF-α: not mentioned
		5. Economic index: not mentioned
		6. TCM tongue and pulse assessment (tongue coating and pulse): not mentioned
		7. Source of funding: not mentioned
		9. Withdrawals: not mentioned; however, the full text suggested that there were no withdrawals
		10. The study was approved by the ethics committee and participants provided informed consent
		11. Overall, the participant demographic data were similar between groups
Chi and Li [42]
	Methods	RCT: randomization described in detail
		Allocation concealment: not mentioned; however, the randomization method would have prevented participants/investigators from knowing or influencing the treatment group before eligible participant were enrolled in the study
		Follow-up: follow-up was mentioned; however, the follow-up duration was not mentioned
		Study duration: 7 days
		Parallel/crossover/factorial RCT: parallel RCT
		Randomization method: a random number table was used in the study
		Blinding: not mentioned
		ITT: not mentioned
	Participants	Setting: outpatients and inpatients
		Country: China
		Number (randomized/analyzed): treatment group (44/44); control group (38/38)
		Treatment group and control group: the ratio of male to female and disease duration: not mentioned
	Interventions	Treatment group: Chinese patent medicine Tong-Feng-Ding-Jiao-Nang capsules plus conventional treatment
		Tongfengding capsules containing Huangbai, Qinjiao, Chishao; the Chinese medicine dose was not mentioned. Tong-Feng-Ding-Jiao-Nang capsules: 3–4 capsules orally tid for 7 days
		Conventional treatment was the same as that used in the control group
		Control group: conventional treatment included colchicine tablets 3 mg orally at first, then 0.5 mg every 1–2 h until the symptoms subsided or adverse effects occurred, with the stipulation of no more than 6 mg per 24 h, and 0.5 to 1 mg per day after 72 h; allopurinol tablets 0.1 g orally bid or tid
	Outcomes	1. Total effective rate
		2. SCr
		3. BUN
	Notes	1. BUA: not mentioned
		2. Relapse rate: not mentioned
		3. Adverse effects (rash, diarrhea, and gastrointestinal discomfort): not mentioned
		4. All-cause mortality: not mentioned
		5. CRP: not mentioned
		6. ESR: not mentioned
		7. Il-6, Il-8, and TNF-α: not mentioned
		8. Economic index: not mentioned
		9. TCM tongue and pulse assessment (tongue coating and pulse): not mentioned
		10. Withdrawals: not mentioned; however, the full text suggested that there were no withdrawals
		11. Source of funding: not mentioned
		12. The study was approved by the ethics committee and participants provided informed consent
		13. Overall, the participant demographic data were similar between groups
Tang [43]
	Methods	RCT: randomization mentioned, but not described in detail
		Allocation concealment: not mentioned in the paper; however, allocation concealment was confirmed in a telephone interview with the author
		Follow-up: not mentioned
		Study duration: 3 months
		Parallel/crossover/factorial RCT: parallel RCT
		Randomization method: random number table use was confirmed via telephone interview
		Blinding: double-blinding was confirmed via telephone interview
		ITT: not mentioned
	Participants	Setting: Chinese patients of hospital, but did not mention if inpatients or outpatients
		Country: China
		Number (randomized/analyzed): treatment group (40/40); control group (40/40)
		Treatment group: 22 males (55%) and 18 females (45%), age 26–68 (45.6 ± 8.2) years, disease duration: 2–14 (6.3 ± 2.1) years
		Control group: 24 males (60%) and 16 females (40%), age 23–67 (44.8 ± 7.8) years, disease duration: 1–12 (6.1 ± 1.8) years
	Interventions	Treatment group: Chinese patent medicine Tongfengding capsules plus conventional treatment
		Tongfengding capsules containing Huangbai, Qinjiao, Chishao; the Chinese medicine dose was not mentioned. Tongfengding capsules
		4 capsules orally tid for 3 months
		Conventional treatment was the same as that used in the control group
		Control group: conventional treatment included febuxostat tablets 80 mg orally qd for 3 months
	Outcomes	1. Total effective rate
		2. Il-6, Il-8, and TNF-α
		3. BUA
	Notes	1. Relapse rate: not mentioned
		2. Adverse effects (rash, diarrhea, and gastrointestinal discomfort): not mentioned
		3. All-cause mortality: not mentioned
		4. CRP: not mentioned
		5. ESR: not mentioned
		6. Economic index: not mentioned
		Economic index: not mentioned
		7. TCM tongue and pulse assessment (tongue coating and pulse): not mentioned
		8. Source of funding: not mentioned
