Effect of MLS® Laser Therapy for the treatment of experimentally induced acute tendinopathy in sheep – a preliminary study

ABSTRACT

Tendon injuries are common in human athletes and sport horses. Unfortunately, traditional treatments are limited in their ability to completely heal injured tendons. Recent advances in low-level laser therapy (LLLT) have shown promising results. This study evaluated the effect of Multiwave Locked System (MLS ®) laser therapy in          
collagenase-induced tendon lesions in sheep. Six animals were randomly assigned to two groups, with group 1 receiving ten MLS ® Laser Therapy treatments at 5 J/cm² on the left hind limb and group 2 receiving the same number of treatment at 2.5 J/cm² on left hind limb. The right hind limb was considered a control for both groups. Clinical follow-up, ultrasonography and histological examinations were performed on the injured tendons. Clinical and histological evaluations demonstrated that using a therapeutic dose less than 5 J/cm² resulted in an anti-inflammatory effect. Moreover, the histological examinations showed a statistically significant reduction in cell number in both treated groups and a          
significant decrease in vascularization in the treated tendons in group 2. MLS ® Laser Therapy appears to be an effective tool to improve collagen fiber organization in the deep digital flexor tendon.

INTRODUCTION

Overuse tendinitis and other tendon injuries are common among athletes and represent a frequent cause of lameness in sport horses. In the human medical field, Low Level Laser Therapy (LLLT) has been used to treat acute and chronic musculoskeletal pain and foster wound healing. However, few studies have evaluated its effectiveness in treating patients with acute tendonitis and other tendinopathies. As demonstrated in the literature, LLLT acts on two phases of the healing process. First, it reduces PGE2 concentrations and inhibits cyclo-oxygenase. Secondly, it modulates fibroblast metabolism and collagen deposition due to its anti-inflammatory effect. Histological changes observed in tendons receiving LLLT include increased collagen production, improved collagen bundle organization and an increased number of small blood vessels. Animal models are commonly utilized in tendon disorder research and the collagenase-induced tendinitis model has been used to study acute inflammatory responses. This model has been used in rats, sheep and horses, and mimics a traumatic tendon injury. The sheep is recognised as a model for human and equine orthopaedic injuries, including          
tendinopathy, due to the similar connective tissue structure of the flexor tendons in these          
species. Numerous authors have described the positive effects of LLLT in experimental trials in rats, mice and rabbits. However, to our knowledge, there are no studies investigating the effect of LLLT on experimentally induced tendinitis in sheep. This preliminary study was designed to investigate the effect of MLS ® (Multiwave Locked System) laser therapy on an experimental model of collagenase-induced tendinitis in sheep in order to evaluate a specific treatment for human and animal athletes.

