Abstract
Introduction
Various acupuncture techniques are widely applied in clinics for pain control and dysfunction relief in patients with knee osteoarthritis (KOA). The purpose of this trial was to investigate whether the different acupuncture techniques were more effective in treating joint pain and dysfunction than were sham acupuncture or drug treatment in patients with KOA and to determine the differences in efficacy among them.
Methods
In this multi-center, single-blind, randomized, controlled trial, participants were randomly assigned to the manual acupuncture (MA), electroacupuncture (EA), warm-needling acupuncture (WA), mild moxibustion (MM), sham acupuncture (SA), or drug treatment (Celebrex) groups. Each participant in the above groups received individual treatments for 4 consecutive weeks. The primary outcome measures included the visual analog scale score (VAS) and the physical function score of the Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC).
Results
Compared with the SA group, the acupuncture technique groups (MA, EA, WA, and MM) had markedly lower patient VAS scores (− 0.61; 95% CI − 1.09 to − 0.13; P = 0.01) and lower WOMAC physical function scores (− 13.84; 95% CI − 21.14 to − 6.54; P < 0.01). Compared with Celebrex, EA had a significant advantage in reducing the VAS score (1.14; 95% CI 0.55 to 1.72; P < 0.01) and WOMAC physical function score (14.81; 95% CI 5.69 to 23.93; P < 0.01).
Conclusions
The observed acupuncture techniques effectively relieve pain and ameliorate knee joint dysfunction in patients with KOA. EA is the most effective method of alleviating pain intensity in treating KOA.
Trial registration
The trial was registered on ClinicalTrials.gov (NCT03563690).
Supplementary Information
The online version contains supplementary material available at 10.1007/s40122-025-00713-x.
Keywords: Acupuncture techniques, Electroacupuncture, Knee osteoarthritis, Pain control, Physical dysfunction, Randomized controlled trial
Plain Language Summary
Chronic pain and joint functional disability are the main symptoms that occur in patients with knee osteoarthritis and decrease their quality of life. As a non-pharmacological treatment, acupuncture, a traditional complementary therapy originating in China, is an effective therapy for pain control and addressing knee-related disorders in the clinic. However, the efficiency of various acupuncture techniques in treating diseases is different. The purpose of this trial was to investigate whether acupuncture techniques were more effective at controlling pain and physical dysfunction than sham acupuncture or drug treatment and to determine the differences in efficacy among them. The participants experienced different acupuncture technique treatments, including manual acupuncture, electroacupuncture, warm-needling acupuncture, and mild moxibustion. The control treatments included sham acupuncture and drug treatment with Celebrex. We measured changes in pain perception via visual analog scale scores and physical dysfunction via physical function scores from the Western Ontario and McMaster Universities Osteoarthritis Index. Compared with sham acupuncture, the observed acupuncture techniques were effective for treating joint pain and dysfunction in patients with knee osteoarthritis. We compared the efficiency of different acupuncture techniques and reported that electroacupuncture was the most effective at alleviating pain intensity. Moreover, we compared the efficiency of electroacupuncture with that of Celebrex administration. The results revealed that electroacupuncture had an advantage over drug treatment. This finding could provide sufficient evidence that demonstrates the disparity in the efficacy of acupuncture techniques and could lead to proper acupuncture therapy for treating knee osteoarthritis.
Supplementary Information
The online version contains supplementary material available at 10.1007/s40122-025-00713-x.