		9. Withdrawals: not specifically mentioned; however, careful reading of the paper confirmed that no participants withdrew from the study
		10. Ethics committee approval and signed informed consent were not mentioned in the paper, but were confirmed in a telephone interview
		11. Overall, the participant demographic data were similar between groups
Ao [44]
	Methods	RCT: randomization was mentioned, but not described in detail
		Allocation concealment: not mentioned; however, the use of allocation concealment was confirmed in a telephone interview with the original author
		Follow-up: not mentioned
		Study duration: 3 months
		Parallel/factorial/crossover RCT: parallel RCT
		Randomization method: not mentioned; however, a telephone interview with the original author confirmed that a computer was used to generate random sequences
		Blinding: not mentioned; however, a telephone interview with the original author confirmed the use of double-blinding
		ITT: not mentioned
	Participants	Setting: outpatients
		Country: China
		Number (randomized/analyzed): treatment group (32/32); control group (32/32)
		Treatment group: 32 (19 males; 59.4%; 13 females; 40.6%), age 61–85 years (75.2 ± 1.2) years, disease duration: 6 months −5 (2.6 ± 0.2) years
		Control group: 32 (20 males; 62.5%; 12 females; 37.5%), age 63–87 (75.5 ± 1.5) years, disease duration: 7 months −5 (2.8 ± 0.2) years
	Interventions	Treatment group: Chinese patent medicine Tongfengding capsules plus conventional treatment
		Tongfengding capsules containing Huangbai, Qinjiao, and Chishao, the Chinese medicine dose was not mentioned. Tongfengding capsules 4 capsules orally tid for 8 weeks
		Conventional treatment was the same as that used in the control group
		Control group: conventional treatment included diclofenac sodium double-release enteric capsules, 75 mg orally qd for 8 weeks
	Outcomes	1. Total effective rate
	Notes	1. Il-6, Il-8, and TNF-α: not mentioned
		2. BUA: not mentioned
		3. Relapse rate: not mentioned
		4. Adverse effects (rash, diarrhea, and gastrointestinal discomfort): not mentioned
		5. All-cause mortality: not mentioned
		6. CRP: not mentioned
		7. ESR: not mentioned
		8. Economic index: not mentioned
		9. TCM tongue and pulse assessment (tongue coating and pulse): not mentioned
		10. Source of funding: not mentioned
		11. Withdrawals: not specifically mentioned; however, careful reading of the paper confirmed that no participants withdrew from the study
		12. Ethics committee approval and signed informed consent were not mentioned in the paper, but were confirmed in a telephone interview
		13. Overall, the participant demographic data were similar between groups
Wang et al. [45]
	Methods	RCT: random sequences were generated using a random number table
		Allocation concealment: allocation concealment was confirmed in a telephone interview
		Follow-up: 6 months
		Study duration: 4 weeks
		Parallel/factorial/crossover RCT: parallel RCT
		Randomization method: random number table
		Blinding: double-blinding was confirmed in a telephone interview
		ITT: not mentioned
	Participants	Setting: outpatients
		Country: China
		Number (randomized/analyzed): treatment group (60/60); control group (60/60)
		Treatment group: 60 (38 males; 63.33%; 22 females; 36.67%), age 45.6 ± 5.7 years, disease duration: 6.8 ± 3.4 years
		Control group: 60 (40 males; 66.67%; 20 females; 33.33%), age 46.7 ± 5.3 years, disease duration: 6.5 ± 2.8 years
	Interventions	Treatment group: Chinese patent medicine Tongfengding capsule plus conventional treatment
		Tongfengding capsules including Huangbai, Qinjiao, and Chishao; the Chinese medicine dose was not mentioned. Tongfengding
		capsules 4 capsules orally tid for 4 weeks
		Conventional treatment was the same as that used in the control group
		Control group: conventional treatment included anti-infection, low purine diet, diclofenac sodium enteric-coated sustained-release capsules 0.1 g orally qid, and indomethacin (dose not mentioned) orally during the acute phase of gout
	Outcomes	1. BUA
		2. Relapse rate
	Notes	6. Economic index: not mentioned
		7. TCM tongue and pulse assessment (tongue coating and pulse): not mentioned
		8. Source of funding: not mentioned
		9. Withdrawals: not specifically mentioned; however, careful reading of the paper confirmed that no participants withdrew from the study
		10. Ethics committee approval and signed informed consent were not mentioned in the paper, but were confirmed in a telephone interview
		11. Overall, the participant demographic data were similar between groups