MATERIALS AND METHODS

This study was approved by the University Ethics Committee for Animal Experimentation (CEASA) and by the Italian Ministry of Health on 17 May 2010 (DM no. 97/2010-B). Six healthy adult female Bergamasca sheep weighing 50-60 Kg were included in the study. Prior to enrollment, clinical and ultrasound examinations were performed to confirm tendon integrity. A defect was produced in the deep digital flexor tendons (DDFT) of both hind limbs by collagenase injection as previously described. Intravenous administration of 10μg/kg of medetomidine (Sedator®, Ati srl Ozzano dell’Emilia, Italy), and 2 mg/kg of propofol (Rapinovet® Intervet Italia, Peschiera Borromeo, Italy) were used to anaesthetize the animals. After aseptic disinfection and placement in lateral recumbency, 500 IU of sterilized bacterial collagenase type 1A (C-9891; Sigma, Milan, Italy) in 0.13 ml of          
saline solution was injected bilaterally (left and right hind limbs) into the DDFT under          
ultrasound guidance. A 23-gauge needle was used to perform the injection. The needle was introduced 15 cm distal to the calcaneal bone and was inserted into the full thickness          
of the DDFT using a lateral approach with the hock joint flexed at 90°. A suture was          
applied close to the injection site to mark the precise location for treatment and tendon harvesting. Antibiotic therapy using amoxicillin-clavulanic acid (Synulox® Pfizer Italia, Rome, Italy) at a dose of 12.5 mg/kg SC was started and continued for 5 consecutive days. Buprenorphine (Temgesic® RB Pharmaceuticals, Slough, UK) at a dose of 0.01 mg/kg IM BID for 5 days was used to provide analgesia. Seven days after collagenase injection, the 6 sheep were divided into two groups (group 1 and 2) and treated using MLS® Laser Therapy. The MLS® Laser Therapy was performed using an Mphi veterinary laser device          
(ASA, Arcugnano-VI, Italy), equipped with combined, synchronized and overlapping          
continuous and pulsed emissions from a single handpiece. Continuous emissions or continuous interrupted emissions were produced by an InGa(Al)As diode laser with the following parameters: wavelength of 808 nm, peak power of 1000 mW for continuous wave, mean power of 500 mW for continuous interrupted wave, spot area of 3.14 cm2, spot diameter of 2 cm. Pulsed emissions were produced by an InGaAs/GaAs diode with the following parameters: wavelength of 905 nm, peak power of 25 W, mean power of 54 mW at 1500 Hz, pulsed wave, spot area of 3.14 cm2, spot diameter of 2 cm. Following the protocol of Bjordal and Lopes-Martins (2013), the applications were performed daily for 5 days followed by 2 days of no treatment and then daily for 5 additional days. All treatments were conducted by the same individual. Scan modality was based on the size and shape of the treatment area (Fig. 1). The equipment was calibrated before the start of every session using the Powermeter Ophir Nova II Display S/N 573995. In group 1, the left hind DDFT received MLS® laser treatment at a dose of 5 J/cm². In group 2, the left hind DDFT received MLS® laser treatment at a dose of 2.5 J/cm². The right hind DDFT was considered an internal control (without treatment) for both groups.

Fig. 1 MLS® Laser Therapy

Sheep in both groups were monitored daily by evaluating the circumference, swelling and heat of the limb at the point of injury. Pain on limb palpation and degree of lameness were also assessed using a previously developed scoring system ranging from a grade of 0 to 4. Tendon thickness and echogenicity of the wound area were evaluated ultrasonographically. Ultrasound examinations, using a GE Medical System LOGIQ P5 machine and linear 6-10 MHz probe, were performed 7, 21 and 37 days after lesion creation. At day 37 after tendon lesion creation (30 days after the first laser treatment), the animals were sedated and anesthetized as previously described. The animals were subsequently euthanized using an intravenous injection into the auricular vein of 10 ml of a combination of drugs approved for euthanasia (Tanax®, Intervet, Milan, Italy). After euthanasia, the tendons were surgically removed from the calcaneus to the end of          
the metatarsal region and the DDFT of both hind limbs harvested for histological analysis.          
Tendons were removed 5 cm proximally to 5 cm distally of the lesion previously marked by a cutaneous surgical stitch. Harvested DDFTs were cut into 1 cm pieces and the proximal–distal orientations were marked. Tissue samples for histology were fixed in 4% parformaldehyde (PFA) and embedded in paraffin. Sections were cut into 5 μm          
slices, mounted on microscope slides and stained using Harris hematoxylin and eosin          
(HE). Sections were analyzed for cell density, vascularization and tissue organization using specific markers to evaluate fibroblast and tissue/matrix organisation characteristics. A quantitative analysis was performed to compare differences in cell number between          
groups. Differences in vascularization were also evaluate by looking at the ratios of blood          
vessel areas. Three segments were processed from each tendon, with 5 slides taken from          
each segment and three microscopic fields examined per slide, resulting in a total of 540          
fields evaluated. Analyses were performed using STATISTICA 9 (StaSoft) software, and data were assessed for normality using a Shapiro–Wilk test. Differences among the experimental groups within each sampling were evaluated using a Kruskal–Wallis Test. In all analyses, a p < 0.05 value was considered significant.

