Abstract
Background:
Acute gouty arthritis is accompanied by severe pain during an acute attack. This systematic review aimed to evaluate the efficacy and safety of herbal medicines acting directly on the affected area of acute gouty arthritis for external use.
Methods:
An envelope search was performed using 4 electronic databases (CNKI, PubMed, EMBASE, Cochrane), resulting in 27 clinical studies from inception to February 2023. Randomized controlled trials on external use herbal medicines for acute gouty arthritis were considered. The assessed outcomes were total effective rate, uric acid level, pain score, and inflammatory factor levels such as erythrocyte sedimentation rate and C-reactive protein. Quality assessment and meta-analysis of the included randomized controlled trials were also performed.
Results:
Twenty-seven randomized controlled trials with a total of 1951 participants were included in the meta-analysis. All assessed outcomes including pain, inflammation, and uric acid levels, indicated that the treatment effects in the external use herbal medicine group were significantly better than those of the western medicine control group. Of the 10 studies mentioning side effects, no side effects were reported in 4, and in the remaining 6, the incidence of complications in the intervention group was much lower than that in the control group.
Conclusions:
This systematic review and meta-analysis suggests that external use herbal medicines may be a safe and effective alternative for treatment of pain and symptoms of acute gouty arthritis. However, owing to the heterogeneity of interventions, outcomes, and regional bias, further high-quality clinical trials on this topic are needed to confirm the level of evidence.
Keywords: acute gouty arthritis, external medicine, gout, herbal medicine, meta-analysis, systematic review
1. Introduction
Gout is a metabolic disease with excessive accumulation of uric acid in the joints and surrounding tissues due to a purine metabolism disorder in the kidneys. Its symptoms include fever and redness, swelling, pain, and limited activity of the joints.[1,2] In the early stages of arthritis, there is recurrence of localized symptoms, including paroxysmal pain, fever, and swelling, accompanied by systemic symptoms, such as fever, chills, and headache. In chronic joint deformity, gout nodules develop and kidney disease or uric acid stones are induced.[3] According to a report by the World Health Organization, the prevalence of gout is 3.9% in the world population, and its incidence is increasing every year[4]; it is not limited to older people and tends to develop early in the young population.[5]
In Korea, the National Health Insurance Service treatment data from 2016 to 2020 indicate that the number of patients treated for gout steadily increased from 372,898 in 2016 to 466,766 in 2020. Medical expenses have increased from approximately 152.1 billion won in 2016 to 212.1 billion won in 2020. Of the patients, 92.2% were men, 22.7% were in their 50s, and patients in their 20s showed a rapid increase by 61.7%. Gout is strongly associated with metabolic syndrome and arthritis.[3,6] It can be life-threatening due to disease complications, side effects of various drugs, and accompanying diseases,[7,8] and causes a more significant economic burden than other diseases.[9]
Since gout treatment is accompanied by severe pain during an acute attack, its treatment is focused on administering anti-inflammatory drugs and pain relief in the acute phase. Non-steroidal anti-inflammatory drugs, colchicine, and glucocorticoids are the primary treatments used in western medicine (WM).[10] These drugs are effective for short-term pain relief, but long-term use can cause side effects, such as gastrointestinal reactions, liver or kidney dysfunction, and rashes.[11,12] In addition, medications can be discontinued due to side effects, which significantly restrict the treatment process; therefore, a treatment that can replace them is needed.[13]
Gout corresponds to a category of arthralgia syndrome in traditional medicine, such as in Korean medicine (KM) and traditional Chinese medicine (TCM). Various KM and TCM treatment methods, such as acupuncture, bloodletting, cupping, moxibustion, pharmacopuncture, and herbal medicine, are clinically effective. Several systematic reviews have reported that with traditional medicine, clinical symptoms, uric acid levels, pain, and treatment effectiveness are improved and side effects are reduced as compared with WM.[2,14–16] In TCM, step-by-step treatment methods have been proposed from the viewpoint that it is possible to strengthen the body resistance and remove the cause of the disease by controlling the yin–yang imbalance. Clinical studies have used various interventions, such as herbal bath therapy and external patches.[2]
External drugs act directly on the affected areas. Because the concentration of a topical medication is high and it is applied precisely on the affected area, its therapeutic effect can be confirmed more clearly.[17,18] Although there have been reports of herbal medicines for external use (HMEU) in the treatment of gout, a comparative analysis through a systematic literature review of HMEU for gout treatment is yet to be performed. The KM literature on gout mentions kneading Sophora flavescens powder with alcohol and applying it to the affected area[2]; however, relevant clinical reports are scarce. Therefore, this study aimed to provide a review and meta-analysis of published studies to explore the effectiveness and safety of HMEU for patients with acute gouty arthritis.
2. Methods
2.1. Study registration
The protocol for this systematic review has been published in the Medicine Journal[13] and registered in the International Prospective Register of Systematic Reviews. This systematic review is reported in compliance with the Preferred Items for Systematic Reviews and Meta-Analyses.[19]
2.2. Criteria for study inclusion
2.2.1. Types of participants.
Adult patients (aged ≥18 years) diagnosed with acute gout based on the standard Chinese acute gout diagnostic criteria[20] or American diagnostic criteria[21] for gout arthritis were included in the study regardless of the severity of symptoms, sex, nationality, or education status.
2.2.2. Types of interventions and controls.
Interventions can be applied alone or in combination with other treatments. However, TCM treatments, except for HMEU, were not allowed, and other combined treatments were considered acceptable in that both the intervention and control groups were provided the same. Further, studies evaluating all types of HMEU were included, regardless of application, ointment, washing solution, or patch. All control interventions, such as placebo or sham, no intervention, and WM, were considered.
2.2.3. Types of studies.
Prospective randomized controlled trials (RCT) that evaluated the effectiveness of HMEU for acute gout were considered. We excluded: literature not related to gout or HMEU treatment; observational and animal studies; and non-RCTs, protocols, meta-analyses, review studies, and case reports, which were not appropriate for the direction of this study.
2.2.4. Outcomes.
For data synthesis, outcomes included blood uric acid levels, total effective rate (TER), pain scores assessed using a visual analog scale (VAS), and inflammatory markers such as erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP). The incidence of adverse events was also included.
