THE SHORT-TERM EFFECTS OF LOW-LEVEL LASER THERAPY ON ADULTS WITH KNEE ARTHRITIS ON PAIN AND STIFFNESS AS TAKEN FROM THE WOMAC: A META-ANALYSIS

Transcription

1 ABSTRACT THE SHORT-TERM EFFECTS OF LOW-LEVEL LASER THERAPY ON ADULTS WITH KNEE ARTHRITIS ON PAIN AND STIFFNESS AS TAKEN FROM THE WOMAC: A META-ANALYSIS Objective: To investigate the effects of low-level laser therapy (LLLT) on adults with knee osteoarthritis (OA) and improving pain and stiffness according to the pain and stiffness subscales of the WOMAC. Study Design: A meta-analysis of randomized placebo controlled studies that investigated the effects of LLLT on pain and stiffness in subjects with knee OA. Methods: Following the PRISMA guidelines, selected studies comparing LLLT devices compared to placebo with an exercise program. The age of subjects ranged from year olds and included both males and females. Knee OA as defined by the American College of Rheumatology (ACR) and, a Kellgren and Lawrence grade between 2-4 were included. All studies utilized the WOMAC and needed to specifically report subscores for pain and stiffness. Studies also used acceptable follow-up periods ranging from 2 to 6 weeks. Data from the pain and stiffness subscores of the WOMAC were analyzed to determine homogeneity. Results: Four randomized controlled trial (RCT) articles met the inclusion criteria. After analysis, it was determined that the studies were heterogeneous and we were unable to draw statistical conclusions from our analysis. Conclusion: Based on the 4 studies, the use of LLLT for patients with knee OA was inconclusive due to the presence of heterogeneity of the data included in the study. Key Words: knee osteoarthritis, Low-Level Laser Therapy (LLLT, WOMAC, therapeutic exercise) Ricardo Puente December 2016

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3 THE SHORT-TERM EFFECTS OF LOW-LEVEL LASER THERAPY ON ADULTS WITH KNEE ARTHRITIS ON PAIN AND STIFFNESS AS TAKEN FROM THE WOMAC: A META-ANALYSIS by Ricardo Puente A project submitted in partial fulfillment of the requirements for the degree of Doctor of Physical Therapy in the Department of Physical Therapy College of Health and Human Services California State University, Fresno December 2016

4 APPROVED For the Department of Physical Therapy: We, the undersigned, certify that the project of the following student meets the required standards of scholarship, format, and style of the university and the student's graduate degree program for the awarding of the doctoral degree. Ricardo Puente Project Author Bhupinder Singh. (Chair) Physical Therapy Stacy Winans Physical Therapy Peggy Trueblood Physical Therapy For the University Graduate Committee: Dean, Division of Graduate Studies

5 AUTHORIZATION FOR REPRODUCTION OF DOCTORAL PROJECT I grant permission for the reproduction of this project in part or in its entirety without further authorization from me, on the condition that the person or agency requesting reproduction absorbs the cost and provides proper acknowledgment of authorship. X Permission to reproduce this project in part or in its entirety must be obtained from me. Signature of project author:

6 TABLE OF CONTENTS Page LIST OF TABLES... vi LIST OF FIGURES... vii BACKGROUND... 1 What Is Osteoarthritis?... 1 Etiology & Cost... 2 Severity/Diagnosis... 2 Medications for OA... 3 Treatments & Modalities... 4 How It Is Different... 4 What Is Low-Level Laser Therapy?... 5 Mechanism of LLLT... 6 Effectiveness of LLLT... 6 Are LLLT Guidelines Useful?... 7 WALT Recommendations... 7 Fill the Gap... 8 Clinical Relevance... 8 Outcome Measures... 8 Purpose... 9 METHODS Identification of Sources Eligibility Criteria Quality Assessment Outcome Data... 11

7 v Page Statistical Analysis RESULTS Study Selection Characteristics of Included Studies Quality of Included Studies Synthesis of Results DISCUSSION Summary of Evidence Limitations Clinical Implications Gaps in Literature Future Research Conclusion REFERENCES TABLES FIGURES... 46

8 LIST OF TABLES Page Table 1: Subscale Sections used in WOMAC: Pain and Stiffness Table 2. PEDro Scores for Included Studies Table 3. General Data of Included Studies Table 4. Severity of Knee OA of Included Studies Table 5. Laser Dosing Data of Included Studies Table 6. Aflredo et al. 52 Exercise Program

9 LIST OF FIGURES Page Figure 1. Flow Chart for Study Selection Figure 2. Forest Plot of WOMAC Pain Data Figure 3. Forest Plot of WOMAC Stiffness Data... 49