RESULTS

After the collagenase 1A injection, an inflammatory reaction with a mild localized thickening of the DDFT was detected in all subjects. Lameness, ranging from grade 3 to 4, and pain (detected by palpation) remained evident for the first 3-5 days. A localized increase in temperature around the point of injury was detected manually for the first 3 days. From day 7 of the MLS® Laser Therapy, an inflammatory reaction was observed in the treated limbs of group 1, with about 1 centimeter increase in wound circumference          
and an increase in the temperature of the metatarsus (Fig.2); whereas no worsening of lameness or pain was observed. This inflammatory response was not observed in the treated limbs of group 2.

Fig. 2 Inflammatory reaction observed in the treated limbs of group 1 during MLS® Laser Therapy in left limb: A after collagenase induction, B 7 days after MLS® Laser Therapy

A progressive reduction in limb circumference was observed by the end of treatment for          
both groups. Limb circumference returned to a value close to the starting size only in group 2. In addition, local temperature, lameness and pain decreased in all subjects.          
The treated left DDFT showed a more rapid reduction in local inflammation compared to the right DDFT in all sheep. Ultrasound examinations detected the presence of a lesion in the DDFT 7 days after lesion creation and during the entire follow-up period. Better collagen-fiber alignment and more uniform filling of the lesions were observed in the treated limbs compared to the control limbs. During the follow-up period, group 1’s treated limbs showed a marked thickening of the DDFT compared to the control limbs. Histological analysis revealed that there was disorganization of the extracellular matrix, increased vascularization and increased cell density in the DDFTs of the control limbs. In contrast, the sections obtained from tendons treated with MLS® Laser Therapy showed a more uniform and organized extracellular matrix, a lower number of cells and a better realignment of collagen fibers. The quantitative analysis revealed a significant decrease in fibroblasts in the treated legs compared to the control legs in group 1 (5 J/cm²). However, the ratio of the vessel areas did not differ between the control and treated tendons. In group 2 (2.5 J/cm²), the treated legs also had a decrease in fibroblast number compared to the control legs. A significant decrease in vascularity was observed in the treated tendons compared to the control tendons.

DISCUSSION

This is the first experimental study to evaluate the effect of LLLT on the tendon healing          
process in a sheep model. We evaluated the effects of two different doses of MLS® Laser Therapy in the acute phase of induced tendon lesions in order to determine a suitable therapeutic range for physiotherapy in human and veterinary medicine. The latest reviews on the effectiveness of LLLT in human medicine, highlighted the need to identify a specific treatment protocol for tendinopathy. Several authors have reported the efficacy of LLLT in increasing the calcaneal tendon’s mechanical properties as well as increasing the alignment of collagen fibers and angiogenesis, with doses between 3 and 5 J/cm². In the present animal model study, we initially decided to use 5 J/cm², which is the average value reported in the literature for treatment of acute tendinitis in human medicine. A 50% reduction in radiant fluence was elected for the second group (2.5 J/cm²) because the clinical symptoms and ultrasonographical data demostrated an increase of inflammatory response in group 1 during and after MLS® treatment. The tendon circumference in the first treatment group did not return to normal after a month of follow-up. In contrast, in the second group, the tendons’ external morphology returned to the physiological state by the end of the trial. In particular, the clinical manifestations of two sheep worsened slightly in the initial treatment phase, with an increase in circumference at the injection site, a local rise in temperature and a slow remission of symptoms. The aggravation of the inflammatory condition, observed during the applications of MLS® Laser Therapy in group 1, appears to indicate that a dose of 5 J/cm² was excessive for treatment of acute tendinitis with this type of laser emission. Instead, the dose of 2.5 J/cm² (group 2) appears to be suitable to produce an anti-inflammatory and biostimulating effect on tendon healing. Results from histological examinations indicated that both treatments induced a statistically significant decrease in cell number, although the values only returned to normal in the second group. Moreover, the MLS® dose of 2.5 J/cm² (group 2) caused a significant decrease in blood vessel area and better improvement of collagen fiber organization in deep digital flexor tendon compared to group 1 and the control group.