2.3. Data sources and search strategy
Databases and search terms were determined through discussions among all authors prior to the literature search. Two independent authors conducted a literature search in the following databases from their inceptions to February 2023: China National Knowledge Infrastructure (CNKI; http://www.cnki.net), PubMed (https://pubmed.ncbi.nlm.nih.gov/), EMBASE (https://www.embase.com), Cochrane (https://www.cochranelibrary.com/). The search was conducted using the following keywords “gout,” “acute gouty arthritis,” “herbal drug,” “herbal medicine,” and “Traditional Chinese Medicine.” There were no restrictions on the publication status or language (Fig. 1).
Figure 1.
Flow chart. Preferred items for systematic reviews and meta-analyses (PRISMA) flow diagram. CNKI = China National Knowledge Infrastructure, RCT = Randomized controlled trials, TCM = Traditional Chinese Medicine.
2.4. Data extraction
All identified documents were assessed for inclusion eligibility using Endnote software (Clarivate Analytics, New York, NY). Articles were screened and removed according to the inclusion and exclusion criteria, and duplicate reports were manually removed. After selecting the studies, 2 researchers independently performed data extraction in a predesigned form. Data extracted from the selected articles included publication information (author and year of publication), sample size, age, sex, treatment methods of intervention and control groups, dosage and duration, outcome measurements, adverse effects, and summary of results. Any uncertainties or disagreements between the 2 researchers during the review were resolved through discussion and consensus. If no agreement was reached, it was resolved by a third researcher.
2.5. Data analysis
Data were synthesized and analyzed using the Cochrane Review Manager 5.4.1 software (The Nordic Cochrane Centre, The Cochrane Collaboration, Copenhagen, Denmark). The TER was presented as an odds ratio and 95% confidence interval (CI). Continuous variables, such as VAS score, blood uric acid level, ESR, and CRP level, are presented as standardized mean differences (SMD) and 95% CIs. Statistical heterogeneity was assessed using I2 and P values according to 95% Cis. I2 < 25% was considered low heterogeneity, 25% to 50% was moderate, >50% as high heterogeneity, and P < .05 was considered significant. If heterogeneity was significant, the meta-analysis used random effects, whereas for insignificant heterogeneity, fixed effects were used.
2.6. Quality assessment
The Cochrane Bias (risk of bias) tool was used to evaluate the risk of bias in the included RCTs. The following contents were included: random sequence generation, allocation concealment, blinding of participants and personnel, and outcome assessors, completeness of data outcome, selective reporting, and other biases were assessed as “low risk,” “unclear risk,” or “high risk.” Two researchers independently assessed risk of bias. Disagreements between the 2 researchers were resolved through discussions and consensus.
3. Results
3.1. Literature search
Among the 17,285 articles searched until February 28, 2023, 9149 from CNKI, 7425 from PubMed, 327 from Cochrane, and 374 from Embase were retrieved. Among them, except for the duplicated 574 articles, 16,702 articles were screened through titles and abstracts, excluding a total of 13,828 articles, those unrelated to gout or TCM (KM) treatment, experimental literature (animals, etc), protocols, meta-analyses, reviews, and case studies. Of the remaining 2884 articles, 2832 unrelated to the purpose of this study were excluded, including articles that included TCM and KM interventions other than herbal medicines in the intervention group and articles that did not include contents of acute gouty arthritis or HMEU. Of the 52 selected articles, 27 original texts[22–47] reported clinical results, such as of efficacy rate, uric acid level, ESR, CRP level, and VAS pain scores, and were subjected to final analysis. Twenty-five original texts that did not include these findings were excluded (Fig. 1).
3.2. Study characteristics
The characteristics of the 27 included studies are presented in Table 1. The present study analyzed the effects of HMEU on acute gouty arthritis. In the intervention group, HMEU was used either alone or combined with WM. In the control group, conventional WM for acute gouty arthritis was used. The 1951 included participants ranged from 18 to 85 years (average age, 30–50 years). Excluding 4 articles that did not specify participant sex distribution, a total of 1408 (83%) men and 281 (17%) women were included, indicating a greater proportion of men. Regarding the form of HMEU used, 23 studies involved treatment with HMEU in powder form, and 1 transdermal patch, 1 ointment, and 2 bath therapies were used. HMEU included Shuanghuangbai powder, Zijin-ding, Sanhuang powder, Jinhuang powder, Shuangbai powder, Zhenggu-powder, Tuihuang powder, Zhihuangzhitong powder, Kushen powder, Yangtong-fang, and Sihuang-gao. An overview of the components of the HMEU preparations is provided in Table 2. The Jinhuang, Shuangbai, and Zhihuangzhitong powders were the most used, and the frequency of treatments was 1 to 2 times a day. HMEU were applied either alone or in combination with WM. The analysis showed that a higher proportion of patients were treated with a combination of HMEU and WM. WMs used for the treatment of acute gouty arthritis in this study included indomethacin, allopurinol, diclofenac, colchicine, sodium bicarbonate, nimesulide, benzbromarone, arcoxia, celecoxib, meloxicam, of which colchicine was the most commonly used. As for the prescription of WM, the dose was increased during an acute attack and lowered when the pain was relieved. Side effects after treatment were mentioned in 10 articles, whereas 17 articles did not specify any adverse effects.
Table 1.
