Effect of laser moxibustion for knee osteoarthritis: a multi-site double-blind randomized controlled trial

Background A laser device that mimics traditional moxibustion without smoke may be effective and safe for treating patients with knee osteoarthritis. Methods A double-blind randomized clinical trial was conducted. A total of 392 patients with osteoarthritis of the knee were randomly assigned to receive laser treatment or sham control three times a week for 4 weeks with 20-week follow-up. Primary outcomes were changes in the WOMAC pain scores at week 4. Results Among the 392 randomized participants, 364 (92.86%) completed the trial. The median WOMAC pain score significantly decreased at week 4 in the active group than in the sham group (2.2; 95% CI, 1.7 to 2.8; P < .01). At week 24, compared to the sham laser, active laser treatment resulted in significant pain reduction and function improvement (3.3; 95% CI, 2.7 to 3.9; P < 0.01, and 15.7; 95% CI, 12.8 to 18.8; P < .01, respectively). The physical component of the quality of life significantly improved in the active group than in the sham control at week 4 (3.0; 95% CI, 1.1 to 4.9; P = 0.002) up to week 24 (5.1; 95% CI, 3.2 to 7.0; P < .001). No serious adverse effects were reported. Conclusion Laser moxibustion resulted in statistically and clinically significant pain reduction and function improvement following a 4-week treatment in patients with knee osteoarthritis.

Background Osteoarthritis (OA) is the most common form of arthritis and the leading cause of disability among older adults. The knee is the joint most commonly affected by OA. 1 The prevalence of knee OA among people aged 60 years or older in the USA is 12.1%, [2][3][4] which is expected to increase in the next 20 years. 5 The prevalence of knee OA among elderly in China is nearly 30%. 6 Conventional treatment of knee OA mainly aims at alleviation of pain including pharmacological, such as non-steroidal anti-inflammatory drugs (NSAIDs) [7][8][9][10][11][12][13][14][15] and non-pharmacological managements 11,13 . NSAIDs are associated with a moderate effect on pain relief. 9,10 However, evidence on their effectiveness is limited, 9-12, 14,15 and often associated with undesirable side effects. 11,14,15 Recent review showed that appropriate treatments for knee OA included biomechanical interventions, intra-articular corticosteroids, exercise (land-based and water-based), self-management and education, strength training, and weight management. 13 As many as 41% 16 people with OA seek out complementary and alternative medicine therapies, including traditional Chinese medicine (TCM), acupuncture, moxibustion, and laser irradiation. According to the TCM theory, joint pain is associated with coldness and dampness. Therefore, the treatment often involves thermal stimulation on acupuncture points, known as moxibustion, by burning mugwort (Artemisia vulgaris). However, moxibustion therapy produces heavy smoke with unpleasant smell. The smoke of moxibustion is considered as a biological hazard to health, 17 which is therefore prohibited from use in many clinics and hospitals. Recently, low-level laser therapy has been widely used to treat musculoskeletal pain including pain in knee OA. [18][19][20][21] We have developed a laser moxibustion (LM) device of 10.6 μm wavelength, which has the thermal nature of moxibustion without smoke and smell. Our previous small studies showed that LM may be effective in alleviating the symptoms of knee OA. 22 The institutional review board at each site approved the trial protocol. We established an international data and safety monitoring board (DSMB) to monitor data safety to ensure the quality of the trial and safety of patients in the trial.
A total of 603 patients were screened between January 2015 and November 2017 primarily through print advertisements on local newspapers and posters distributed in nearby communities ( Figure 1). Participants were included if they were 50 years old or older, reported moderate or greater clinically significant knee pain on most days during the past month, had knee pain of at least 40/100 mm on a visual analogue scale (VAS), and had been diagnosed with idiopathic knee OA according to the American Rheumatism Association classification criteria. 25 Kellgren-Lawrence grade ≥ 1 in the tibiofemoral joint on radiograph was also an inclusion requirement. 5 Patients with other diseases affecting the knee, such as rheumatoid arthritis, fibromyalgia syndrome, chronic fatigue syndrome, and ankylosing spondylitis, were excluded. Other exclusion criteria were as follows: steroid medication or acupuncture/moxibustion treatment in the previous 3 months; intra-articular hyaluronate injection during the past 6 months; arthrocentesis or arthroscopy in the past 1 year; previous history of knee/hip replacement surgery and plan to have such surgery during the trial; use of other external treatments, such as topical medication; presence of serious medical conditions including cardiac diseases, pulmonary diseases, kidney diseases, liver diseases or malignant tumors, systemic infection or contagious diseases, and psychopathy; use of trial drug in the past 30 days; previous participation in other laser therapies; recruited in other clinical trial simultaneously; and unable to fill measurement questionnaires.