Laser therapy in the management of neuropathic pain: preliminary experience on 43 patients

ABSTRACT

The aim of this case series is to report on the effect of MiS, a new laser therapy device which uses two synchronized emissions with 905 nm and 808 nm wavelengths, pulsed and continuous, respectively, with high peak power, in the management of neuropathic pain. A total of 43 patients (mean age: 53 years, from 23 to 85 years) presenting neuropathic pain associated to different anatomical areas, such as cervical zone, spine, foot/ankle, hand/wrist, shoulder, elbow, hip and knee were treated with laser therapy by MiS. Pain (VAS score) and functionality (therapist evaluation) were evaluated at the end of treatment. The severity of pain decreased over time and was lower at the end of treatment. MiS laser therapy demonstrated to be safe and effective in patients affected by neuropathic pain and represents a valuable tool for the management of these patients.

INTRODUCTION

Pain is described as a complex, subjective experience, involving the transduction of harmful environmental stimuli together with the cognitive and emotional processing by the brain. Neuropathic pain is a form of chronic pain resulting from any kind of damage          
to the central or peripheral nervous system without nociception. Neuropathic pain is a painful condition that may comprise different types of pathologies: such as postherpetic neuralgia, painful diabetic polyneuropathy, post-surgery neuropathic pain, multiple sclerosis, spinal cord injury, stroke and cancer. Patients with neuropathic pain often have spontaneous pain, allodynia, and hyperalgesia. The estimation of the incidence and prevalence of neuropathic pain is difficult because of the lack of simple diagnostic criteria for large epidemiological surveys in the general population. A portion of these patients is          
specifically affected by peripheral neuropathy and seek medical treatment to alleviate the          
pain and improve the function associated to conditions that are localised at several body levels: spine, being lumbar-sciatic pain a very common problem, cervical area, elbow, wrist and hand, knee, ankle and foot, hip. For instance, sciatica is a form of radicular pain, and is described as a disease of the peripheral nervous system. It is a very common condition and the main cause of absences from work, with great economic impact on society. The trend in terms of life expectations getting longer suggests that more and more people will be experiencing this type of pain in their life. Chronic neuropathic pain is characterised by complexity of neuropathic symptoms, poor outcomes and difficult treatment decisions. On the biological side, nerve inflammation plays an important role in the development and progression of neuropathic pain. For instance, recent studies have indicated that hypoxia-inducible factor 1a (HIF-1a) is crucial in inflammation, while other previous studies have identified the relationship between proinflammatory cytokines, and neuropathic pain development. Therapeutic options are in many cases          
related to conservative treatment, consisting of modifying the pain-precipitating activity,          
biomechanical correction with physiotherapy or the use of antidepressants, analgesics and/or steroids. Specifically, painkillers are the main drugs to treat pain, although these          
have shown only 30% effectiveness in patients with neuropathic pain. Unfortunately,          
these drugs have undesirable side effects and, currently, there is a worldwide trend in          
opioid reduction for acute and chronic pain management. Physical methods are an          
interesting alternative to the pharmacological treatment because of the absence of side effects. Recent studies have reported the use of laser therapy in patients with peripheral          
somatosensory neuropathy and neuropathic pain. Specifically, clinical studies on the effects of laser therapy on injured nerves reported an increase in nerve function.          
Moreover, laser therapy demonstrated to be effective for promoting axonal growth in          
injured nerves in animal models. Positive effects of MLS® therapy in promoting repair processes of peripheral nerves, acting on the recovery of the lesioned function and the muscle mass and inducing faster myelinization of the regenerated nerve fibers, have been reported by Gigo-Benato et al. In vitro studies were carried out to characterize the effect of MLS® pulse and have shown that MLS® treatment induces an increase of NLRP 10, a protein with anti-inflammatory action. NLPR 10 inhibits the activity of caspase 1 and          
PYCARD protein complex, which promote the maturation of the inflammatory cytokines interleukin-1β (IL-1β) and interleukin 18 (IL-18). Therefore, ultimately, NLPR 10 inhibits the production of pro-inflammatory interleukins IL-1β and IL-18, reducing inflammation. The decrease in inflammation leads to a normalization of vascular function and thus to a decrease of the edema. Obviously, the decrease in inflammation and edema results in a decrease of pain symptoms, that are frequently present in patients. MiS is a medical device for laser therapy which combines the synchronized pulse of traditional MLS® therapy with the high peak power typical of high intensity laser therapy. These specific characteristics allow MiS to act on pain and its causes, leading to significant and persistent improvement of pain symptomatology and concomitant recovery of functionality. This case series collects the case reports of two physiotherapy centers that have treated 43 patients for peripheral neuropathy using MiS, a new laser therapy, reporting changes in pain and in function, and safety associated to the use of the device.