Study characteristics.
| Study | Sample size (I/C) | Age (I/C) | Gender | Treatments | Dosages/Duration | Outcomes | Adverse effect | ||||
|---|---|---|---|---|---|---|---|---|---|---|---|
| M | F | Intervention | Control | Intervention | Control | Main | Others | ||||
| Huang 2005[22] | 47 (25/22) | 35~75 (51.6) | 45 | 2 | CT + SBP(EA) | INN + ALL | 1/d (7d) | INN 25~50mg, 2~3/d; ALL 0.1g, 2~3/d (7d) | TER; UA | - | None |
| Liu 2005[23] | 90 (60/30) | I: 26~65 (50.70 ± 12.30) C: 28~65 (52.17 ± 11.65) | 84 | 6 | TFP(PA) | DCF | 1/d (7d) | 3/d (7d) | TER; UA; ESR | - | None |
| Fang 2006[24] | 60 (30/30) | 35~85 (63.5) | 58 | 2 | ZJD(EA) | CC | 5tb/t, 1~2/d | N/A | TER | - | N/A |
| Jiang 2014[25] | 60 (30/30) | 32~59 (38.6 ± 12.5) | N/A | N/A | RLI (20 min/t, 2/d) + SHP(EA) | CC | 1/d (7d) | 0.5mg/t, 8h/t (7d) | TER; UA; ESR; VAS CRP | - | N/A |
| Ju 2015[26] | 40 (20/20) | 39~69 (I: 55.6 ± 5.2, C: 55.8 ± 5.1) | 26 | 14 | JHP(EA) | DCF(OM) | 2/d (5~7d) | 2/d (7d) | TER | - | N/A |
| Zhu 2017[27] | 60 (30/30) | 42~67 (53.5) | 52 | 8 | CT + JHP(EA) | CC | 2/d (7d) | 1mg/t, 4/d (7d) | TER; VAS | - | N/A |
| Wang 2017[28] | 58 (29/29) | I: 18~38 (23.28 ± 3.63) C: 20~40 (22.93 ± 3.16) | 53 | 5 | CT + JHP(EA) | INN | 1/d (7d) | 50mg (Ac), 25mg/t (7d) | TER; VAS; BUA; ESR | WBC | I: SA 2; C: SA 3 |
| Cheng 2017[29] | 50 (25/25) | I: 23~55 (42.3 ± 3.6) C:28~53 (43.7 ± 2.9) | 40 | 10 | CT + SBP(EA) | DCF, SBC | 2/d (7d) | DCF 75mg, 1/d; SBC 1g, 3/d (7d) |
TER | IL-1, IL-8 | N/A |
| Du 2017[30] | 120 (60/60) | I:28~53 (41.22 ± 6.11) C:29~55 (42.65 ± 5.75) | 110 | 10 | ZGP(EA) | CC | 2/d (6d) | 1mg/d(Ac), p.5mg/t, 3/d (6d) | TER; VAS; CRP | - | I: IT 1, MI 2; C: GD 19 |
| Wu 2017[31] | 66 (33/33) | I: 18~65 (36.5 ± 8.6) C:18~62 (35.8 ± 7.9) | 39 | 27 | HF | NM + BZ | 1/d, 30 min/t (10d) | NM 0.2g/t, 1/d(Ac); BZ 50mg/t, 1/d (10d) | TER; UA; CRP; ESR | - | N/A |
| Chen 2018[32] | 70 (35/35) | I: 23~46 (43.1 ± 0.5) C:21~47 (41.8 ± 0.8) | N/A | N/A | CT + THP(EA) | CC | 2~3/d, 2h/d | <12h 0.5mg/t, 1~2/d, <72h 0.5mg/t, 1/d (7d) | TER | - | N/A |
| Li 2018[33] | 80 (40/40) | I: 23~66 (38.7 ± 13.9) C: 24~69 (32.9 ± 8.0) |
75 | 5 | CT + ZHZT(EA) | ARC | 1/d (7d) | ~3d 120mg/d, <3d 60mg/d (7d) | TER; VAS; UA; CRP; ESR | - | N/A |
| Wen 2018[34] | 60 (30/30) | I: 26~57 (40.17 ± 7.05) C:28~59 (41.48 ± 6.91) | 55 | 5 | CT + ZHZT(EA) | ARC | 1/d (7d) | ~3d 120mg/d, <3d 60mg/d (7d) | TER; VAS; UA; CRP; ESR | IL-1β, TNF-α | N/A |
| Hu 2019[35] | 60 (30/30) | I: 25~70 (41.43 ± 10.68) C:30~69 (41.10 ± 11.65) | 49 | 11 | CT + KSP(EA) | IBP + COD | 2/d, 3~4h (5d) | 0.4~0.6g/t, 1/12h (5d) | TER; CRP; ESR; UA; VAS | - | N/A |
| Ma 2019[36] | 94 (47/47) | I: 29~70 (46.11 ± 5.32) C:27~72 (45.89 ± 5.11) | 51 | 43 | CT + SHP(EA) | CC | 1/d, 4~6h (14d) | <72h 0.5~1mg/d (14d) | TER; VAS | - | N/A |
| Liang 2019[37] | 121 (61/60) | I:19~75 (51.67 ± 9.02) C:19~72 (51.09 ± 8.85) | 108 | 13 | SBP(EA) | IBP + SBC | 1/d, 4~6h (7d) | IBP 0.3g, 2/d; SBC 1~2tb/t, 3/d (7d) | TER; VAS; UA | - | N/A |
| Dai 2019[38] | 69 (35/34) | I:58.7 ± 15.0; C:58.7 ± 16.7 | 61 | 8 | YTF(EA) | CCX | 1/d (7d) | 1/d (7d) | VAS; UA | WBC | I: None; C: GD 2 |
| Ju 2019[39] | 120 (60/60) | I:41~67 (53.1 ± 2.31) C: 43~65 (51.3 ± 3.15) |
107 | 13 | EC + WTJB(OM) | CCX | 1/d (7d) | 200mg/d, 1/d (7d) | TER | - | None |
| Liu 2019[40] | 90 (45/45) | I: 27~62 (45.72 ± 8.05) C:25~63 (46.17 ± 7.89) | 70 | 20 | SHG(EA) | CC | 1/d (7d) | <72h 0.5mg, 2/d (7d) | TER; CRP; ESR; UA; VAS | - | I: SR 2; C: GD 7 |
| Dong 2019[41] | 70 (35/35) | 18~69 (27 ± 1.3) | N/A | N/A | CT + HF | CC | 1/d (7d) | N/A (7d) | VAS; CRP; UA; ESR | WBC | N/A |
| Zheng 2020[42] | 63 (32/31) | I: 49.5 ± 15; C:48.3 ± 12.6 | N/A | N/A | CT + JHP(EA) | DCF | 1/d, 6~8h (5d) | 50mg/t, 2/d (5d) | VAS; UA ESR; CRP; | - | N/A |
| Fang 2020[43] | 72 (36/36) | I: 43~68 (53.60 ± 4.70) C:42~69 (53.90 ± 4.50) | 65 | 7 | CT + JHP(EA) | SBC + CC + CCX | 2/d, 1h (7d) | SBC 1.0g/t, 3/d; CC 1mg/2h, >3mg/d; CCX 0.2g/t, 2/d | TER; VAS; UA | IL-1β, TNF-α, XOD | N/A |
| He 2020[44] | 72 (36/36) | I: 20~65 (32.3 ± 5.41) C:18~64 (33.7 ± 4.68) | 61 | 11 | SBP + JHP(EA) | ARC | 2/d (7d) | 120mg/t, 1/d (7d) | TER; UA; CRP; ESR | - | I: None; C: GD 1 |
| Cai 2020[45] | 60 (30/30) | I: 29~70; C:29~66 | 41 | 19 | CT + SBP(EA) | MEL + SBC | 2/d (10d) | MEL 7.5mg/t, 1/d; SBC: 1.0g/t, 3/d (10d) | TER; VAS; UA; CRP; ESR | - | None |