10 BACKGROUND What Is Osteoarthritis? Osteoarthritis is (OA) a progressive degenerative disease affecting the articular cartilage of the weight bearing joints and smaller joints that undergo significant stress. Joints of the knees, hips, hands and spine are commonly affected by OA. 1 The etiology of knee OA can be classified into primary or secondary OA. In healthy individuals, the cartilaginous lining at the end of osseous structures allow for smooth, pain-free movement. In contrast, primary OA is characterized by the break down of cartilage resulting in inflammation, stiffness, pain, and development of bone spurs within the joint. 2 Changes in the cartilaginous lining often results in increased pain and subsequently lead to movement dysfunctions. The main risk factor for development of primary knee OA is age-related changes due to mechanical stresses placed on the joint. 1 However, current research is investigating the precise etiology of senescence changes resulting in articular cartilage alterations as a possible cause of primary OA. 3 Early findings suggest that chondrocyte activity declines, thereby reducing the quality and quantity of osteoblasts, and ultimately reducing cellular proliferation. Cartilage senescence further reduces the responsiveness to anabolic cytokines and less receptive to mechanical stresses overtime. 3 The reduced ability of the aging chondrocyte to repair and rebuild after being stressed over time can give rise to primary OA. While primary OA is due to the aging process, secondary OA is linked to a known cause, such as traumatic injury, disease, and obesity, which can quickly degrade or directly damage the articular cartilage. 2,4 Other causes that can lead to this type of OA include congenital conditions and foot deformities such as genu valgum, genu varum, and clubfoot can lead to knee OA. 2,4 These conditions can

11 2 accelerate the deterioration of the articular surface due to abnormal load bearing of the joint. 2,4 Other causes of secondary knee OA consist of systemic or metabolic diseases comprised of hemochromatosis, endocrine disease such as of hypothyroidism, and bone dysplasia s of the epiphysis. 2,4 Etiology & Cost Arthritis is the most common cause of disability in the United States. 5 In 2012, it was estimated that 1 in 5 adults were diagnosed with some form of OA by their physician; this equates to over 52 million adults with OA. 5 It is projected that 67 million adults will have some form of OA by Data from the National Health Interview Survey from 2012 reports 29.1% of adults ages 45-64, 47.3% ages 65-74, and 50.9% ages 75 and older were diagnosed with OA. 7 Furthermore, 26.0% of women were found with OA compared to 19.1% of men. 5 This data demonstrates that women are more prone to being diagnosed with OA, and this prevalence increases with age. 5-7 Not only is the rate of people being diagnosed with OA increasing, but the cost attributed to this disease is also on the rise. In 2011, the Medical Expenditures Panel Survey estimated that the national average per-person direct cost associated with all OA conditions was approximately $11,029 per year with an average indirect cost of $7,548 per-person per year. 8 These estimates can total to approximately $460 billion in costs attributed to OA. 8 These figures demonstrate the high prevalence of OA and its associated costs here in the United States. Severity/Diagnosis The American College of Rheumatology (ACR) has proposed the use of specific criteria when diagnosing knee OA. 4 With a thorough history and physical examination, an individual with knee pain must meet 3 of the following to indicate

12 3 the presence of knee OA: over 50 years of age, less than 30 minutes of morning stiffness, crepitus during active motion, bony tenderness, bony enlargement, or absent palpable warmth of the synovium. 4 Diagnostic assessment of suspected knee OA is typically performed using radiographic imaging. Primary and secondary knee OA result in specific deformities that can be classified according to the Kellgren and Lawrence system, which is considered the gold standard in grading knee OA. 9,10 The Kellgren and Lawrence system uses radiographs to grade knee OA on a scale from 0-4. Grade 0 is defined as the absence of any OA related changes. Grade 1 contains minute or possible osteophyte development with potential narrowing of the joint space. Grade 2 is characterized by the presence of osteophytes with questionable or absent narrowing of the joint space. Moderate presence of osteophytes and narrowing of the joint space, minor sclerosis, and possible bony deformity characterize grade 3. Finally, Grade 4 demonstrates large osteophytes, marked narrowing of the joint space, severe sclerosis, and definite deformity. 9,11 Medications for OA The conservative treatment approach for patients with knee OA aims to reduce pain and stiffness to allow overall improved function. 2 Current treatment options include pharmacological and non-pharmacological approaches, which are considered non-curative. The pharmacological approach commonly relies on the use of non-steroidal anti-inflammatory drugs (NSAIDs), acetaminophen, steroid injections, and opioids. However, a study by Bjordal et al. 12 found that these pharmaceuticals yielded little to no benefits for pain relief after 1 month of use. 12 Moreover, the long-term use of these drugs has detrimental side effects to the

13 4 user s gastrointestinal tract increasing the chance of bleeding or perforation that may negatively affect the patient s overall health Treatments & Modalities According to the World Health Organization (WHO), 80% of those diagnosed with OA will have movement-related limitations. 18 Individuals with knee OA have difficulty with activities of daily living such as: ambulation, kneeling, standing, ascending and descending stairs, and sitting. 19 In 2012, the ACR published recommendations for the use of different therapies for individuals with OA, in the joints of the hand, hip and knee. 20 The ACR recommends supervised exercise programs developed by a physical therapist, to manage symptoms and restore function. 20,21 Physical therapy is a non-pharmacological approach that utilizes therapeutic exercises, functional activities, and modalities to address impairments associated with knee OA. Modalities used by a physical therapist include the following: pulsed electromagnetic field, pulsed short wave diathermy, transcutaneous electrical nerve stimulation, electrical muscle stimulation, thermotherapy, ultrasound, and low-level laser therapy (LLLT). 2,22,23 A systematic review of physical therapy interventions found that there is moderate evidence for the use of LLLT in reducing pain in patients with knee OA. 22 How It Is Different What helps set LLLT apart from the previously mentioned modalities is how it transfers energy to produce therapeutic effects; it s ease of use and administration, and relative short list of contraindications. The listed Contraindications with LLLT include cancer, pregnancy, and light sensitivity. 24,25