Randomization and Blinding
The 392 eligible participants were randomly assigned to receive either active LM or sham control. Randomization sequence with random blocks was generated using computer software. Allocation concealment was ensured with disguised letter codes of the LM devices (either active or sham devices) that were generated and sent to the site coordinators via a central randomization system. After receiving the device code from the site coordinator, the device operator used the LM device labeled with that code for patient treatment. The operators were unaware of the active or sham device as both produced the same red light. The whole procedure was supervised by the coordinators to ensure that the protocol was followed. Participants in the two groups were treated by trained operators. Communication among participants was discouraged and avoided as they were treated in separate rooms. Therefore, all involved personnel including participants, device operators, outcome assessors, research coordinators, and statistician were blinded to the treatment allocation.

Interventions
The LM devices (SX10-C1) were manufactured by Shanghai Wonderful Opto-Electrics Tech. The sham treatment procedure was the same as the active treatment except no laser output irradiated from the device. However, in both active and sham devices, a red lightemitting diode with an output of 3 mW was used as visible indicator light on the skin to confirm accuracy of irradiation on the targeting acupoint. Participants were allowed to receive their usual care medications but were encouraged not to change to new drugs. In case of drug change, the name and dosage of the medication were documented.

Outcome Measurements
The patients were assessed at baseline and at weeks 2, 4, 8, 12, and 24. All assessment instruments were in Chinese language version and previously validated. 27 4=poor). Adverse events, whether related to treatment or not, reported by the participants and practitioners were documented at each visit. We also communicated each participant weekly through telephone to follow up any adverse event or side effect.
Possible side effects of LM include skin rash, redness, and blisters. To assess the masking effectiveness of the trial, the treatment providers and the participants were asked to guess their group assignment after the end of treatment at week 4.

Sample Size and Statistical Analysis
A minimum of 36% improvement in WOMAC score was considered to be clinically meaningful. 34 Based on previous small-scale preliminary studies, 22-24, 35,36 a sample size of 324 participants (162 for each group) would be sufficient to detect the difference of 36% between the two groups to achieve a 2-sided 5% significance level with at least 80% power. 37 Considering possible dropout (i.e., 17% dropout) during the trial, a total of 392 patients were thus required.
The analysis plan was determined and approved by the independent DSMB committee before the study was conducted. The primary analysis was an intention-to-treat analysis to compare the 4-week improvement in WOMAC pain score between the treated and the control in all randomized patients whose 4-week improvement was available. A chi-square test was used for categorical data and 2-sample t-test or Mann-Whitney U test was used for continuous data, to evaluate statistically significant differences in the distribution of different variables at baseline according to whether the data are normally distributed.
Two-sample t-test or Mann-Whitney U test was performed for the primary (WOMAC pain) and secondary endpoints (WOMAC scores at other time points, SF-36, medication usage, and serum levels of different cytokines) at each time point. Chi-square test was performed for the categorical data (self-evaluation, credibility of the sham assessment, and safety assessment). For non-normally distributed variables, 95% bootstrap confidence instead of large sample normal based interval was calculated. All statistical analyses were conducted using SPSS (version 23.0; Chicago, USA). All reported P values were two-sided and used a significance level of 0.05.