MATERIALS AND METHODS

This is a case series collecting patients from routine practice in two Italian physiotherapy centers: Fisiolab (Vicenza- Italy) and Rehability Center (Padova- Italy). Forty-three patients of both sexes affected by several conditions related to peripheral neuropathies have been included in the series. During the treatment, patients and therapists wore safety glasses to prevent eye damage. Diagnosis and instrumental evaluation (i.e. X-Ray, Ultrasounds, CT, MRI), when available, were recorded. Additionally, patients were evaluated by the specialist performing the treatment before therapy start. The patients that were included in this series received MiS (ASA Srl, Italy) treatment focused on the peripheral neuropathy as stand-alone treatment or as a part of their treatment programme. MiS is a class IV NIR laser with two synchronised sources, one consists in 6 pulsed 905 nm laser diodes, the second is a continuous/frequency-modulate 808 nm laser diode. Maximum average power is 6W± 20%, while maximum peak power is 1kW. MiS has 2 interchangeable          
handpieces (with diameters of 2 and 5 cm). The total number of sessions and the time of          
each session were adjusted based on each patient response to the treatment and ranged from 2 to 13 sessions, with a duration ranging from 6 to 20 minutes (according to body          
location). The used frequency was 30 Hz for all the body areas, while intensity was adapted to the anatomical site as follows: 80% for shoulder and hip, 70% for spine, 60% for elbow, wrist/hand, knee, ankle/foot and 50% for head and  cervical area. Dosage was adjusted based on size of the area to be treated, patient and pathology characteristics and condition stage. Trigger points, when present, were treated in all patients with the following parameters: Frequency: 10 Hz, time: 23 s, Intensity: 25%. In the trigger point phase, the hand piece was perpendicular to the treated points. Pain evaluation was performed before and after each laser session using a Visual Analogue Scale (VAS) scale. It is a scale comprising 10 grades, with 10 representing ‘unbearable pain’ and 0 representing ‘no pain’. It is a pain scale commonly used in the medical field, and it was shown to be a reliable and valid measure of pain [29,30]. Safety has been specifically assessed and the therapists recorded any side effect and/or rebound effect happened during the treatment. Functional evaluation and global assessment were reported by the specialist for each patient.

RESULTS

Demographic and clinical characteristics of all patients at baseline were recorded. Patients demographic characteristics are reported in Table I. For 34 patients, peripheral neuropathy treatment was the focus of the overall therapy cycle, while 9 patients received other MiS treatments beside the peripheral neuropathy protocol (i.e. specific for edema, muscle pain and contracture) in their therapeutic path. VAS pre and post treatment, along with change in VAS expressed as a percentage of the initial value are reported in Table II, divided by treated anatomic areas. As expected when dealing with neuropathic pain, average pain at baseline was moderate to severe (mean was >7 for all groups). Overall, VAS pre-treatment mean was 7,8 and VAS post-treatment mean was 1,6, corresponding to a decrease in pain of 79,5%. Pain completely disappeared in patients          
treated for elbow, hip and shoulder problems. Considering all the groups, improvement was at least 60% respect to baseline, meaning that initial pain score was reduced of above 60% at the end of the treatment cycle. It has to be noted that some patients were          
not seeking medical treatment for pain, but for symptoms related to nerve irritation, as for example paraesthesia, dysesthesia, hyporeflexia, etc. In these cases, the treatment with MiS gave excellent results and the therapists have reported strong improvements in sensitivity and dysesthesia reduction. In general, looking at VAS value trend, it was possible to appreciate pain decrease during time, rather than intra-session. Some patients, reported fluctuation in VAS score between the sessions during the treatment cycle. This could be related to a prompt increase of physically demanding activities by the patients after perceiving benefit from the initial laser therapy sessions.          
In general, laser treatment provided a positive impact on pain and function on the majority of the patients, only for 2 of them no significant improvement after the laser therapy cycle was reported.