Key Summary Points
| Why carry out this study? |
| Knee osteoarthritis (KOA) is one of the most common types of osteoarthritis and is characterized by chronic pain and joint functional disability of the knee. Approximately 10% of people over 60 years of age worldwide have KOA-related syndromes, and approximately 30% of individuals over 45 years of age have radiographic evidence of KOA, which increases healthcare costs and decreases quality of life. As a non-pharmacological treatment, acupuncture is an effective therapy to address knee-related disorders associated with KOA. |
| Previous studies have verified the efficacy of true and sham acupuncture for KOA treatment. In the clinic, various acupuncture techniques have been widely applied, one of which is the most proper acupuncture technique in treating KOA, and its superiority over drug treatment is worth exploring. |
| Manual acupuncture (MA) is a basic technique applied in the clinic with its needling and manipulation by acupuncturists. Electroacupuncture (EA) and warm-needling acupuncture (WA) belongs to combination therapy, which are combined manual acupuncture and electric stimulation or moxa-burning thermal stimulation, respectively. Mild moxibustion (MM) is a treatment in which the burnt moxa away from the local skin without needling. Hence, the main purpose of this randomized, controlled clinical trial was to investigate whether acupuncture techniques are effective in treating joint pain and dysfunction in patients with KOA and to identify the best acupuncture technique of above four. |
| What was learned from the study? |
| The study revealed that all of our observed acupuncture techniques, including manual acupuncture, electroacupuncture, warm-needling acupuncture and mild moxibustion, were effective for treating joint pain and dysfunction in patients with knee osteoarthritis compared with sham acupuncture. We then compared the efficiency of acupuncture techniques and reported that EA was the most effective at alleviating pain intensity of KOA. Moreover, we compared the efficiency of EA with that of Celebrex administration. The results also revealed that EA had an absolute advantage in improving the VAS score and WOMAC physical function score over drug treatment. |
| A comparison of the different efficiencies of different acupuncture techniques may provide a basis for choosing proper acupuncture therapy in treating KOA. These findings suggest that different acupuncture techniques have different effects and that EA is the best technique for treating KOA. |
Introduction
Knee osteoarthritis (KOA) is one of the most common types of osteoarthritis and is characterized by cartilage deterioration, with a proliferative reaction of the subchondral bone and inflammation of the synovial membrane, resulting in chronic pain, joint stiffness, and functional disability [14, 31]. Approximately 10% of people over 60 years of age worldwide have KOA-related syndromes, and approximately 30% of individuals over 45 years of age have radiographic evidence of KOA, which increases healthcare costs and decreases quality of life [17, 41, 48].
According to the American College of Rheumatology and Osteoarthritis Research Society International (OARSI) guidelines, current recommendations for managing KOA at early stages focus on relieving pain and maintaining or improving physical function as important goals of therapy [3, 18]. KOA is a progressive disease that requires long-term management with various treatments. Pharmacological therapies, including non-steroidal anti-inflammatory drugs (NSAIDs), are usually first taken to relieve pain and impaired motor function [36]. Although these drug treatments can be effective, they have several side effects, including gastrointestinal discomfort, hepatotoxicity, renal failure, which results in the inability to use drugs for a long period [4, 30, 35]. Therefore, non-pharmacological treatment is preferable for treating KOA [16].
As a non-pharmacological treatment, acupuncture, a traditional complementary therapy originating in China, is an effective therapy to address knee-related disorders of KOA in the clinic. Previous studies have shown that acupuncture treatment of KOA is effective in promoting cartilage repair to relieve pain, improve physical function, and reduce the rate of surgery for KOA patients [11, 19, 26, 53]. Manual acupuncture (MA) is a basic technique used to treat painful problems and arthritis, and is based on needling and manipulation by acupuncturists [56]. Electroacupuncture (EA) is a combination of acupuncture and electric stimulation. The evidence from meta-analysis and randomized controlled trial have shown that EA therapy is beneficial for KOA by improving the clinical symptoms and quality of life [7, 19, 28]. Warm-needling acupuncture (WA) is a combination of acupuncture and a warm effect with a burnt moxa cone fixed at the top of the needle. Mild moxibustion (MM) is a treatment in which the burnt moxa protrude from the local skin, which is warm enough to promote blood circulation. Although the above acupuncture techniques are utilized in clinical settings, and some studies have verified the efficacy of true and sham acupuncture [44], sufficient evidence demonstrating the disparity in the efficacy of these techniques in treating KOA and their superiority over sham acupuncture and drug treatment is still needed.
Hence, the main purpose of this trial was to investigate whether acupuncture techniques are more effective at treating chronic pain and joint dysfunction than are sham acupuncture and drug treatments in patients with KOA. A comparison of the efficiencies of different acupuncture techniques may provide a basis for proper acupuncture therapy in treating KOA.
Methods
Study Design
This was a multi-center, single-blinded, randomized, controlled trial to verify the effect of acupuncture techniques which had been supported by prior literature as effective in treating KOA patients [7, 26, 28] with sham acupuncture for pain control and dysfunction relief. Then, the efficiencies of different acupuncture techniques (MA, EA, WA, and MM) were observed and compared. Furthermore, the best one of observed acupuncture techniques would be compared with the drug treatment to determine the efficiency.