14 5 While some evidence supports the use of LLLT, further research is essential to determine its efficacy within this population. What Is Low-Level Laser Therapy? Since the late 1960s, researchers have been investigating the therapeutic effects of LLLT on various disorders and medical procedures. 24 The term laser is an acronym that stands for light amplification by stimulated emission of radiation. 25 Lasers have 3 main characteristics, which include monochromatic, coherent, and collimated light. 24 Monochromatic properties indicate that the light emitting from the laser is of one color or wavelength. The coherent property suggests that the wavelengths are traveling in the same phase. Collimated means that the light is narrow and not diffused. 24 These 3 characteristics are unique to lasers and distinguish laser light apart from light that is being emitted by other sources. Two common types of lasers that are used in LLLT are Aluminum- Gallium-Arsenide (GaAlAs) and Gallium-Arsenide (GaAs). 26 These lasers use GaAs and GaAlAs as semi-conductive material within the laser diode to create the laser beam. 26,27 LLLT is commonly referred to as cold lasers due to its power densities, which do not produce heat within the tissue. 24 Wavelengths are measured in nanometers (nm), which determines if the laser operates within the visible spectrum or not. Visible laser light uses wavelengths that are within the visual spectrum, between nm. 24 Near infrared and infrared light lasers are undetectable by the human eye, and utilize wavelengths of 750nm and greater. 24 LLLT devices use wavelengths in the therapeutic window that are between 600 nm and 1070 nm, which can be both visible and invisible. 24

15 6 Mechanism of LLLT The physiologic process associated with LLLT is not fully understood, but it is believed that LLLT triggers a photochemical reaction, which is referred to as biostimulation or photobiomodulation. 24 Both reactions are believed to act upon the mitochondria and one of its cellular membrane channels, Cytochrome C Oxidase (CCO). 24,26,27 The application of LLLT, excites the CCO, which leads to an increase in electron transport and production of ATP. 24,27,28 Therefore, increases in cellular activity further induces the production of transcription factors known to modulate inflammation, pain, and increased oxygenation. 26,28,30 This bio stimulation effect would be an important process in controlling the symptoms related to OA. This theory has not been fundamentally proven and remains one of the many reasons why LLLT remains controversial as a therapeutic intervention. Effectiveness of LLLT LLLT has been shown to be beneficial in treating various conditions such as: chronic joint disease, myofascial trigger points, and neuropathic pain. 24,29,30 LLLT has also been reported to stimulate osteoblast activity, facilitate wound healing, and increase blood flow. 39,31 A systematic review by Bjordal et al. 32 concluded that LLLT was an effective modality in reducing inflammatory pain levels. 32 In addition to the systematic review by Bjordal et al., 32 a double-blinded study by Gur et al. 33 found that LLLT was an effective means in reducing knee OA pain. Soliemanpur et al. 34 in a prospective study also concluded that LLLT was able to reduce pain in knee OA. In another double-blind study by Hegedus et al. 35 their results found LLLT capable of reducing pain and improving microcirculation in knee OA patients. Conversely, other studies have also found that LLLT is not efficacious when compared to a placebo. 36,37 A study by Hinman et al. 36 found that LLLT did

16 7 not demonstrate any positive effects on pain or function with knee OA patients. The controversy regarding the effectiveness of LLLT is further highlighted by the lack of agreement regarding optimal parameters, application, and the specific physiological process that occurs when using this modality. It is this lack of consistency between studies that requires continued research to determine the efficacy of LLLT with patients suffering from knee OA. Are LLLT Guidelines Useful? This lack of consistency in the research creates a gap regarding the effectiveness of LLLT in managing pain in knee OA patients. WALT Recommendations Prior to 2010, there was no recognized dosing standard when using LLLT on knee OA patients. To address this void, the World Association of Laser Therapy (WALT) recommended dosing and research reporting guidelines. 38 WALT is an organization that has stepped forward to aid clinicians and researchers with dosing parameters for various diagnoses including knee OA. The WALT organization defines acceptable dosing parameters for each LLLT device for researchers and clinicians to utilize. 39 These recommendations can vary depending on the laser type and wavelength. 39 WALT s states that their guidelines are a safe and effective approach to applying LLLT in reducing pain in knee OA patients. However, independent research utilizing these new guidelines has not been investigated which also contributes to the knowledge gap with LLLT. Now that their guidelines have been available for current researchers, a closer look into their effectiveness in reducing pain in knee OA patients can be investigated.

17 8 Fill the Gap To help close this gap, this meta-analysis will look at current research and look at whether the WALT s guidelines can produce beneficial effects in reducing pain or stiffness in knee OA patients. This meta-analysis will also provide a current look into using LLLT, and its effectiveness of reducing pain or stiffness in knee OA patients. Also, this meta-analysis will also provide practicing physical therapist as an effective resource when considering to utilize LLLT on this patient population. Clinical Relevance Use of Laser Therapy in Clinic LLLT is a safe and painless modality that can be easily integrated into a physical therapy clinic. These devices are no bigger than ultrasound units that are currently being used in clinics. Other than eye protection LLLT units do not require additional cost such as creams or pads when applying to the patient. Clinically LLLT can be a useful modality in clinics when comparing to what is known about OA. Not only is the chance of developing OA going to rise with aging but the population of people with this disease will continue to increase. If the new guidelines can consistently show it to be effective, this modality can be easily implemented by clinicians to help patients manage the effects of OA and increase quality of life. Outcome Measures For this meta-analysis, the outcome measure employed to assess pain and stiffness were the subscores of the Western Ontario and McMaster University Osteoarthritis Index (WOMAC). The WOMAC is considered the gold standard outcome instrument for hip and knee OA It has demonstrated high reliability,