Table I - Demographics

Table II - VAS pre and post treatment divided by anatomical distribution of the treated areas

DISCUSSION

Neuropathic pain can substantially impair quality of life as it often associates with other problems, such as loss of function, anxiety, depression, disturbed sleep and impaired cognition and physical therapies have been suggested as potential alternative for treatment. The results of this case series show that patients treated with MiS for peripheral neuropathy had an improvement in terms of pain symptoms measured with VAS, even when starting from high VAS values, typical of neuropathic pain. The improvement was gradual and was normally seen after some sessions rather than at the end of each laser treatment, suggesting that MiS is able to induce biological responses whose effects depend on the evolution of the underlying biological processes over time, which could be interesting to address in future basic and clinical studies. MiS inherits the wavelengths (808 nm and 905 nm), the characteristic synchronized modulation of continuous and pulsed emissions, and the scientific evidence of the action mechanisms from MLS® laser therapy. Experimental and clinical research demonstrated that MLS®          
pulse exerts a positive effect in the treatment of many musculoskeletal diseases. This effect is related to anti-inflammatory, anti-edema an tissue healing actions. Besides relying on MLS® pulse features, MiS is characterised by a very high peak power in the order of kW. The modulation in short pulses allows to control the peak power avoiding damaging thermal effects. In the literature, Kobiela Ketz et al suggested that the reduction of hypersensitivity mediated by laser treatment in a model of neuropathic pain induced by spinal nerve injury could be exerted by modulating macrophages and microglia components. Preliminary in vivo investigation related to laser therapy use in neuropathic pain relief highlighted therapeutic effects that might be used for clinical application in neuropathic cases. In the specific field of neuropathic pain, preclinical experiments carried out on animal models demonstrated that the treatment with MiS promotes the recovery of the myelin sheat in nerve fibres that have been damaged in the lesion area, as confirmed by histological and immunohistochemical evaluations. These data support the concept that laser therapy by MiS could be a suitable tool in the management of neuropathic pain. No rebound effect has been observed, thus confirming the safety of the device in this cases series, which included individuals with different characteristics, pathologies and stage of conditions.          
Patients gave a positive feedback on the treatment feeling, especially when the 5 cm          
handpiece was used on large areas, as its shape allowed a sort of massage over the patient’s skin, making the treatment well accepted and contributing to build compliance to session attendance.

CONCLUSION

This case series reports on the use of MiS in the management of 43 cases of neuropathic          
pain localised in different anatomical areas. Based on the results reported, the new MiS          
laser therapy demonstrated to be safe and effective in patients affected by neuropathic pain. Therefore, laser therapy by Mis may represent a valuable and well-accepted tool for          
the management of peripheral neuropathies

Photobiomodulation therapy (PBMT) on acute pain and inflammation in patients who underwent total hip arthroplasty—a randomized, triple-blind, placebo-controlled clinical trial

Abstract

When conservative treatments fail, hip osteoarthritis (OA), a chronic degenerative d          
isease characterized by cartilage wear, progressive joint deformity, and loss of function, can result in the need for a total hip arthroplasty (THA). Surgical procedures induced tissue trauma and incite an immune response. Photobiomodulation therapy (PBMt) using low-level laser therapy (LLLT) and/or light-emitting diode therapy (LEDT) has proven effective in tissue repair by modulating the inflammatory process and promoting pain relief. Therefore, the aim of this study was to analyze the immediate effect of PBMt on          
inflammation and pain of patients undergoing total hip arthroplasty. The study consisted of 18 post-surgical hip arthroplasty patients divided into two groups (n = 9 each) placebo and active PBMt who received one of the treatments in a period from 8 to 12 h following THA surgery. PBMt (active or placebo) was applied using a device consisting of nine diodes (one super-pulsed laser of 905 nm, four infrared LEDs of 875 nm, and four          
red LEDs 640 nm, 40.3 J per point) applied to 5 points along the incision. Visual analog scale (VAS) and blood samples for analysis of the levels of the cytokines TNF-α, IL-6, and IL-8 were recorded before and after PBMt application. The values for the visual analog scale as well as those in the analysis of TNF-α and IL-8 serum levels decreased in the active PBMt group compared to placebo-control group (p < 0.05). No decrease was observed for IL-6 levels. We conclude that PBMt is effective in decreasing pain intensity and post-surgery inflammation in patients receiving total hip arthroplasty.