| Qiao 2020[45] | 70 (35/35) | I: 23~52 (35.4 ± 10.3) C: 25~54 (36.7 ± 7.2) | 48 | 22 | CT + ZHZT(EA) | ARC | 1/2d (10d) | 1tb/t, 1/d (10d) | TER; VAS | - | N/A |
| Zhang 2020[46] | 60 (30/30) | I: 24~56 (41.42 ± 13.37) C:27~62 (37.75 ± 9.22) | 49 | 11 | CT + ZHZT(EA) | ARC | 1/3d (14d) | 60mg/t, 1/d (14d) | TER; VAS’ UA’ CRP; ESR | - | N/A |
| Xie 2020[47] | 70 (35/35) | I: 28~54 (30.5 ± 4.3) C: 23~59 (35.2 ± 5.0) | 61 | 9 | CT + SKHS(EA) | IBP | 2/d, 3h (7d) | 1tb/t, 3/d (7d) | TER; VAS; UA; CRP; ESR | - | I: GD 1, Al 1; C: GD 3 |
Al = Allergy, ALL = Allopurinol, ARC = Arcoxia, BZ = Benzbromarone, C = Control, CC = Colchicine, CCX = Celecoxib, Cod = Codeine, CRP = C-reactive protein, d = day, DCF = diclofenac, EA = external apply, EC = ercha-powder, ESR = erythrocyte sedimentation rate, F = female, GD = gastric dyspepsia, h = hour, HF = herbal fumigation, I = intervention, IBP = ibuprofent = times, IL = interleukin, INN = indomethacin, IT = itch, JHP = jinhuang-powder, KSP = kushen-powder, M = male, MEL = meloxicam, Mi = Milium, N/A = not available, NM = nimesulide, OM = ointment, PA = patch, RLI = Red light irradiation, SA = stomache, SBC = sodium bicarbonate, SBP = shuangbai-powder, SHBP = shuanghuangbai-powder, SHG = sihuanggao, SHP = sanhuang-powder, SKHS = shangkehuangshui, SR = skin redness, tb = tablet, TER = total effective rate, TFP = tongfeng-patch, THP = tuihuang-powder, TNF- α = tumor necrosis factor-α, UA = uric acid, VAS = visual analog scale, WBC = white blood cell, WTJB = wentongjuanbi-powder, XOD = xanthine oxidase, YTF = yangtongfang, ZGP = zhenggu-powder, ZHZT = zhihuangzhitong-powder, ZJD = zijin-ding.
Table 2.
Overview of external use herbal medicines.
| Main varieties | Drug type (TCM) | Drug composition (Chinese pinyin) |
|---|---|---|
| Zhihuangzhitong-powder | Promotes blood circulation and resolves stasis, reduces swelling and pain, clears heat, and has a detoxifying effect | Fructus Gardeniae (Zhizi), Rhei Radix Et Rhizoma (Dahuang), Olibanum (Ruxiang), Commiphora Myrrha (Moyao), Aucklandiae Radix (Muxiang), Turmeric (Jianghuang), Paeoniae Radix Rubra (Chishao), Angelicae Dahuricae Radix (Baizhi), Radix Trichosanthis (Tianhuafen), Radix Ampelopsis (Bailian), Adzuki Beans (Chixiaodou), Phellodendri Chinensis Cortex (Huangbo), Borneolum (Bingpian), Moschus (Shexiang) |
| Ercha-ointment | Clears heat, has a detoxifying effect, reduces swelling and pain | Catechu (Ercha), Coptidis Rhizoma (Huanglian), Sodium tetraborate (Pengsha), Halloysitum Rubrum (Chishizhi), Compound Calamine Topical Powder (Luganshi), Borneolum (Bingpian) |
| Jinhuang-powder | Clears heat, has a detoxifying effect, promotes dampness, promotes blood circulation, resolves stasis, reduces swelling and pain | Rhei Radix Et Rhizoma (Dahuang), Turmeric (Jianghuang), Phellodendri Chinensis Cortex (Huangbo), Atractlodis Rhizoma (Cangzhu), Magnoliae Officmalis Cortex (Houpo), Citrus reticulata Blanco (Chenpi), Glycyrrhizae Radix et Rhizoma (Gancao), Rhizoma Arisaematis (Tiannanxing), Angelica Dahurica (Baizhi), Radix Trichosanthis (Tianhuafen), Honey |
| Kushen-powder | Clears heat, purges fire, has a detoxifying effect, clears heat, removes dampness, unblocks collaterals, dispells wind, removes obstruction, promotes blood circulation, and promotes blood stasis | Sophorae Flavescentis Radix (Kushen), Harlequin Glorybower Leaf (Chouwutongye), Coptidis Rhizoma (Huanglian), Phellodendri Chinensis Cortex (Huangbo), Fructus Gardeniae (Zhizi), Rhei Radix Et Rhizoma (Dahuang) |
| Sanhuang-powder | Clears heat, removes dampness, reduces swelling and pain, promotes blood circulation, and unblocks collateral vessels | Scutellariae Radix (Huangqin), Phellodendri Chinensis Cortex (Huangbo), Rhei Radix Et Rhizoma (Dahuang), Borneolum (Bingpian), Natrii Sulfas (Mangxiao)) |
| Shangke-huangshui, | Clears heat, has a detoxifying effect, reduces swelling and pain, promotes blood circulation,resolves blood stasis, removes decay, and promotes muscle growth |
Scutellariae Radix (Huangqin), Phellodendri Chinensis Cortex (Huangbo), Coptidis Rhizoma (Huanglian), Giant Knotweed Rhizome (Huzhang), Aluminium potassium sulfate dodecahydrate (Mingfan), Peppermint (Bohe), Sophorae Flavescentis Radix (Kushen), Garden Burnet Root (Diyu), Arnebiae Radix (Zicao), Fructus Gardeniae (Zhizi) |