18 9 validity, and sensitivity to changes with hip and knee OA patients The WOMAC is a self-administered questionnaire consisting of 24 items divided into 3 subscales. 40 The subscales include pain, stiffness, and physical function. 40 There are 5 items for assessing pain during activities of daily living (ADL) such as walking, stair climbing and weight bearing. 40 For assessing stiffness, there are 2 questions regarding perceived stiffness felt in the morning and later in the day. 40 Each item is scored on a Likert scale 0-4 of difficulty, the higher the score the greater the difficulty. 40 This also relates to pain, where higher scores indicate worse pain, stiffness, and greater difficulty with the specific task. 40 Refer to Table 1 for WOMAC criteria. Purpose The purpose of this meta-analysis was to compare the effects of LLLT to placebo with exercise in patients with knee OA, in reducing pain and stiffness, from the measures of the WOMAC subscores. The alternative hypothesis states that LLLT with exercise will demonstrate a larger treatment effect on pain and stiffness when compared to placebo and exercise. The null hypothesis indicates that there will be no effect on pain and stiffness levels with LLLT and exercise when compared to placebo with exercise.

19 METHODS Identification of Sources This review was performed in accordance with PRISMA guidelines for the reporting of systematic reviews and meta-analyses. 47 Databases searched include PubMed, CINAHL, Physiotherapy Evidence Database (PEDro), Sage Journals Online and Cochrane Online. Search terms used in each of the databases included the following: osteoarthritis, arthritis, degenerative arthritis, knee, knee joint, physical therapy, physiotherapy, low level laser therapy, light therapy, function, pain, adult and elderly. Eligibility Criteria Level 1a evidence, which includes RCTs or randomized controlled studies examining the effects of LLLT versus placebo with exercise in patients with knee OA, were reviewed. Studies were selected for this meta-analysis if they included data from the pain and stiffness subscales of the WOMAC functional outcome measure. Pain and stiffness data was the focus because these are 2 common symptoms of knee OA that can reduce the overall function of these subjects. If LLLT modality can reduce the symptoms of this disease it will be reflected in these 2 categories of the WOMAC. Additional requirements included the following: male and female subjects between 40 to 75 years of age, individuals diagnosed with knee OA according to the ACR, a reported Kellgren and Lawrence grade between 2-4, and minimum score of 25 on the WOMAC. This score was based off the total WOMAC score. To reflect that included subjects experienced some functional dysfunction due to knee OA a score of 25 out of 96 was selected. Exclusion criteria for this meta-analysis included: rheumatoid arthritis or other joint disease of knee or hip, knee surgery, diabetes, intra-articular corticosteroid or

20 hyaluronic acid injections during the previous 6 months, and central or peripheral neuropathy. 11 Quality Assessment Four studies met the eligibility requirements of this meta-analysis and were individually scored using the PEDro scale. This scale has 11 criteria and 1 point is awarded if a criterion is clearly specified in the study. The final PEDro score is based on 10 points. 48,49 The purpose of the PEDro score is to highlight any studies that may have internal validity flaws as well as to ensure the quality of data provided in each individual study. 48,49 A summary of each study s PEDro score can be viewed in Table 2. Outcome Data For this meta-analysis, only the WOMAC data from the pain and stiffness subscale sections were extracted and analyzed from the 5 eligible studies. Pre-and post-intervention mean and standard deviation data for pain and stiffness was analyzed. Refer to Table 1 for WOMAC criteria. Statistical Analysis The 4 studies that met the criteria for this meta-analysis were assessed for the presence of homogeneity or heterogeneity using the Q test for both pain and stiffness subscore data. From each study, the mean and standard deviation from both experimental and control groups were entered into a spreadsheet in order for the Q test to be performed. After the data was entered a Q score, degrees of freedom, and p-value were given for each set of subscore data. There are different methods of interpreting these values to determine the presence of either homogeneity or heterogeneity. The approach used in this meta-analysis took into

21 12 consideration the relationship of the Q score and p-value. When there is a large Q score and a small p-value, this suggests the presence of heterogeneity. Heterogeneity indicates other contributing factors within the studies that make them too different to compare to one another and draw conclusions. Forest plots were also produced utilizing calculated effect size with corresponding upper and lower confidence intervals from each study. The forest plots depict each study s calculated effect size along with its standard deviation to better visualize presence of homogeneity or heterogeneity of the included studies.