The trial protocol [52] adhered to the Consolidated Standards of Reporting Trials (CONSORT) and Standards for Reporting Interventions in Clinical Trials of Acupuncture (STRICTA) guidelines for reporting randomized trials [29, 32]. The trial protocol was approved by the ethics committees of the six hospitals and registered on Clinical Trials.gov (NCT03563690) on June 20, 2018.
Ethical Approval
The trial was approved by the Ethics Committees of the six hospitals. They are the Third Affiliated Hospital of Zhejiang Chinese Medical University (NO. ZSLL-KY-2017-030), Jiaxing TCM Hospital (NO. 2018-JZLS-001), Hangzhou Red Cross Hospital (NO. 2018 LS05), Tongde Hospital of Zhejiang Province (NO. 2018,019), Zhejiang Hospital (NO. 2018KA006) and Zhejiang Provincial Hospital of TCM (NO. 2018-KL-010-01). This study was performed in accordance with the Helsinki Declaration of 1964 and its later amendments. Participants provided their consent by signing a written informed consent form.
Participants
A total of 360 participants were recruited from six hospitals in China. They are the Third Affiliated Hospital of Zhejiang Chinese Medical University, Jiaxing Traditional Chinese Medicine Hospital, Hangzhou Red Cross Hospital, Tongde Hospital of Zhejiang Province, Zhejiang Hospital and Zhejiang Provincial Hospital of Traditional Chinese Medicine. People aged between 40 and 75 years who met the diagnostic criteria, inclusion criteria and exclusion criteria were deemed eligible for inclusion as described in the trial protocol [52]. All the participants signed informed consent before participation, and the rights of the participants were protected.
Randomization and Masking
Randomization was performed by an independent investigator at each hospital who responsible for generating random number by the Evaluated and Analysis Centre of Zhejiang Provincial Hospital of TCM. The allocation sequence was concealed until the end of the study. The participants were randomized at a 1:1:1:1:1:1 ratio to receive the manual acupuncture, electroacupuncture, warm-needing acupuncture, mild moxibustion, sham acupuncture and Celebrex treatment.
The enrolled participants were informed that they would receive treatment via one of six interventions with or without acupuncture. Each participant was treated separately to prevent any exchange of treatment information. The assessors, acupuncturists and statisticians were operated independently. The participants, assessors and statisticians were blinded to the group allocation throughout the study, since it was not feasible to blind the acupuncturists.
Interventions
In this trial, the groups of manual acupuncture, electroacupuncture, warm-needing acupuncture and mild moxibustion were considered the acupuncture techniques (ACU). The acupuncturists underwent training on the treatment techniques to ensure standardization of the intervention protocol. The acupuncture treatments were administered for 30 min every time and treated every other day for three sessions per week for 4 consecutive weeks.
Manual Acupuncture (MA) Group
Acupuncturists performed manual acupuncture at the Neixiyan (EX-LE4), Dubi (ST35), Liangqiu (ST34), Xuehai (SP10), Yanglingquan, (GB34) and Yinlingquan (SP9) acupoints. The locations of the acupoints and the operational details above are presented in Table S1 and Figure S1 (Supplementary material). The needles (length 50 mm, diameter 0.3 mm; Hwato brand, Suzhou Medical Appliance Factory, China) were inserted into the acupoints at a depth of 25–30 mm with lifting, thrusting, and twisting to elicit Deqi (a sensation of aching, soreness, swelling, heaviness, or numbness) [57].
Electroacupuncture (EA) Group
After the Deqi sensation was felt, the electrodes of the electroacupuncture apparatus (SDZ-IIBb, Hwato, Suzhou Medical Supplies Factory Co., Ltd., China) were applied in EX-LE4 and ST35. The stimulus parameters were dense-disperse waves with a frequency of 2/100 Hz at a strength that was tolerable to the patients.
Warm-Needing Acupuncture (WA) Group
After the Deqi sensation was felt, two segments (approximately 2 cm) of moxa cones (Z32020253; Yufu Brand, Jiangsu Kangmei Pharmaceutical Co., Ltd., China) were placed on the top of the needle and burnt at the lower end at EX-LE4 and ST35.
Mild Moxibustion (MM) Group
The EX-LE4 and ST35 acupoints were subjected to mild moxibustion stimulation with a burnt moxa stick at a distance of 2–3 cm away from the local skin.