| Shuangbai-powder | Clears heat, has a detoxifying effect, promotes blood circulation, resolves blood stasis, reduces swelling and pain | Rhei Radix Et Rhizoma (Dahuang), Peppermint (Bohe), Phellodendri Chinensis Cortex (Huangbo), Herba Lycopi (Zeran), Platycladi Cacumen (Cebaiye) |
| Sihuang-gao | Clearing heat and detoxifying, reducing swelling and pain | Scutellariae Radix (Huangqin), Phellodendri Chinensis Cortex (Huangbo), Coptidis Rhizoma (Huanglian), Rhei Radix Et Rhizoma (Dahuang), Borneolum (Bingpian) |
| Tongfeng-patch | Clears heat, has a detoxifying effect, removes dampness and phlegm, reduces swelling and pain | Phellodendri Chinensis Cortex (Huangbo), Rhei Radix Et Rhizoma (Dahuang), Sophorae Flavescentis Radix (Kushen), Peach Seed (Taoren), et al Composed of 12 herbal medicines |
| Tuihuang-powder | Eliminates wind and dampness, unblocks collateral vessels and resolves blood stasis, reduces swelling and pain | Phellodendri Chinensis Cortex (Huangbo), Rhei Radix Et Rhizoma (Dahuang), Garden Burnet Root (Diyu), Rhizoma Arisaematis (Tiannanxing), Angelica Dahurica (Baizhi) |
| Wentongjuanbi-oointment | Warm meridians unblock collaterals, promote blood circulation, and relieve pain | Aconiti Radix (Chuanwu), Rhizoma Arisaematis (Shengnanxing), Aconiti Lateralis Radix Praeparata (Fuzi), Sinomenii Caulis (Qingfengteng), Angelicae Pubescentis Radix (Duhuo), Chaenomelis Fructus (Mugua), Notopterygii Rhizoma Et Radix (Duhuo), Angelicae Sinensis Radix (Danggui), Herba Speranskiae Tuberculatae (Tougucao), Cinnabaris (Zhusha), Realgar (Xionghuang), Safflower (Honghua), Flos Caryophyllata (Dingxiang), Olibanum (Ruxiang), Commiphora Myrrha (Moyao), Szechwan Lovage Rhizome (Chuanxiong), Camphor (Zhangnao), DriedGinger (Ganjiang), Magnoliae Flos (Xinyi), Ceylon Cinnamon (Rougui) |
| Yangtongfang | Relieves pain quickly | Rhei Radix Et Rhizoma (Dahuang), Turmeric (Jianghuang), Phellodendri Chinensis Cortex (Huangbo), Indigo Naturalis (Qingdai), Malt Sugar |
| Zhenggu-powder | Promotes blood circulation, resolves blood stasis, reduces arthralgia, clears heat, and removes dampness |
Safflower (Honghua), Fructus Gardeniae (Zhizi), Angelicae Sinensis Radix (Danggui), Olibanum (Ruxiang), Commiphora Myrrha (Moyao), Ephedra Herb (Mahuang), Draconis Sanguis (Xuejie), Divaricate Saposhniovia Root (Fangfeng), Rhizoma Arisaematis (Tiannanxing), Angelica Dahurica (Baizhi), Drynariae Rhizoma (Gusuibu), Dipsaci Radix (Xudan), Catechu (Ercha) |
| Zijin-ding | Removes dampness, has a detoxifying effect, promotes blood stasis, reduces swelling and nodules, and relieves pain | Cremastrae Pseudobulbus Pleiones Pseudobulbus (Shancigu), Knoxiae Radix (Hongdaji), Galla Chinensis (Wubeizi), Euphorbiae Semen (Jinqianzi), Cinnabaris (Zhusha), Moschus (Shexiang), Realgar (Xionghuang), Notoginseng Radix Et Rhizome (Sanqi) |
TCM = traditional Chinese medicine.
3.3. Quality assessment
For quality assessment, 27 clinical data points were analyzed by dividing them into 6 items. On evaluation of random sequence generation, the bias was judged to be low because all 27 clinical data points were collected using a random assignment method. However, allocation concealment, blinding of participants and personnel, outcome assessors, completeness of data outcomes, and selective reporting were not mentioned separately; therefore, the risk of bias was evaluated as uncertain. For the other bias items, the risk of bias was assessed as high because there was a possibility of bias in the 5 clinical datasets (Fig. 2).
Figure 2.
Risk of bias summary (A) and graph (B).
3.4. Effect of interventions
3.4.1. Total effective rate.
Data from a total of 24 clinical studies were collected, with 892 and 858 patients in the intervention and control groups, respectively, and a total of 1750 patients. The TER of the HMEU intervention group was 93.7%, which was 12.9% higher than that of the control group (80.8%). A fixed-effects model was chosen for meta-analysis because of no heterogeneity among the 24 studies (I2 = 0%). The results showed that HMEU groups were superior to the control groups in increasing the TER (odds ratio = 3.69, 95% CI = 2.66 to 5.10, P < .00001) (Table 3, Fig. 3).
Table 3.