22 RESULTS Study Selection The initial combined search of databases (PubMed, Cochrane, CINAHL, PEDro and SAGE journals) yielded thousands of articles relating to arthritis and the use of LLLT. The first attempt to narrow down search results began with eliminating any study that was not: peer-reviewed, randomized, in the English language, human, and or related to the knee. The second effort in consolidating search results was to eliminate studies that did not meet the established metaanalysis PICO inclusion criterion. This vastly condensed search results, yielding 146 studies to assess for eligibility. Finally, the remaining eligible studies were screened using the set inclusion criteria. The concluding process qualified 4 studies that were included in this meta-analysis. Refer to study consort in Figure 1. Characteristics of Included Studies The first study by Alfredo et al. 50 investigated the effectiveness of LLLT combined with exercise in reducing pain, improving function, range of motion (ROM), and quality of life (QOL) on the knee OA population. This study was a randomized double-blind study in which patients were sequentially assigned to either LLLT or placebo groups. Forty subjects between the ages of years old and between grades 2-4 of the Kellgren and Lawrence system were used in the calculation of results (Tables 3 and 4). Outcome measures used in this study were the visual analog scale (VAS) for pain, Lequesne questionnaire for functionality, universal goniometer for ROM, a dynamometer for strength and WOMAC for function. The same physiotherapist treated subjects in both groups; this therapist was not a part of the evaluation process. For both the LLLT and placebo groups the

23 14 therapist would place the same LLLT device over 5 designated points along the medial joint line and 4 points along the lateral joint line. The same application sites were applied to the placebo group, however the device was not switched on. All subjects received either LLLT or placebo 3 times per week for 3 weeks see Table 5 for LLLT dosing data. After this period, subjects were instructed to continue exercising for the remaining 8 weeks. The frequency of exercise was 3 times per week with each session lasting 45 minutes. The subjects participated in a 10-minute cardiovascular warm-up, 30 minutes of exercises and 5 minutes of stretching. Exercises were broken in to 3 phases with designated length of time and objectives (see Alfredo et al. 50 exercise program in Table 6). Measurements were taken at baseline, again at the end of 3 weeks of LLLT treatment, and at the conclusion of exercise at 8 weeks. The results of this study showed a significant difference in activity (p=0.03) after comparing the 2 groups. However, when looking at within group differences compared to baseline, subjects in the LLLT group showed improvements in pain (p=0.001), ROM (p=0.01), functionality (p=0.001) and activity (<0.001). No changes were seen in the placebo group. Alghadir et al. 51 investigated the effects of LLLT on pain relief and function in people with chronic knee OA. This was a single-blind study with 40 subjects between years of age that were randomly assigned into either LLLT or placebo groups (Table 3). Subjects were included into the study if they had been diagnosed with knee OA at least 3 months prior to enrollment, had a minimum score of 25 on the WOMAC, and classified as having either grade 2-3 knee OA (Table 4). Outcome measures used to track progress were the VAS for pain, WOMAC for function, and a timed 50-foot walk test.

24 15 The subjects in both the intervention and placebo groups had their target knee wrapped in a hot pack for 20 minutes before receiving the designated treatment. There was a total of 8 predetermined laser locations that included 3 spots along the medial and lateral side of the knee. Two additional points were located in the popliteal fossa near the distal medial tendon of the biceps femoris and semitendinosus muscles. The same unit was applied for both intervention and control groups however, the device was not turned on for the placebo group. Each subject reported to a physical therapy department for LLLT treatment 2 times per week for 4 weeks. Refer to Table 5 for LLLT dosing data. This study issued all subjects a home-based exercise program, with instruction and demonstration of isometric knee extension and straight-leg raises. After instruction, the subjects were given a handout with pictures and detailed instructions of both exercises. Frequency and intensity of home exercises included 10 repetitions for 3 sets with a 2-minute rest in between exercises. They were also instructed to hold the isometric contractions for 10 seconds with a 5-second rest in between repetitions. Patients were encouraged to keep a workout diary to keep track of how many days of exercises were performed each week. The results of this study found improvements in the WOMAC subcores of pain and stiffness compared to baseline values (p<0.05). However, only the pain subscores were statistically different, while stiffness was not. 51 Kheshie et al 52 studied the effects of LLLT on pain and function in patients with knee OA. This was a single blind study with a total of 33 subjects that were randomized into treatment and placebo groups (see Table 3). The primary outcome measures used to assess of treatment was the pain VAS and the WOMAC. Interventions were performed in a physical therapy department 2 times a week for 6 weeks. The LLLT device was used in a scanning motion, where it was

25 16 placed on the skin and moved along the lateral, anterior and medial aspects of the joint line of the knee for both treatment and placebo groups (see Table 5 for LLT dosing data). For the exercise component, the subjects were given a home-based exercise program. This consisted of a pre-workout 10 min walk followed by active ROM, muscle strengthening and flexibility exercises. After being trained on each exercise, the subjects received a detailed print out of their exercise program. Each subject was encouraged to comply with the home-based exercises throughout the study. The results of this study found that LLLT was effective at reducing WOMAC subscores for both pain and stiffness after 6 weeks of intervention combined with exercise. 52 Yurtkuran et al 53 was the final study included in this meta-analysis. This study was a double-blinded randomized placebo controlled study that assessed the effects of LLLT acupuncture compared to placebo. The LLLT acupuncture technique involves applying LLLT to known acupuncture locations. There was a total of 52 subjects with ages ranging from 42 to 65 years old and with knee OA that was between grades 2-3 on the Kellgren and Lawrence scale (Tables 3 and 4). These subjects were randomized to either active LLLT or placebo groups and given a home-based exercise program. This study used the VAS, knee circumference, medial tenderness score, WOMAC, and quality of life questionnaire as their outcomes measures. In this study, 53 outcome measurements were taken at 2 different times: first at baseline and then again following the 2-week intervention. During the intervention phase, subjects received treatments for 2 minutes once a day for a total of 10 days. The intervention group received pulsed LLLT to just one acupuncture point, Sp9, which was located on the inferior-medial boarder of the tibial condyle on the affected knee (see Table 5 for LLLT dosing data). The