Sham Acupuncture (SA) Group
The participants underwent non-meridian and nonacupoint needling [6, 22]. The location details of sham acupoints are described in Table S2 and Figure S2 (Supplementary material B). The operation was performed with a disposable needle (length 25 mm, diameter 0.18 mm) and placed superficially at a depth of 1–2 mm without any manipulation.
Celebrex Drug Treatment (Celebrex) Group
The participants received Celebrex capsules (Pfizer Pharmaceuticals Ltd.) once a day (0.2 g once orally), for a total of 4 consecutive weeks.
Outcome Measurements
The participants completed assessments before treatment (baseline), during the treatment period (week 2 and week 4) and during follow-up (month 3 and month 6). The primary outcomes were the changes in the visual analog scale (VAS) score and the physical function score of the Western Ontario and McMaster Universities (WOMAC) from baseline to week 4. The VAS score ranges from 0 (no pain) to 10 (severe pain) and was measured with the average pain intensity for the last 3 days. The WOMAC index consists of three domains, namely pain, stiffness, and physical function. The WOMAC physical function score consists of 17 items regarding the degree of difficulty experienced due to the studied knee. Each item ranges from 0 (no symptoms) to 10 (severe symptoms), with higher scores indicating worse physical function.
The secondary outcomes included changes in the VAS score and WOMAC physical function score at all time points except week 4. Changes in the WOMAC pain score, WOMAC stiffness score, Physical Activity Scale for the Elderly (PASE) score, WHO-BREF 36-Item Form score across all time points. The specific measurement methods or grading criteria for secondary outcomes in detail were described in the study protocol of Supplementary material A.
Severe adverse events (AEs) and side effects associated with acupuncture techniques and drugs were documented. The researchers from the six hospitals recorded details related to the treatment and provided proper medical advice and care to prevent participant safety.
Sample Size Determination and Statistical Analysis
The sample size was calculated on the basis of previous trials and clinical experience [12, 25, 45]. Previous studies revealed that the change in the WOMAC physical function score was 8.8, with a standard deviation (SD) of 3.7 (8.8 (3.7)) in the MA group, 8.9 (4.0) in the EA group, 12.0 (6.1) in the WA group, 10.0 (4.7) in the MM group, 5.8 (3.0) in the SA group and 13.0 (5.6) in the Celebrex group. Owing to the guidance on multiple endpoints in clinical trials, no multiplicity adjustment is necessary for the co-primary endpoint [10]. We assumed that the sample size calculation revealed at least 42 patients in each group. Considering a 20% dropout rate and the equal distribution of all cases in the six hospitals, the sample size was increased to 60 participants in each group, with a total of 360 cases [52].
Statistical analysis was performed by a single statistician. Analyses of the outcomes were based on the intention-to-treat (ITT) population, which included participants who had been randomized and received at least one session of treatment (n = 339). Missing data imputation was performed via the last observation carried forward method. The baseline characteristics are presented as n (%) for categorical variables, and comparisons of categorical data among groups were performed via the chi-square test or Fisher’s exact test. The continuous variables are expressed as the means (SDs). The 95% confidence intervals (CIs) of the rate differences were estimated. The outcomes were assessed by independent sample t tests between two groups and analysis of variance (ANOVA) among three or more than three groups with Bonferroni’s multiple comparisons test. A safety analysis was performed by analyzing the frequency, which was presented as the n (%) of AEs related to the acupuncture-related and drug-related interventions. All tests applied were two-tailed, and P < 0.05 was considered statistically significant.
Results
Participants and Baseline Characteristics
A total of 678 patients were screened between July 3, 2018, and October 31, 2022, among six hospitals, of whom 357 were randomly assigned to the MA (n = 60), EA (n = 59), WA (n = 59), MM (n = 60), SA (n = 59), Celebrex (n = 60) groups. Among them, 332 (93.0%) patients completed the study, 339 (95.0%) patients were included in the ITT data analysis (Fig. 1). No differences were found among the groups in terms of the expulsion rates (P > 0.05, Supplementary material B: Table S3). No significant difference among the groups in any demographic feature, which confirmed that the groups were well matched (Table 1).
Fig. 1.
The trial flowchart
Table 1.