Results
Between January 2015 and November 2017, we screened 603 participants for eligibility and 211 were excluded because of unmet eligibility criteria ( Figure 1). Thus, 392 patients were randomly assigned to either the LM (n=201) or the sham LM group (n=191). Three hundred and sixty-four patients (92.86%) completed the study and available for analysis ( Figure 1). Baseline characteristics were similar between the groups (Table 1). Most study patients were women (75%). No significant difference was found between the two groups in age, sex, disease course, medication use, severity of disease, WOMAC scores for knee pain or physical function, and cytokine level. This result suggests that the two groups were comparable.
Primary Outcome: At week 4, the patients receiving LM treatment reported more pain reduction in WOMAC pain score of 2.6 (39.4%) compared with those receiving sham LM of 0.1 (1.5%). A significant difference was found between the two groups (2.2; 95% confidence interval [CI], 1.7 to 2.8; P < 0.01) ( improved significantly more in patients who received active LM than those who received sham LM (see Table 2 for details). The patients in the active LM group reported more VAS pain score reduction than those in the sham LM group at all time points (Table 2) (Table 4).

Discussion
Over a 4-week treatment period of thrice weekly treatments, 10.6-μm LM (61.2-68.8 J/cm 2 ) showed significant efficacy in relieving knee pain and function improvement compared with sham LM measured using WOMAC scores and VAS. The effect was prolonged up to 20 weeks after the completion of laser treatment. Our findings are similar to those of previous reports. 35,36 In a systematic review reported by Wyszynska and Bal-Bochenska, 35 high-intensity laser therapy produces significant benefit in pain reduction and function improvement in patients with knee OA. However, most of these studies suffered from methodological flaws such as small sample size, 35,37,38 insufficient treatment time, 18 and inadequate follow-up time. 39 The strength of our laser treatment was that our laser device used CO 2 laser, which produces a far-infrared light beam of 10.6 μm, whereas previous studies used Gal-Al-As laser with wavelengths ranging from 830 nm to 1064 nm. 40 The unique feature of 10.6-μm LM is that it produces potent superficial heat, 41 which mimics moxibustion in TCM.
According to the TCM theory, joint pain, such as in knee OA, is considered as "Bi syndrome," which is caused by wind, cold, and dampness affecting the joint. Traditionally, thermal stimulation produced by burning A. vulgaris is commonly used to treat "Bi syndrome" to eliminate cold and dampness in the joint. 26 However, traditional moxibustion has its limitation in clinical practice due to the nature of smoke and smell.
Some studies suggested that the smoke may be hazardous for health. 42,43 In the present study, we used 10.6-μm CO 2 laser beam, which produced a thermal effect similar to that of traditional moxibustion but without smoke and smell, for treating knee arthritic pain. 21,34,[44][45][46][47] A recent systematic review 40  The other strengths of this trial are as follows. First, we conducted a double-blind clinical trial. This was achieved by the same appearance of active and sham laser devices; not only the patients but also the operators of the laser devices were unaware of the group allocation. Further validation test showed that the blinding was successful, and all other investigators were also blinded to the treatment allocation. Second, the patient compliance rate of the trial was high (92.86%), possibly because most of the participants were elderly and retired with more time for treatment. Most of the participants lived nearby the hospitals. Third, the incidence of side effects observed during trial was low (7.65%).
To understand the mechanisms of action, we collected peripheral blood from subjects and examined the serum biochemical components that may be associated with inflammation status of knee OA. Interestingly, no changes were observed in all cytokines; the only change we noted was COMP. Some studies suggested that serum COMP is potentially useful to be a prognostic marker of disease progression for joint injury. 51, 52 COMP is a large pentameric glycoprotein that interacts with multiple extracellular matrix proteins in the cartilage. 53 Our study suggested that the effect of the 10.6-μm laser may be associated with protecting the cartilage from degeneration in patients with knee OA.
This study has a number of limitations. First, the trial was conducted at six sites and the number of subjects recruited from each site varied, which might introduce selection bias and conditional bias. Second, the treatment only used two fixed points, whereas in real-       Figure 1 flow chart