26 17 placebo group received treatment to the same area, but utilized a sham laser. After the intervention phase, the patients were given a home exercise program, which consisted of isometric knee extension (10 repetitions) and active knee ROM (20 repetitions). After treatment, the 2 groups were compared to baseline, and found LLLT was only effective in reducing knee circumference (p=0.005). 53 Quality of Included Studies The quality of the studies included within this meta-analysis was evaluated using the PEDro scale. After scoring, the studies by Alfredo et al., 50 Alghadir et al., 51 Kheshie et al., 52 and Yurtkuran et al. 53 received high quality ratings. See Table 2 for PEDro scores. Synthesis of Results Stiffness Subset The statistical analysis for stiffness revealed that the data was heterogeneous with a Q score of (7.83) and a p-value of (0.04). Forest plots from this outcome data were created for visual interpretation (see Figure 2). Pain Subset The statistical analysis for pain revealed that the data was heterogeneous with a Q score of (17.95) and a p-value of ( ). Forest plots from this outcome data was created for visual interpretation (see Figure 3).

27 DISCUSSION Summary of Evidence This meta-analysis investigated current literature to determine whether utilizing LLLT versus placebo with exercise reduces pain and stiffness based on the WOMAC subscores in knee OA patients. Originally, it was hypothesized that LLLT with exercise would demonstrate a larger treatment effect on pain and stiffness when compared to placebo with exercise. Due to the findings of this meta-analysis it could not exclusively support or reject this hypothesis. After both pain and stiffness subscore analysis, the statistical data produced large q-values in relation to degrees of freedom. This relationship suggests heterogeneity among the included studies. Also, supporting this finding were the small p-values produced in both pain and stiffness data. Ultimately, despite some studies individually showing positive effects of LLLT, collectively, these studies could not explicitly determine LLLT s effectiveness due to presence of heterogeneity. Taking a closer look at the analysis and how it can help guide this metaanalysis and clinical judgment. With any meta-analysis, different studies are looked at together to better understand interventions and, their effects. The results also give clinicians an idea of the interventions usefulness in a clinical setting. One would want stronger evidence and strength in a meta-analysis to guide evidence based practice. Studies provides strength if they are similar for comparison. This is where the test for homogeneity plays a role. If gathered studies are homogenous, it suggests that all effects sizes are estimating similar population means and provide stronger evidence. Finding heterogeneity between studies suggest there is difference in the population means and provide no strength behind the findings.

28 19 Looking at the p-value will also provide and idea of either homogeneity or heterogeneity. Here you would want a p-value larger than.05 which will suggest homogeneity, whereas values lower than.05 suggesting heterogeneity. The p- value also help to prove that the results were not simply due to chance. Typically, p-values are set to.05 unless otherwise stated. This means that 95% of the time the results will result in the same values. A grand effect size will also be produced after the gathered studies are statistically analyzed. Unlike the effects size that is produced for each study, which provides the best estimate of the size of effect between groups. The grand effect combines effect sizes to provide an accurate view of overall effect. Direction of both effect size and grand size will be determined based on how the outcome measure is scored. Outcome measures that decrease in score to show a positive effect will produce negative values. While outcome measure that increase in value to show positive effects will produce positive values. The current 4 studies that were included in this meta-analysis are believed to represent the best available current research regarding LLLT. Additionally, these studies were published after the new guidelines by WALT were established so, they do take into count their recommendations. They also represent the inclusion criteria outlined previously as well as being good quality studies based on Pedro scores. Conversely, the study by Tascioglu et al. 54 was not included due to poor quality, did not meet all inclusion criteria and pre-dated WALT guidelines. Similarly, the studies by Gur et al. and Hegedus et al. however of better quality could not be included for not publishing WOMAC subscore data and only using the visual analog scale, respectfully. One possibility that could have led to heterogeneity in this meta-analysis was variation of the exercise programs in some of the studies. The subjects in

29 20 Alghadir et al. 51 incorporated a home-based exercise program that instructed their subjects to perform isometric knee extension exercises and straight leg raises. The subjects were given pictured handouts along with an exercise diary. They were encouraged to follow through with exercises and keep a log of how many days they exercised. Function can vary depending on which exercise program, a clinicbased or a home-based program, is implemented in individuals with knee OA. A study by Deyle et al. 55 found that subjects with knee OA who received a clinicbased exercise program produced better scores on the WOMAC compared to patients who received a home-based exercise program. Having 2 studies with different levels of supervision and exercise protocols could have confounded the results of this meta-analysis. Other aspects of heterogeneity could be the differing grades of knee OA and the extent of pain experienced by subjects. The study by Alfredo et al. 50 included subjects with grades 2-4 knee OA, whereas the remaining studies limited their subjects to only grades 2-3. This could be a source of heterogeneity because of the wider range in knee OA grades. Most of the studies had grades of 3 or less, whereas the study by Alfredo et al. 50 included individuals with grades of 4 or less. Individuals with a grade 4 knee OA may have poorer outcomes compared to an individual with a grade of 3 or lower. As seen in Figures 2 and 3, the subjects in Alfredo et al. 51 demonstrated little to no benefits when using LLLT in both pain and stiffness. Perhaps someone with a grade 4 might be more appropriate for surgical interventions. Therefore, different grades could have confounded the results of the current meta-analysis. Gender was another factor amongst the studies that may have contributed to heterogeneity. Yurtkuran et al. 53 had a disproportionate ratio of female and male subjects. In the entire study, there were a total of 53 women to 2 men. This led to a