Baseline characteristics of participants
| Variable | MA group (n = 59) | EA group (n = 57) | WA group (n = 57) | MM group (n = 59) | SA group (n = 53) | Celebrex group (n = 54) |
|---|---|---|---|---|---|---|
| Age, mean (SD), years | 59.10 (9.81) | 60.74 (9.74) | 59.93 (10.15) | 58.49 (9.19) | 59.98 (8.88) | 59.11 (10.00) |
| Sex, n (%) | ||||||
| Female | 43 (72.88) | 49 (85.96) | 40 (70.18) | 41 (69.49) | 42 (79.25) | 42 (77.78) |
| Male | 16 (27.12) | 8 (14.04) | 17 (29.82) | 18 (30.51) | 11 (20.75) | 12 (22.22) |
| Ethnicity, n (%) | ||||||
| Han | 58 (98.31) | 57 (100.0) | 56 (98.24) | 59 (100.0) | 51 (96.23) | 54 (100.0) |
| Minorities | 1 (1.69) | 0 (0) | 1 (1.76) | 0 (0) | 2 (3.77) | 0 (0) |
| Comorbidities | ||||||
| ≦1 disease, n (%) | 51 (86.44) | 51 (89.47) | 50 (87.72) | 52 (88.14) | 43 (81.13) | 47 (87.04) |
| ≧2 disease, n (%) | 8 (13.56) | 6 (10.53) | 7 (12.28) | 7 (11.86) | 10 (18.87) | 7 (12.96) |
| Height, mean (SD), m | 1.62 (0.06) | 1.60 (0.05) | 1.63 (0.06) | 1.63 (0.07) | 1.61 (0.06) | 1.62 (0.06) |
| Weight, mean (SD), kg | 62.8 (8.38) | 60.55 (8.33) | 62.9 (8.31) | 62.21 (8.33) | 63.17 (7.81) | 61.79 (9.88) |
| BMI | 23.91 (2.67) | 23.62 (3.07) | 23.72 (2.69) | 23.49 (2.84) | 24.29 (2.50) | 23.54 (2.72) |
| Previous treatment, n (%) | ||||||
| Medication | 6 (10.17) | 9 (15.79) | 8 (14.04) | 10 (16.95) | 5 (9.43) | 4 (7.41) |
| Knee local injection | 0 (0) | 1 (1.75) | 0 (0) | 0 (0) | 0 (0) | 0 (0) |
| External plaster | 20 (33.90) | 16 (28.07) | 23 (40.35) | 22 (37.29) | 14 (26.42) | 15 (27.78) |
MA manual acupuncture, EA electroacupuncture, WA warm-needling acupuncture, MM mild moxibustion, SA sham acupuncture, SD standard deviation, BMI body mass index
Primary Outcomes
In Table 2, compared with the SA group, the acupuncture technique groups (MA, EA, WA, and MM) had markedly lower patient VAS scores (between-group difference − 0.61; 95% CI − 1.09 to − 0.13; P = 0.01) and lower WOMAC physical function scores (− 13.84; 95% CI − 21.14 to − 6.54; P < 0.01). Then compared with that of the MA, EA and WA groups, the VAS score in the EA group was significantly lower than that in the MA group (− 0.87; 95% CI − 1.47 to − 0.27; P < 0.01). However, the above scores did not differ between MM and WA groups. The results revealed that EA was the most effective one of our observed acupuncture techniques. Moreover, we compared the efficiency of EA with that of Celebrex administration. The result showed that EA had a significant advantage in reducing the VAS score (1.14; 95% CI 0.55 to 1.72; P < 0.01) and WOMAC physical function score (14.81; 95% CI 5.69 to 23.93; P < 0.01).
Table 2.