Outcomes from 27 randomized controlled trials on the effects of herbal medicines for external use in acute gouty arthritis.
| Study | Total effective rate | UA | ESR | VAS | CRP | |||||
|---|---|---|---|---|---|---|---|---|---|---|
| Intervention | Control | Intervention | Control | Intervention | Control | Intervention | Control | Intervention | Control | |
| Huang 2005[22] | 24/25 | 17/22 | 349.11 ± 165.21 | 424.52 ± 194.53 | - | - | - | |||
| Liu 2005[23] | 56/60 | 25/30 | 440 ± 22.23 | 449 ± 24.30 | 12.87 ± 4.91 | 16.20 ± 5.61 | - | - | ||
| Fang 2006[24] | 28/30 | 20/30 | - | - | - | - | ||||
| Jiang 2014[25] | 28/30 | 20/30 | 351.14 ± 50.32 | 362.47 ± 54.85 | 8.54 ± 4.26 | 15.44 ± 4.55 | 2.5 ± 1.45 | 2.8 ± 1.62 | 6.48 ± 4.36 | 15.47 ± 6.84 |
| Ju 2015[26] | 17/20 | 10/20 | - | - | - | - | ||||
| Zhu 2017[27] | 26/30 | 26/30 | - | - | 2.36 ± 0.37 | 2.57 ± 0.46 | - | |||
| Wang 2017[28] | 27/29 | 21/29 | 363.27 ± 33.36 | 403.72 ± 37.04 | 10.68 ± 3.86 | 14.00 ± 5.23 | 1.32 ± 0.87 | 1.42 ± 0.91 | - | |
| Cheng 2017[29] | 22/25 | 16/25 | - | - | - | - | ||||
| Du 2017[30] | 58/60 | 57/60 | - | - | 0.98 ± 1.13 | 1.23 ± 1.04 | 15.2 ± 1.3 | 17.4 ± 1.1 | ||
| Wu 2017[31] | 32/33 | 29/33 | 408.31 ± 3.85 | 478.42 ± 41.86 | 19.2 ± 3.1 | 25.3 ± 3.9 | - | 13.1 ± 3.3 | 19.6 ± 2.7 | |
| Chen 2018[32] | 32/35 | 27/35 | - | - | - | - | ||||
| Li 2018[33] | 38/40 | 33/40 | 448.33 ± 63.82 | 382.65 ± 56.51 | 15.58 ± 5.48 | 13.33 ± 4.52 | 1.43 ± 1.03 | 1.83 ± 1.08 | 21.48 ± 5.68 | 17.08 ± 5.02 |
| Wen 2018[34] | 28/30 | 26/30 | 386.45 ± 45.52 | 423.83 ± 54.92 | 23.27 ± 4.27 | 25.18 ± 3.59 | 2.40 ± 0.50 | 3.63 ± 0.49 | 24.25 ± 6.95 | 31.28 ± 6.17 |
| Hu 2019[35] | 26/30 | 18/30 | 369.02 ± 75.05 | 415.80 ± 86.22 | 11.41 ± 3.68 | 15.58 ± 6.80 | 1.27 ± 1.12 | 1.93 ± 1.11 | 3.56 ± 1.37 | 5.47 ± 3.21 |
| Ma 2019[36] | 46/47 | 40/47 | - | - | 3.62 ± 1.65 | 4.71 ± 1.78 | - | |||
| Liang 2019[37] | 58/61 | 48/60 | 306.21 ± 51.95 | 391.75 ± 67.29 | - | - | 1.15 ± 0.17 | 2.09 ± 0.35 | ||
| Dai 2019[38] | - | 378.5 ± 111.9 | 365.0 ± 120.4 | - | 1.8 ± 1.4 | 1.1 ± 1.1 | 6.9 ± 35.5 | 9.86 ± 27.7 | ||
| Ju 2019[39] | 58/60 | 57/60 | - | - | - | - | ||||
| Liu 2019[40] | 43/45 | 41/45 | 406.26 ± 32.45 | 424.91 ± 29.74 | 15.57 ± 5.05 | 28.75 ± 7.84 | 3.01 ± 1.02 | 4.81 ± 1.28 | 14.77 ± 5.63 | 21.26 ± 5.74 |
| Dong 2019[41] | - | 496.19 ± 46.21 | 500.83 ± 22.79 | 12.27 ± 2.98 | 17.19 ± 1.69 | 2.49 ± 0.59 | 4.95 ± 0.83 | 6.28 ± 1.72 | 8.39 ± 1.34 | |
| Zheng 2020[42] | - | 493.87 ± 37.32 | 497.87 ± 19.84 | 12.77 ± 4.24 | 15.02 ± 10.63 | 0.80 ± 0.46 | 1.37 ± 0.85 | 9.4 ± 3.84 | 9.55 ± 4.62 | |
| Fang 2020[43] | 33/36 | 26/36 | 375.91 ± 26.37 | 419.32 ± 27.03 | - | 2.38 ± 0.34 | 5.76 ± 0.69 | - | ||
| He 2020[44] | 35/36 | 35/36 | 357 ± 34 | 365 ± 30 | 11.27 ± 3.64 | 10.54 ± 4.02 | - | 5.84 ± 2.57 | 6.15 ± 2.96 | |
| Cai 2020[45] | 28/30 | 22/30 | 285.3 ± 79.9 | 397.4 ± 101.0 | 20.0 ± 5.9 | 26.7 ± 8.7 | 2.6 ± 1.1 | 5.3 ± 1.4 | 8.1 ± 2.3 | 10.7 ± 4.1 |
| Qiao 2020[45] | 32/35 | 28/35 | - | - | 2.3 ± 1.4 | 4.1 ± 0.7 | - | |||
| Zhang 2020[46] | 28/30 | 21/30 | 411.74 ± 53.13 | 452.64 ± 47.62 | 13.26 ± 8.96 | 17.63 ± 7.71 | 3.13 ± 1.26 | 3.72 ± 0.73 | 6.63 ± 1.45 | 9.91 ± 2.44 |
| Xie 2020[47] | 33/35 | 30/35 | 442.58 ± 23.18 | 437.07 ± 45.57 | 10.53 ± 2.74 | 16.24 ± 2.89 | 2.71 ± 0.87 | 5.07 ± 1.20 | 7.24 ± 1.38 | 10.93 ± 2.15 |
CRP = C-reactive protein, ESR = erythrocyte sedimentation rate, TER = total effective rate, UA = uric acid, VAS = visual analog scale.