• RCTs-randomized controlled trials; ITT—intention-to-treat; cholesterol; ESR—erythrocyte sedimentation rate; BUA—blood uric acid; CRP—C-reactive protein; IL-6—interleukin-6; IL-8—interleukin-8; TNF-α—tumor necrosis factor-α; Scr—Serum creatinine; BUN—Blood urea nitrogen; 24-h UTP—24-h urinary total protein

Risk of bias in the included studies

The methodological quality of each study, including the randomization sequence, allocation concealment, blinding (blinding of the personnel and participants and blinding of the outcome assessment), incomplete outcome data, selective outcome reporting, and other bias is shown in Figs. 2 and 3.

Fig. 2
Risk of bias graph

Fig. 3
Methodology quality summary

Randomization and allocation concealment

All six included studies [⁴⁰–⁴⁵] reported that the patients were randomized; however, only four provided sequencing details [⁴⁰–⁴², ⁴⁵], all of which used a random number table to assign groups [⁴⁰–⁴², ⁴⁵]. We conducted telephone interviews with the authors of the remaining two studies and found that one used a computer-generated random sampling table [⁴⁴] and the other used a random number [⁴³]. Although none of the six studies [⁴⁰–⁴⁵] reported their allocation concealment methods, we concluded that the concealment procedures were sufficient because the investigators were not actively involved in treatment, and the physicians treating the participants were unaware of the study outcome parameters.

Blinding

Three studies [⁴³–⁴⁵] reported using double blinding (neither the participants nor investigators were aware of the drug allocation) and single blinding (participants were not aware of the outcome assessment), but did not describe their procedures. We interviewed the original authors by telephone to clarify their blinding procedures and concluded that the studies had low risks of performance and detection biases. In contrast, the risks of performance and detection biases in the three studies [⁴⁰–⁴²] that did not mentioned blinding procedures are unclear.

Incomplete outcome data

The outcome data were clearly reported in the included studies [⁴⁰–⁴⁵], which showed no withdrawals, dropouts, and/or loss to follow-up. However, the methods used to handle missing data (i.e., per-protocol analysis or intention-to-treat) were not described.

Selective reporting

Although none of the six included studies [⁴⁰–⁴⁵] provided detailed evidence of selective reporting, the published papers included all of the expected outcomes, including those that were pre-specified. Funnel plot was not performed due to small sample size.

Other potential sources of bias

The participant demographic characteristics were comparable among the six included studies. Four studies mentioned that their institutional ethics committees approved the protocol and that written informed consent was obtained from each participant [⁴⁰–⁴², ⁴⁵]. We confirmed ethics committee approval and written informed consent in the remaining two studies [⁴³, ⁴⁴] in telephone interviews with the authors.

Excluded studies

We excluded six studies from our review. Of these, one was excluded because the comparator was a Chinese herbal medicine that did not have sufficient evidence of efficacy; two were excluded because they used the wrong intervention; one was excluded because the inclusion and exclusion criteria were not clear; and the remaining two studies were excluded due to unclear exclusion criteria.

Studies awaiting classification

One potentially eligible study is awaiting assessment because the information provided is not adequate to determine whether it meets the inclusion criteria for our review, and we have been unable to contact the original authors directly.

Effects of interventions

Primary outcome

Total effective rate Four studies [⁴¹–⁴⁴] reported that Tongfengding capsules plus conventional treatment significantly increased total effective rate when compared to conventional treatment [Fig. 4; Analysis 1.1; RR 1.21, 95% CI 1.11–1.33; I² = 0%].

Fig. 4
(Analysis 1.1): Comparison. Chinese patent medicine Tong-Feng-Ding-Jiao-Nang capsules plus conventional treatment versus conventional treatment. Outcome 1: Total effective rate

Secondary outcomes

BUA A significant decrease in BUA was observed with Tongfengding capsules plus conventional treatment versus conventional treatment [Fig. 5; Analysis 1.2; MD − 66.05 μm/L, 95% CI − 81.26 to − 50.84; I² = 90%].