Primary outcomes of ITT analysis
| Outcome | Groups | Pairwise comparison | |||||||
|---|---|---|---|---|---|---|---|---|---|
| 1. Comparison between acupuncture techniques and sham acupuncture | |||||||||
| Variabled | ACUa (n = 232) | SA (n = 53) | ACU vs. SA | ||||||
| Effect size (95% CI) | P value | ||||||||
| the change of VAS score at week 4, mean (SD)b | − 2.82 (1.65) | − 2.21 (1.36) | − 0.61 (− 1.09 to − 0.13) | 0.01 | |||||
| the change of WOMAC physical function score at week 4, mean (SD)c | − 26.54 (25.58) | − 12.70 (17.81) | − 13.84 (− 21.14 to − 6.54) | < 0.01 | |||||
| 2.1 Comparison among MA, EA, WA techniques based on needing | |||||||||
| Variabled | MA (n = 59) | EA (n = 57) | WA (n = 57) | EA vs. MA | WA vs. MA | EA vs. WA | |||
| Effect size (95% CI) | P value | Effect size (95% CI) | P value | Effect size (95% CI) | P value | ||||
| the change of VAS score at week 4, mean (SD)b | − 2.41 (1.43) | − 3.28 (1.81) | − 2.96 (1.61) | − 0.87 (− 1.47 to − 0.27) | < 0.01 | − 0.55 (− 1.11 to 0.01) | 0.05 | 0.32 (− 0.32 to 0.95) | 0.33 |
| the change of WOMAC physical function score at week 4, mean (SD)c | − 20.44 (27.49) | − 31.75 (28.06) | − 27.02 (22.98) | − 11.31 (− 21.53 to − 1.09) | 0.03 | − 6.58 (− 15.91 to 2.76) | 0.17 | 4.73 (− 4.78 to 14.26) | 0.33 |
| 2.2 Comparison between WA, MM techniques based on moxibustion | |||||||||
| Variabled | WA (n = 57) | MM (n = 59) | WA vs. MM | ||||||
| Effect size (95% CI) | P value | ||||||||
| the change of VAS score at week 4, mean (SD)b | − 2.96 (1.61) | − 2.63 (1.64) | − 0.33 (− 0.94 to 0.26) | 0.27 | |||||
| the change of WOMAC physical function score at week 4, mean (SD)c | − 27.02 (22.98) | − 27.15 (22.71) | 0.13 (− 8.26 to 8.54) | 0.97 | |||||
| 3. Comparison between EA and drug treatment | |||||||||
| Variabled | EA (n = 57) | Celebrex (n = 54) | EA vs. Celebrex | ||||||
| Effect size (95% CI) | P value | ||||||||
| the change of VAS score at week 4, mean (SD)b | − 3.28 (1.81) | − 2.14 (1.22) | 1.14 (0.55 to 1.72) | < 0.01 | |||||
| the change of WOMAC physical function score at week 4, mean (SD)c | − 31.75 (28.06) | − 16.94 (19.42) | 14.81 (5.69 to 23.93) | < 0.01 | |||||
ITT intention-to-treat, ACU acupuncture, WOMAC Western Ontario and McMaster Universities osteoarthritis index
aACU indicating the acupuncture techniques of MA, EA, WA, and MM
bData was the change of VAS score from baseline to week 4. Rating scales 0 to 10 from 0 (no pain) to 10 (severe pain). Lower value indicates better status
cData was the change of WOMAC physical function score from baseline to week 4. Lower value indicates better status
dAll tests were two-sided. P value of less than 0.05 was considered significant. Bold P value indicates statistical difference
For the primary outcome, the mean (SD) VAS score and WOMAC score at baseline and week 4 for the six groups are presented in Table S4 (Supplementary material B). And the results of the per-protocol (PP) analyses are included in the supporting information (Supplementary material B: Table S5).
Secondary Outcomes
For the secondary outcomes, the analysis revealed similar results for the VAS score; WOMAC physical function score, which was observed at weeks 2, 3, and 6; and the WOMAC pain score and stiffness score, which were observed at weeks 2, 4, 3, and 6, compared with those of the SA and Celebrex groups (P < 0.05 for all comparisons). No significant differences were found in the remaining secondary outcomes (Supplementary material B: Table S6).
Safety
The AEs and side effort rates are presented in Table 3. During the 4-week treatment period, no serious AEs occurred during the trial. Among the 232 participants who received acupuncture technique treatment, 14 AEs were recorded (two fainting, sweating or dizziness, 12 bleeding, local hematoma). In 53 participants who received sham acupuncture, three side effects were recorded (three bleeding, local hematoma). In the 54 participants who received Celebrex treatment, five side efforts were recorded (three with gastrointestinal discomfort, two with dizziness or sleepiness). The total incidence of acupuncture-related AEs was 5.96% (17/285), and that of drug-related AEs was 9.26% (5/54).
Table 3.