30 21 26-to-1 female to male ratio in the experimental group, and a 24-to-1 female to male ratio in the control group. This observation is significant since the prevalence of OA is greater in women than men. Research also suggests that women present with a higher severity of knee OA than men, due to the differences in the anatomy and hormonal characteristics. 5,56,57 It also suggests that women experience higher pain levels and are more sensitive to pain. 58 This disparity in the female to male ratio in the studies might suggest that having women only subjects could misrepresent finding in studies because of lack of research supporting the use of this modality with higher grades of knee OA. It also seems that some women will have an increased sensitivity to pain which could contribute to the lack of pain reduction post LLLT intervention in studies with populations predominantly women. Based on what is known in women with knee OA in regards to presentation and sensitivity to pain, the studies within this meta-analysis could have contributed to the observed heterogeneity due to their population. Another reason for heterogeneity within this meta-analysis was the variations between 2 application methods of LLLT. These 2 application methods during the use of LLLT can be applied in a contact or scanning method. 40 Contact application places the laser emitter directly on the skin statically while delivering a dose. 40 The scanning method places the emitter on the skin while moving it in a back and forth motion on a specific path while delivering the dose. 40 Kheshie et al. 52 used the scanning technique that followed an anterior joint line path of the lateral and medial aspects of the target knee. Due to the use of inconsistent methods of application and the lack of literature regarding if one method is superior in producing therapeutic effects this could be a source of heterogeneity across studies of this meta-analysis.

31 22 Another possible source of heterogeneity could be the varying amount of laser energy absorption that occurs in each individual due to varying skin color. None of the studies included information in regards to skin color of the subjects. It is important to note that skin color is created by the size and distribution of melanin. 61 Depending on the skin color, it can potentially reduce the amount of laser energy reaching deeper targeted tissue since melanin lies within the superficial layer of skin. 59 Based on WALT guidelines, the dose would need to be increased by 50% to be effective for those who have darker skin due to the increased size and distribution of melanin. 61,60 Therefore, lighter skin color would allow more energy to pass into the deeper layers of tissue compared to darker skin color where greater energy is absorbed superficially. 60 Research also suggests that people with darker skin tones require higher doses to reach therapeutic effects compared to individuals with lighter skin tones require lower doses since less energy is being taken up by the melanin. 61 Other aspects of the studies included in this meta-analysis that could have contributed to heterogeneity are the inconsistencies in wavelength, application time, frequency and duration of intervention, and parameters of each LLLT device. As previously discussed, WALT has set recommendations of key parameters that are based on certain wavelengths used by the LLLT device. The recommendation for GaAs lasers are only for the 904 nm wavelenth. 39 Two studies used GaAs laser within the 904nm wavelength. Two studies used GaAs devices that used 830nm and 850nm, which are wavelengths that are not currently supported by WALT recommendations. 39 Wavelength is an important factor to consider since certain wavelengths penetrate skin differently. 62 A recent study by Henderson et al. 63 utilized a wavelength of 810nm, which could only reach an effective depth of 1.9 mm. 63 Henderson et al. 63 also demonstrated a wavelength of

32 23 980nm laser can reach a depth of 30 mm without any significant heating of tissue. 63 This suggests that wavelengths recommended by WALT are able to reach shallow tissue depths therefore higher wavelengths are required to reach deeper tissues. The laser wavelengths used in this meta-analysis may have only been reaching superficial depths and therefore, did not yield beneficial effects for some subjects. WALT suggests GaAs lasers use the 904nm wavelengths with application a time between 30 and 600 seconds. 39 One of the studies 54 in this meta-analysis, utilized frequencies between 780nm and 860nm with an application time of 120 seconds. This was within the WALT recommendations; however, these parameters were on the lower end. The lasers used in Alfredo et al. 50 and Yurtkuran et al. 53 studies both used a 904nm wavelength and their application times were 50 and 120 seconds respectively. Application times used in the Alfredo et al. 50 and Yurtkuran et al. 53 studies were within the suggested guidelines, but also on the lower end. There was no consistency across studies regarding how long the laser was applied and were towards the lower range of the WALT guidelines. This would suggest, the subjects might not be receiving any benefits from LLLT due to such short application times which lead to lower therapeutic doses of LLLT. These short application times could be contributing to heterogeneity in this metaanalysis. Regarding frequency of treatment and duration of LLLT, 2 of the included studies followed the recommendations advised by WALT. The recommendations by WALT suggest either daily therapy for up to 2 weeks or every other day for 3 to 4 weeks. 39 The studies by Alfredo et al. 50 and Yurtkuran et al. 53 implemented treatment schedules that followed these recommendations. The studies performed by Alghadir et al. 51 and Kheshie et al. 52 consisted of treatments lasting 4 and 6