Fig. 5
(Analysis 1.2): Chinese patent medicine Tongfengding capsules plus conventional treatment versus conventional treatment. Outcome 2: BUA. BUA: blood uric acid

Three subgroup studies [⁴⁰, ⁴¹, ⁴³] reported that Tongfengding capsules plus urate-lowering drugs combined with relieve pain drugs significantly decreased BUA when compared to urate-lowering drugs combined with relieve pain drugs [Fig. 5; Analysis 1.2.1; MD − 80.35 μm/L, 95% CI − 83.04 to − 77.66; I² = 0%].

One subgroup study [⁴⁵] reported that Tongfengding capsules plus NSAIDs significantly decreased BUA when compared to NSAIDs [Fig. 5; Analysis 1.2.2; MD − 28.95 μm/L, 95% CI − 47.19 to − 10.71].

Kidney function (24-h UTP, SCr, and BUN) One study [⁴⁰] reported that Tongfengding capsules plus conventional treatment (allopurinol) significantly decreased 24-h UTP and BUN when compared to conventional treatment [Fig. 6; Analysis 1.3.1; MD − 0.83 g/24 h, 95% CI − 0.96 to − 0.70] and [Fig. 6; Analysis 1.3.3; MD − 0.90 mmol/L, 95% CI − 1.60 to − 0.20], respectively. In contrast, the study [⁴⁰] showed that Tongfengding capsules plus conventional treatment did not significantly decrease SCr when compared against conventional treatment [Fig. 6; Analysis 1.3.2; MD − 4.02 μm/L, 95% CI − 8.18 to 0.14].

Fig. 6
(Analysis 1.3): Chinese patent medicine Tongfengding capsules plus conventional treatment versus conventional treatment. Outcome 3: Kidney function (24-h UTP, SCr, and BUN). 24-h UTP: 24-h urinary total protein; SCr: serum creatinine; BUN: blood urea nitrogen

Inflammatory factor (Il-6, Il-8, and TNF-α) Two studies [⁴⁰, ⁴³] reported that Tongfengding capsules plus conventional treatment (allopurinol [⁴⁰] and Febuxostat [⁴³]) significantly decreased Il-6, Il-8, and TNF-α when compared to conventional treatment [Fig. 7; Analysis 1.4.1; MD − 6.99 ng/L, 95% CI − 13.22 to − 0.75; I² = 96%], [Fig. 7; Analysis 1.4.2; MD − 12.17 ng/L, 95% CI − 18.07 to − 6.27; I² = 93%], and [Fig. 7; Analysis 1.4.3; MD − 8.50 ng/L, 95% CI − 15.50 to − 1.51; I² = 97%], respectively.

Fig. 7
(Analysis 1.4): Chinese patent medicine Tongfengding capsules plus conventional treatment versus conventional treatment. Outcome 4: Inflammatory factor (IL-6, IL-8, and TNF-α). IL: interleukin, TNF-α: tumor necrosis factor-alpha

Related indicators (CRP and ESR) One study [⁴⁰] reported that Tongfengding capsules plus conventional treatment (allopurinol) significantly decreased CRP and ESR when compared to conventional treatment [Fig. 8; Analysis 1.5.1; MD − 7.83 mg/L, 95% CI − 9.26 to − 6.40] and [Fig. 8; Analysis 1.5.2; MD − 7.02 mg/L, 95% CI − 8.48 to − 5.56], respectively.

Fig. 8
(Analysis 1.5): Chinese patent medicine Tongfengding capsules plus conventional treatment versus conventional treatment. Outcome 5: Related indicators (CRP and ESR). CRP: C-reactive protein; ESR: erythrocyte sedimentation rate

Relapse rate Two studies [⁴¹, ⁴⁵] reported that Tongfengding capsules plus conventional treatment significantly decreased relapse rate when compared to conventional treatment [Fig. 9; Analysis 1.6; RR 0.24, 95% CI 0.09–0.61; I² = 0%].

Fig. 9
(Analysis 1.6): Chinese patent medicine Tongfengding capsules plus conventional treatment versus conventional treatment. Outcome 6. Relapse rate

Adverse effects (rash, diarrhea, and gastrointestinal discomfort) One study [⁴¹] reported that Tongfengding capsules plus conventional treatment significantly decreased adverse effects on overall effect when compared to conventional treatment [Fig. 10; Analysis 1.7; RR 0.21, 95% CI 0.04–0.95; I² = 0%].