Adverse events evaluation during the treatment period (0–4 weeks)
| Adverse events | ACU (N = 232) | SA (N = 53) | Celebrex (N = 54) | Total, n (%) |
|---|---|---|---|---|
| Acupuncture-related AEs, n (%) | ||||
| Fainting, sweating or dizziness | 2 (0.86) | 0 (0) | – | |
| Bleeding, local hemorrhage | 12(5.17) | 3 (5.66) | – | |
| Total incidence of acupuncture-related AEs, n (%) | 17 (5.96) | |||
| Drug-related AEs, n (%) | ||||
| Gastrointestinal discomfort | – | – | 3 (5.56) | |
| Headache, dizziness or somnolence | – | – | 2 (3.70) | |
| Total incidence of drug-related AEs, n (%) | 5 (9.26) | |||
AEs adverse events
Discussion
In this study, we found that, all of our observed acupuncture techniques were effective for treating joint pain and dysfunction in patients with KOA. In particular, EA was the most effective acupuncture technique observed in this trial and was more effective than NSAIDs for pain control and dysfunction relief in patients with KOA. The results of this trial may fill the current research gap in treating KOA by different acupuncture techniques and provide a basis for choosing proper acupuncture therapy for treating KOA.
In aging populations, the expectation for pain alleviation and enhanced joint functionality in KOA patients is increasing. NSAIDs drug, exercise, and weight loss are strongly recommended for patients with clinical KOA [33, 43]. However, it is difficult for KOA patients to continue for a long period because of the side effects [8] and have no perseverance. As a non-pharmacological treatment, acupuncture has been employed in China for more than 3000 years, and its efficacy in treating KOA has been widely recognized [5, 34]. Nevertheless, there has always been an international aspiration for randomized controlled trial (RCT) studies to furnish evidence-based medical evidence.
Acupuncture encompasses various techniques, such as electroacupuncture, warm-needling acupuncture, manual acupuncture, auricular acupuncture and small needle knives [44, 46, 55]. The dose-dependent effects of different acupuncture techniques can lead to different outcomes in treating KOA [15]. Many studies on acupuncture efficiency for treating KOA have explored the influence of point selection, the retention time of needles, the treatment timing, and the frequency of acupuncture sessions on the therapeutic effect [1, 2, 24, 28, 44]. However, comparisons of the efficacy of different acupuncture techniques, which could impact the acupuncturist’s choice and therapeutic results, have not been explored in previous studies. On the other hand, a clinical trial showed that acupuncture did not confer a benefit over sham treatment for KOA patients, thus denying the role of acupuncture in treating KOA [12]. Another study demonstrated that manual acupuncture and electroacupuncture were better than sham acupuncture in treating KOA [7, 44]. Thus, these different findings do not agree on whether acupuncture should be recommended as an effective non-pharmacological treatment for KOA [3, 9, 18]. Hence, we designed this multi-center, randomized, controlled trial with the aim of determining the efficacy of acupuncture and comparing the efficiency of different acupuncture techniques in treating KOA.
In this study, on the basis of the MA manipulation to elicit Deqi, the other techniques combined another stimulation on the Neixiyan (EX-LE4) and Dubi (ST35) acupoints. EA was given with electrical stimulation and WA treatment involves warm stimulation with burnt mox cones with needing. MM was a warm stimulation with burnt moxa away from the skin without needing. The findings demonstrated that acupuncture techniques presented remarkable disparities in pain control and joint functional enhancement of the KOA patients. Among them, EA was the most effective one observed in this trial for treating KOA, especially in the efficiency of pain control. A growing body of evidence suggests that EA can exert anti-inflammatory and analgesic effects to improve local micro-circulation and bone destruction in the knee [20, 37, 38]. At the same time, EA can enhance the synthesis of endogenous analgesic neurotransmitters, strengthen the function of the endogenous pain inhibitory system and regulate the related signal pathways, gene expression, central and peripheral analgesic systems, and bio-mechanical properties [23, 28, 42, 49, 51].
The predominant analgesic effect of EA technique observed in patients with KOA in this study may be attributed to the chronic pain of KOA. Unlike acute pain, chronic pain is characterized not only by pain sensory abnormalities but also by emotional disturbances and cognitive dysfunction. Research has demonstrated that EA can relieve neuropathic pain and associated anxiety-like behaviors [50, 58], as well as alleviate pain by inhibiting the retrieval of pain memory via a neural signal pathway [39, 40]. Therefore, these underlying mechanisms may contribute to the significant analgesic efficacy of EA in KOA patients.