Figure 3.
Effects of herbal medicine for external use on total effective rate.
3.4.2. Blood uric acid level.
The treatment effect on acute gouty arthritis was judged based on the change in the uric acid level, which is a factor in an acute attack. Further, 1268 patients, described in 18 clinical records, were divided into the intervention group comprising 652 patients and control group comprising 616 patients. For uric acid levels, SMD was used to analyze the groups, and a random effects model was chosen for meta-analysis due to heterogeneity among the trials (I2 = 88%). Results showed that the HMEU group was better at reducing blood uric acid levels than the control group (SMD = −0.58, 95% CI = −0.92 to −0.23, P = .0010) (Table 3, Fig. 4).
Figure 4.
Effects of herbal medicine for external use on uric acid levels.
3.4.3. Pain score.
In this study, we analyzed the effect of HMEU on pain changes in acute gouty arthritis. The data of 1216 patients collected from 17 clinical datasets were divided into those of 609 patients in the intervention group and of 607 patients in the control group. For VAS scores, SMD was used to analyze the groups, and a random effects model was chosen for meta-analysis due to heterogeneity among the trials (I2 = 94%). The results showed that the HMEU group reduced pain significantly more than the control group (SMD = −1.28, 95% CI = −1.80 to −0.76, P < .00001) (Table 3, Fig. 5).
Figure 5.
Effects of herbal medicine for external use on pain score.
3.4.4. Inflammatory markers (ESR, CRP).
Data presented for ESR as an outcome measure from 14 clinical records were collected, with 495 and 492 patients in the intervention and control groups, respectively, and a total of 959 patients. For CRP, results were collected from 15 clinical studies with 562 and 559 patients in the intervention and control groups, respectively, and a total of 1121 patients. A random effects model was chosen for meta-analysis for ESR and CRP due to heterogeneity among the trials (I2 > 50%). All studies on the results of the 2 inflammatory markers showed significant results (P < .05). As a result of meta-analysis of ESR (SMD = −0.91, 95% CI = −1.33 to −0.48, P < .0001) and CRP (SMD = −1.04, 95% CI = −1.58 to −0.50, P = .0002), HMEU group showed better anti-inflammatory effects than the control group (Table 3, Fig. 6).
Figure 6.
Effects of herbal medicine for external use on inflammatory factors (erythrocyte sedimentation rate and C-reactive protein).
3.5. Adverse effects
Adverse effects after treatment were mentioned in 10 studies, whereas 17 studies did not specify any adverse effects. Among the articles that mentioned adverse effects, 4 studies reported no adverse effects. Among the 6 studies, the intervention group had adverse effects in 6 cases (14.6%): 3 cases of gastrointestinal disorders and 3 cases of skin rash and allergic reactions. In the control group, 35 (85.4%) adverse effects were observed, all of which were gastrointestinal disorders caused by drug administration (Table 1).
4. Discussion
Herbal medicines in complementary and alternative medicine (CAM) were developed based on unique theories, such as KM and TCM, and have been used internally and externally for the treatment of various conditions over thousands of years.[48,49] In traditional medicine, external treatment is defined as a method of inducing a therapeutic effect through various stimulation methods, such as through the skin or the respiratory tract, without the use of medicine. It helps achieve therapeutic effects through chemical and physical actions at the lesion, as opposed to systemic treatmen.[50,51] Herbal medicine is applied to acupuncture points to regulate the meridian and correct the deviation of qi blood yin yang through the pharmacological action of herbal medicines and stimulation of acupuncture points for the prevention and treatment of diseases.[52] Its application is mainly focused on surgical diseases but includes various traditional medical diseases, such as those related to internal medicine, dermatology, ophthalmology, otolaryngology, gynecology, pediatrics, and neuropsychiatry.[53] HMEU in traditional medicine can help resolve the lesion and alleviate its symptoms by moisturizing, lubricating, cooling, and protecting the lesion.[54] In CAM, HMEU is considered cheaper and safer than that of conventional medicines, such as oral or topical medications.[55,56] While a variety of external skin preparations are being used because of the development of WM and new drugs and formulations, the diversification of formulations and product development of traditional external use preparations is insufficient.[57]
Acupuncture-related therapies, such as acupuncture, electroacupuncture, fire needling, warm needling, pharmacopuncture, bloodletting, cupping, and herbal medicine, have been reported to be more effective than Western medical treatments by several systematic studies on the treatment effects of acute gouty arthritis symptoms.[2,14–16] However, in the case of HMEU, there is only literature evidence in Korea,[2] and no clinical studies were found. In TCM, HMEU is often applied clinically to relieve pain and symptoms in patients with acute gout; however, a systematic review is lacking. In this study, we attempted to establish a link between herbal medicine and evidence-based medicine through a systematic review and meta-analysis on the effects and safety of HMEU for acute gout. In addition, this study attempts to contribute to the evidence on the development of HMEU, which is currently lacking.
The number of participants in the 27 selected studies varied from 40 to 121, and the total number of participants was 1951. It has been shown that relatively large-scale clinical studies are being conducted. The participant ages ranged from 18 to 85 years, with the average age ranging from 30 to 50 years. The proportion of men was much higher, except for 4 studies in which no specific sex was indicated. Between 2016 and 2020, more men received more gout treatment than women in Korea. All the selected studies were conducted in China; therefore, further studies in other countries are needed.