Fig. 10
(Analysis 1.7): Chinese patent medicine Tongfengding capsules plus conventional treatment versus conventional treatment. Outcome 7: Adverse effects

Other outcomes One study [⁴²] reported no withdrawal symptoms, but provided no further details. All-cause mortality, economic index, and TCM tongue and pulse assessment (e.g., tongue coating and pulse) were not reported in any of the six studies.

GRADE quality of evidence

The “GRADE profiler” provided by the Cochrane Collaboration Network was utilized to classify the results of this systematic review. The GRADE quality of evidence was moderate to high (Table 3).

Table 3
GRADE quality of evidence

Tongfengding capsules plus conventional treatment versus conventional treatment for gout in adults
Patient or population: patients with gout in adults Settings: inpatients or outpatients Intervention: Tongfengding capsules plus conventional treatment versus conventional treatment
Outcomes	Illustrative comparative risks* (95% CI)		Relative effect (95% CI)	No of Participants (studies)	Quality of the evidence (Grade)	Comments
	Assumed risk	Corresponding risk
	Control	Tongfengding capsules plus conventional treatment versus conventional treatment
Total effective rate	Study population		RR 1.21 (1.11-1.33)	307 (4 studies)	⊕ ⊕ ⊕ ⊕	Important
	760 per 1000	920 per 1000 (844-1000)			high
	Moderate 799 per 1000	967 per 1000 (887-1000)
BUA		The mean bua in the intervention groups was 66.05 lower (81.26 to 50.84 lower)		461 (4 studies)	⊕ ⊕ ⊕ ⊕ high	Important
Kidney function		The mean kidney function in the intervention groups was 0.85 lower (1.13-0.58 lower)		340 (2 studies)	⊕ ⊕ ⊕ ⊝ moderatea	Important
Inflammatory factors		The mean inflammatory factors in the intervention groups was 9.18 lower (12.7-5.67 lower)		780 (2 studies)	⊕ ⊕ ⊕ ⊝ moderatea	Important
Related indicators		The mean related indicators in the intervention groups was 7.43 lower (8.46-6.41 lower)		360 (1 study)	⊕ ⊕ ⊕ ⊝ moderateb	Important
Relapse rate	Study population 210 per 1000 Moderate	50 per 1000 (19-128)	RR 0.24 (0.09-0.61)	201 (2 studies)	⊕ ⊕ ⊕ ⊝ moderatea	Important
Adverse effects	217 per 1000 Study population	52 per 1000 (20-132)	RR 0.21 (0.04-0.95)	223 (1 study)	⊕ ⊕ ⊕ ⊝	Important
	70 per 1000 Moderate	15 per 1000 (3-66)			moderateb
	100 per 1000 Moderate	21 per 1000 (4-95)
	25 per 1000 100 per 1000 Moderate	8 per 1000 (0-194) 10 per 1000 (1-199)
	100 per 1000 100 per 1000 Moderate	10 per 1000 (1-199) 24 per 1000 (3-209)
	100 per 1000	24 per 1000 (3-209)

• GRADE Working Group grades of evidence
• High quality: Further research is very unlikely to change our confidence in the estimate of effect. Handbook description: randomized controlled trial
• Moderate quality: Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate. Cochrane Handbook description: relegation randomized controlled trial
• Low quality: Further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate. Cochrane Handbook description: two or more degradation factors of randomized controlled trials
• Very low quality: We are very uncertain about the estimate. Cochrane Handbook description: more than three degradation factors of randomized controlled trials Reduce the evidence quality factors: methodology defect, included in the research results of the inconsistency, indirect evidence, inexactness, and publication bias Increase the level of evidence factor: large effect quantity, confounding factors cannot change effect quantity, or the existing concentration-response relationship CI: Confidence interval; RR: Risk ratio
• ^*
  The basis for the assumed risk (e.g. the median control group risk across studies) is provided in footnotes. The corresponding risk (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI)
• ^a
  Only two studies included
• ^b
  Only one study included

Discussion

Based on six RCTs [⁴⁰–⁴⁵] conducted in China, we found limited evidence that Chinese patent medicine Tongfengding capsule plus conventional treatment confers positive effects by increasing total effective rate and reducing BUA, 24-h UTP, BUN, IL-6, IL-8, TNF-α, CRP, ESR, relapse rate, and adverse effects (e.g., rash, diarrhea, and gastrointestinal discomfort), when compared with conventional treatment. However, there was insufficient evidence to confirm whether Chinese patent medicine Tongfengding capsules plus conventional treatment has positive effects on SCr, when compared with conventional treatment.