33 24 weeks respectfully, but only applying LLLT 2 times a week to their intervention groups. The duration of the treatments was within the recommendations, but the frequency of treatments per week was below WALT s guidelines. The delay of treatments could have reduced the overall treatment effect due to the frequency of treatments in these studies. The studies by Alghadir et al. 51 and Kheshie et al. 52 may have not attained significant benefits compared to the other 3 studies, which adhered to the set of parameters proposed by WALT. Specific device parameters, in each study, such as mean laser output and energy per point demonstrated wide variation in the settings. WALT designates acceptable ranges for the GaAs lasers. For example, WALT recommends a minimum of 1-4 J/point for GaAs lasers. 39 The study by Yurtkuran et al. 53 used a GaAs laser, but only used.48 J/point. The parameters of energy per point are important because this lets the user know how much total energy is being delivered. The energy delivered may not be sufficient enough to produce therapeutic effect based on the suggested parameters utilized within each of the studies. This demonstrates yet another difference among the included studies potentially resulting in heterogeneity in the meta-analysis. Regarding parameters of mean laser output, 4 studies used GaAs lasers, which WALT recommends a mean output of at least 5 mw. 39 Yurtkuran et al. 53 was the only study out of the 4 that did not meet the recommended mean output power suggested by WALT, utilizing a mean output power of 4 mw. The remaining studies that used GaAs lasers used mean power output that ranged from the lower to higher ranges of WALT s recommendations. The mean power output is an important factor because an increase in power will increase the rate of energy transfer into the skin resulting in shorter application times. The study by Yurtkuran et al. 53 utilized low mean power outputs, therefore, the application time

34 25 must be longer in duration to be able to deliver appropriate energy to result in a therapeutic effect. There could be a possibility that due to low mean power outputs utilized in this studies 53,54 in combination with short application times, may have failed to produce a meaningful therapeutic effect. The discrepancy between the parameters suggested by WALT and those applied in the studies could have also affected the results of this meta-analysis. Finally, the risk of bias within all of the studies in this meta-analysis may have contributed to heterogeneity of the results. Kheshie et al., 52 scored 7/10, while the remaining 3 studies by Alfredo et al., 50 Alghadir et al., 51 and Yurtkuran et al. 53 scored 8/10. All 4 studies did not meet criterion number 6, which relates to blinding of all therapists working with subjects. The fact that therapists were not blinded could lead to bias from the treating therapist, potentially affecting the intervention outcomes. Alfredo et al. 50 did not meet criterion number 3 for concealment allocation and criterion number 5 for indicating blinding of all subjects. This indicates that the person designating patients into the study was not concealed, which could influence the interventions subjects received. The lack of blinding of all subjects could affect how subjects perceive their intervention biasing the results of the current meta-analysis. Yurtkuran et al. 53 and Kheshie et al. 52 did not achieve a point for criterion number 9 indicating subjects did not receive treatment as planned. These differences in blinding, allocation, and intension to treat can increase the chances of internal validity and bias within each study, which ultimately could have affected heterogeneity in this meta-analysis. Limitations One limitation of this meta-analysis may include the PEDro scores of the 4 included studies, which increased the risk of bias within each of the study s. Other

35 26 limitations due to methodological faults include; small number of studies, and small sample sizes, no inclusion or exclusion criteria regarding minimum knee pain, precise definition of treatment duration, or use of a specific laser wavelength. Lastly no secondary appraisal tool to assess quality of included studies. Clinical Implications Based on the results of this meta-analysis, heterogeneity was found among the included studies, which leads to cautious interpretation of the results. The findings were not in agreement with other researchers in the use of LLLT with exercise in individuals with knee OA. In order for practicing clinicians to have an optimal therapeutic effect with LLLT, more consistent research needs to be performed on laser parameters in patients with knee OA. WALT is one source clinicians can refer to when choosing LLLT treatment parameters for knee OA patients. For individuals within this study population, physical therapists attempt to seek the best modalities to help reduce the limiting factors of OA, particularly pain and stiffness. This meta-analysis was unsuccessful in determining whether LLLT with exercise was an effective modality due to the considerable presence of heterogeneity. However, the study by Hegidus et al. 35 found that LLLT when compared to placebo, showed significant therapeutic effects in reducing pain levels in knee OA subjects. Another study by Gur et al. 33 investigated the effects of LLLT combined with exercise and found that LLLT was effective at reducing pain in knee OA patients. Despite the results of this meta-analysis, other studies show that LLLT with exercise does have positive therapeutic effects as an intervention for individuals with knee OA. Therefore, the findings of this meta-

36 27 analysis should be interpreted with caution because of the inconsistencies among the literature. Physical therapists should be aware of certain factors regarding patient characteristics when deciding to utilize LLLT with exercise in knee OA patients. Some of which were noted in this meta-analysis and include: gender, grade of knee OA, and skin color. The grade of knee OA needs to be considered since there is limited research with the use of LLLT and its effectiveness at reducing symptoms with moderate or severe grades of knee OA. Further research will have to consider the different factors that can possibly result in poor outcomes when using LLLT with exercise as a treatment in knee OA patients. Physical therapists need to consider skin tone when applying LLLT. Studies have demonstrated that people with darker skin color have been shown to absorb greater amounts of light due to melanin. 60,61 This can reduce the amount of laser light that passes through the superficial layer of the skin and can ultimately reduce the amount of light reaching the target tissue. Therefore, therapists may need to increase the normal dosing recommendations by 50% to produce desired effects. 60 Gaps in Literature Currently, there still is an unclear understanding of the actual physiological process triggered by LLLT creating the pain modulating effects. There are a couple of hypotheses that have been proposed about what occurs at the cellular level when LLLT is applied. One theory suggests that LLLT alters the threshold level of nociceptor binding sites located on axons, which can reduce transmission of the nerve cell. 64,65 This modulation of nerve conduction helps to reduce the sensation of pain. 64