There were more cases of HMEU treatment in addition to WM rather than of treatment with HMEU alone. HMEU were chiefly in a powdered form, and various types of herbal medicines were used. The treatment period was relatively short, ranging from 5 to 14 days, which is similar to the that described in studies on KM treatments, such as electroacupuncture, fire needling, and warm needling, for acute gout.[15,16]
Five evaluation tools were used in this study: TER, uric acid level, VAS pain score, ESR, and CRP level. The review indicated that HMEU used alone or in combination with WM was more effective than WM in terms of TER in 24 studies, change in the uric acid level in 18 studies, and pain reduction in 17 studies. Regarding inflammation, the ESR in 14 studies and CRP levels in 15 studies showed greater improvement in the intervention group than in the control group. The therapeutic effects of HMEU on uric acid level, pain and symptoms, and inflammation of patients with acute gouty arthritis were similar to those observed in previous studies comparing KM and WM treatments.[14–16] TER was used in most studies, and 5 studies assessed only the TER. Because the validity and reliability of TER as an evaluation tool have not yet been verified,[16] there were limitations in interpreting the results. In future clinical studies, evaluation tools with more diverse validity and reliability than those of TER should be used, especially when investigating combination therapy.
Among the various types of HMEU, Jinhuang, Shuangbai, and Zhihuangzhitong powders were the most commonly used. Jinhuang Powder, a 9-herb complex, removes blood stasis and frees the collateral vessels, reduces swelling and pain, clears heat, and eliminates dampness; it has been frequently used for diseases, such as swelling and pain, trauma, carbuncle, furuncle, acute lymphadenitis, and mastitis, in TCM clinical practice.[58–60] Shuangbai San, including five major components, is effective for blood circulation, detoxification, and swelling and pain relief. It is widely used in the surgical and orthopedic fields; its benefits have also been reported to improve the pain and quality of life in patients with primary liver cancer.[61] Zhihuang Zhitong Powder, composed of 14 herbs, relieves swelling and pain, removes blood stasis, promotes blood circulation, detoxifies and cools the blood, and can effectively relieve local pain and swelling symptoms in patients with acute soft tissue injuries.[62,63] The 3 herbal medicines seemed to have pain and edema reduction, detoxification, and blood circulation-promoting effects in common, and all contained rhubarb root and phellodendron bark, which help remove pathogenic heat, reduce the toxicity of pathogens, and neutralize toxic properties of poisons. The characteristics of these herbal medicines appear related to the mechanisms underlying pain, swelling, and inflammation in acute gouty arthritis. Studies on the mechanisms underlying these effects and high-quality clinical trials focusing on frequently used herbal medicines are necessary.
Sophora flavescens (Sophorae Flavescentis Radix), which is mentioned as a HMEU for gout in KM college textbooks,[2] can eliminate dampness and clear heat effects. It has been shown to have low toxicity and side effects in clinical trials.[57,64] Quercetin is a flavonoid with antioxidant, antiviral, and antibacterial effects and is an anti-inflammatory compound that plays a role in initiating the p38 and NF-κB signaling pathways in lipopolysaccharide-induced Kupffer cells; luteolin is a substance that can reduce inflammation through the activation of Nrf2/ARE, NF-κB, and MAPK signaling pathways.[65] Therefore, it would be beneficial to include Sophora flavescens as a candidate drug for future clinical trials of HMEU.
There were no side effects in 4 cases, and most side effects were gastrointestinal disorders due to drug intake. There were only 3 cases of skin rash and allergic reactions that were attributed to HMEU. Of the 27 articles, side effects were mentioned in only 10 articles; therefore, the safety of the herbal medicines could not be confirmed. However, no serious side effect of HMEU was reported, and it may therefore be a relatively safe treatment.
The results indicate that HMEU is effective in improving uric acid levels, pain, and inflammation in patients with acute gouty arthritis and are relatively free of side effects. This is consistent with reviews showing that existing CAM treatment is effective and relatively safe for reducing uric acid levels, pain, and symptoms in patients with acute gout.[14] The present study can be used as a reference when determining the type of herbal medicine, its application as a monotherapy or in combination with WM, and the duration of treatment in future clinical studies on HMEU. In addition, our data can be used to establish optimal clinical treatment strategies for clinicians, patients, researchers, and health policy makers and can serve as a basis for establishing a combination KM (TCM) and WM treatment model for gout. Nevertheless, this study has limitations, such as the risk of regional bias and linguistic bias, heterogeneity due to various treatment and control drugs, a lack of placebo no use of placebo control, unspecified dosage of herbal medicine, and inconsistent treatment periods. In future, high-quality clinical trials using more rigorous methodologies should further prove the potential benefits of HMEU in acute gouty arthritis.
5. Conclusions
In conclusion, this review shows that HMEU used alone or in combination with Western drugs reduced uric acid levels, pain intensity, and inflammation; had greater efficacy than that of Western drug treatment; and did not pose a serious risk. These results suggest that HMEU can be a safe and effective alternative for the treatment of pain and symptoms of acute gouty arthritis. However, owing to the heterogeneity of interventions, outcomes and regional bias, further high-quality trials from different regions using more rigorous methodologies on this topic are needed to confirm the level of evidence.
Author contributions
Conceptualization: Jihye Hwang, Ho-Sueb Song.
Formal analysis: Su Hyeon Choi.
Investigation: Jihye Hwang, Su Hyeon Choi.
Writing – original draft: Jihye Hwang, Su Hyeon Choi.
Writing – review & editing: Ji Hye Hwang, Ho-Sueb Song.
Abbreviations:
- CAM
- complementary and alternative medicine
- CI
- confidence interval
- CRP
- C-reactive protein
- ESR
- erythrocyte sedimentation rate
- HMEU
- herbal medicines for external use
- KM
- Korean medicine
- RCT
- randomized controlled trial
- SMD
- standardized mean differences
- TCM
- traditional Chinese medicine
- TER
- total effective rate
- VAS
- visual analog scale
- WM
- western medicine.
This work was supported by a National Research Foundation of Korea (NRF) grant funded by the Korean government (MSIT) (No. NRF-2022R1A2C1013518). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
As this meta-analysis included published literature, no patient content or ethical approval was required.
The authors have no conflicts of interest to disclose.
The datasets generated during and/or analyzed during the current study are available from the corresponding author on reasonable request.
How to cite this article: Choi SH, Song H-S, Hwang J. Herbal medicine for external use in acute gouty arthritis: A PRISMA-compliant systematic review and meta-analysis. Medicine 2023;102:37(e34936).
Contributor Information
Su Hyeon Choi, Email: youngeun0922@naver.com.
Ho-Sueb Song, Email: fruit0015@naver.com.
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