According to our analysis, the analgesic efficacy of EA is influenced by multiple parameters including waveform, frequency, intensity, treatment duration, frequency (interval time) and course of treatment of pulsed electricity. Different waveforms, such as dilatational wave, continuous wave and intermittent wave, exert varying effects on different types of pain [27]. Previous studies have indicated that dilatational wave can improve the clinical symptoms of inflammatory pain [13, 54], which is why we opted for this waveform of EA technique in treating KOA. However, there is a lack of controlled studies examining other factors like intensity and treatment duration. Further research is necessary to elucidate the impact of these different EA parameters on treating KOA.
Limitations
The limitations of this study include the following. First, acupuncture techniques are widely used in China. Most of the recruited participants were of Han ethnicity, and many of them were aware of acupuncture. Therefore, the blinding effect was not satisfactory because the participants might be aware of their treatment allocation. Second, the KOA patients could observe the operation of the acupuncturist. Hence, the acupuncturist could only be truly inserted into the skin during the implementation of the SA group. This might result in a situation in which even sham acupuncture would produce an effect [47]. This might be the reason why the outcomes of the SA in this study also demonstrated a downward trend. Third, bias is unavoidable due to differences in the results obtained from multiple hospitals. Fourth, the sample size is still not large enough for each group. Nonetheless, the efficacy of acupuncture techniques for treating KOA has been confirmed. EA is one of the most effective therapies among the observed acupuncture techniques for pain control and dysfunction relief during KOA management.
Conclusions
The observed acupuncture technique is effective in treating KOA. EA is the most effective therapy for alleviating pain intensity among observed acupuncture techniques. This study may help acupuncturists choose the optimal acupuncture technique and promote the clinical effect of acupuncture treatment for KOA management.
Supplementary Information
Below is the link to the electronic supplementary material.
Acknowledgements
We are grateful to all the patients who consented to participate in the trial. We appreciate Shan Liu and Peng-Lei Zhou for their technical support in establishing the electronic data capture system.
Author Contributions
Jian-Qiao Fang, Jing Sun conceived and designed the study, had full access to all the data in the study and had final responsibility for the decision to submit for publication. Kai-Tao Luo, Fang Liu, Xin-Wei Li, Yi-Dan Chen, Fu Xu and Qi-Fei Zhang recruited patients. Ming-Qi Tu, Xiao-Ting Wu, Rong-Rong Li and Xiao-Yu Li were responsible for the data collection. Jing Sun, Cong-Hua Ji, Xiao-Mei Shao and Yi Liang were responsible for the data statistical analysis. The manuscript was prepared by Jing Sun, Ming-Qi Tu and revised by Jian-Qiao Fang, Fu Xu and Yi Liang. All authors had full access to the data in the study, gave the final approval of the manuscript and agreed to be accountable for all aspects of the work.
Funding
Sponsorship for this study and Rapid Service Fee were funded by the key plan of Zhejiang Province Traditional Chinese Medicine Prevention and Treatment of Major Disease (No. 2018ZY008). The funding source was not involved in the study design, data collection, or data analysis and interpretation.
Data Availability
The datasets generated during and/or analyzed during the current study are available from the corresponding author upon reasonable request.
Declarations
Ethical Approval
The trial was approved by the Ethics Committees of the six hospitals. They are the Third Affiliated Hospital of Zhejiang Chinese Medical University (NO. ZSLL-KY-2017–030), Jiaxing TCM Hospital (NO. 2018-JZLS-001), Hangzhou Red Cross Hospital (NO. 2018 LS05), Tongde Hospital of Zhejiang Province (NO. 2018,019), Zhejiang Hospital (NO. 2018KA006) and Zhejiang Provincial Hospital of TCM (NO. 2018-KL-010–01). This study was performed in accordance with the Helsinki Declaration of 1964 and its later amendments. Participants provided their consent by signing a written informed consent form.
Conflict of Interest
All the authors (Jing Sun, Yi Liang, Kai-Tao Luo, Xiao-Mei Shao, Ming-Qi Tu, Xiao-Ting Wu, Fang Liu, Xin-Wei Li, Yi-Dan Chen, Qi-Fei Zhang, Cong-Hua Ji, Rong-Rong Li, Xiao-Yu Li, Fu Xu, Jian-Qiao Fang) declare that they have no competing interests.
Footnotes
Jing Sun and Yi Liang contributed equally to this work.
Contributor Information
Fu Xu, Email: xufu36@126.com.
Jian-Qiao Fang, Email: fangjianqiao7532@163.com.
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Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.
Supplementary Materials
Data Availability Statement
The datasets generated during and/or analyzed during the current study are available from the corresponding author upon reasonable request.