The quality of evidence in our review was high to moderate (Table 3: GRADE Quality of Evidence). The results were robust (e.g., further research is very unlikely to change and/or is likely to have an important impact on our confidence in the estimate of effect and may change the estimate), but many studies were inadequately powered, and the methodological processes were either not described and/or flawed in many instances. For example, randomization was mentioned in two studies, but the randomization method was not reported [⁴³, ⁴⁴]; in the six included studies, allocation concealment was not mentioned [⁴⁰–⁴⁵], although telephone interviews with the original authors showed that allocation concealment was indeed used; in the six included trials, the blinding procedures were not mentioned [⁴⁰–⁴⁵], although the authenticity of blinding in three included trials was confirmed by telephone [⁴³–⁴⁵]. Consequently, the risks of performance and detection biases were unclear in the remaining three included studies [⁴⁰–⁴²]. In the review, despite our efforts to expand and clarify the reported data by contacting the original trial authors, we did not obtain significant and/or sufficient additional data to increase our assessments in one of the studies.

We determined that three of six included studies were of high methodological quality, three were of moderate methodological quality. Therefore, it is possible that these deficits may be wholly or partly related to the absence of sufficient reporting. We presume that selection, performance, and detection biases may have been present in the reviewed studies.

This evidence-based review investigated six RCTs of gout treatment among adults in China [⁴⁰–⁴⁵]. The six RCTs reported that Chinese patent medicine Tongfengding capsules (which acts by clearing heat, eliminating dampness, and activating blood to relieve pain) plus conventional treatment for gout demonstrated benefits through increased total effective rate and reduction of BUA, 24-h UTP, BUN, IL-6, IL-8, TNF-α, CRP, ESR, relapse rate, and adverse effects (e.g., rash, diarrhea, and gastrointestinal discomfort). Based on the findings of this review, the authors consider Chinese patent medicine Tongfengding capsules to be safe and beneficial in the management of gout when used in combination with conventional treatment. However, the results reported were from three studies with moderate methodological quality and three studies with high methodological quality.

Therefore, larger multicenter trials with high methodological quality are needed to assess further the use of Chinese patent medicine Tongfengding capsule in adults. These trials should include patients who have gout and are undergoing treatment with Tongfengding capsules. More data are necessary, particularly concerning TCM outcomes (such as tongue coating and pulse). The effect of Tongfengding capsule should also be explored based on TCM syndrome differentiation. Future trials should assess the most suitable treatment method, the role of Tongfengding capsule, and the optimal dosages for treatment of gout. Such studies would help to confirm the validity of our findings and could more clearly establish the efficacy of Tongfengding capsules for gout in adults, in comparison with other treatments.

Limitations of study

One of the limitation of this study is its sample size. Due to small sample size, subgroup analysis results based on different type of drugs obtained was limited. Future studies may involve a larger size sample with high methodological quality. Besides, all the available data is in the Chinese population. Therefore, its application to other populations is limited at the moment.

Conclusion

The Chinese patent medicine Tongfengding capsules plus conventional treatment is safe and beneficial for adults with gout when compared with conventional treatment.

• Funding
  This work was supported by grants from the program of the National Natural Science Foundation of China (Grant No. 81873261).
• Declarations
  Ethics approval and consent to participate
  All analyses were based on previous published studies, thus no ethical approval and patient consent are required.
• Consent for publication
  Informed consent was obtained.
• Publisher's Note
  Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Availability of data and materials

The data used to support the findings of this study are available from the corresponding author upon request.

Acknowledgements

The authors thank Guangzhou University of Chinese Medicine; Second Outpatient Department, First Affiliated Hospital, Guangzhou University of Chinese Medicine; Chinese Clinical Trial Registry; The Second Clinical Medical College, Guangzhou University of Chinese Medicine; Department of Nephrology, Guangdong Provincial Hospital of Chinese Medicine; and Department of Hemodialysis, Guangdong Provincial Hospital of Chinese Medicine.

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Publication Dates

• Publication in this collection
  07 Aug 2023
• Date of issue
  2023

History

• Received
  01 Feb 2023
• Accepted
  12 June 2023
• Published
  18 July 2023