Introduction

Osteoarthritis (OA) is a degenerative joint disease characterized by the wear of articular cartilage, marginal osteophyte formation, ligament, synovial and meniscal changes, and damages of the subchondral bone. During early stages of the disease, the degenerative process is slow but progresses over time. In advanced stages of OA, abnormal remodeling of cartilage and formation of osteophytes irreversibly destroy the affected joint. Activities of daily living (ADLs) involving load bearing at the hip joint become compromised due to pain, and prognosis is often poor directly interfering with quality          
of life of patients. Conservative treatment is often no longer effective in later stage of OA, and total hip arthroplasty (THA) is an alternative often used in these cases to relieve symptoms.

Although known as a surgical extreme procedure, post-surgical quality of life (QoL) improves and many patients often return to work. Even knowing that THA surgery          
can be successful, there are issues that need to be addressed related to postoperative pain management. Inadequate postoperative pain management is a worldwide problem, and the need to improve its management is well documented. However, the tissue trauma leads to an inflammatory reaction and immune response with release of some mediators such as cytokines; therefore, the surgical procedure can cause significant postoperative pain. Postoperative pain is associated with increased hospital length of stay, delayed ambulation, and long-term functional impairment. A more focused effort is needed to develop postoperative pain management, particularly during the first few days after surgery. 

Postoperative pain management following THA is a major concern for both patients and their caregivers particularly during the first few days after surgery. The rise of inflamma-          
tion dominates the initial phase of repair and a postoperative pain management will likely include the use of NSAIDs for analgesia. Published studies show that most NSAIDs have an adverse effect on osteoblast growth by cell cycle arrest and apoptosis induction. Also, the potential risk of heart attacks and strokes has been known for years, and it applies to          
even short-term use of the medication for people with or without heart disease. Photobiomodulation therapy (PBMt), using low-level laser therapy (LLLT) and lightemitting diode therapy (LEDT), has been shown to be an effective in pain reduction, modulation of inflammation, and promoting repair of tissue. Additional studies have demonstrated          
positive effects of PBMt in cell proliferation, microcirculation, vascular neoformation, collagen production from fibroblasts, and bone repair. PBMt is virtually without side effects and has minimal contraindications for use. Comparisons with non-steroidal anti-inflammatory drugs (NSAIDs) in animal studies found optimal doses of PBMt and NSAIDs to be equally effective in treatment of different musculoskeletal disorders. PBMt offers a better risk-benefit profile compared to NSAIDs and is a safe, non-pharmacological adjunct therapy in the management of acute pain. 

However, there is a lack of information regarding the use of non-pharmacological complementary therapies that offer less risk of side effects, since the use of non-steroidal anti-inflammatory drugs (NSAIDs) are commonly associated with these effects. In addition, although NSAIDs are widely prescribed, they have been shown to have limited efficacy in pain relief. In this perspective, the aim of this study was to evaluate the effect of PBMt that combines multiple light sources, power outputs, and wavelengths on acute pain and serum levels of inflammatory markers in patients following postoperative hip arthroplasty.

Material and methods

Study design and ethics statement

A randomized, triple-blinded (patients, therapists, and outcome assessors), placebo-controlled trial was performed. The present study was submitted and approved by the research ethics committee (process number 066490). All patients voluntarily agreed to participate and signed the informed consent statement. The study was conducted at, between July and August of 2015. 

Characterization of sample

The sample size calculation was performed based on a pilot study performed by our research group. For sample size calculation, we considered the β value of 20% and α of 5%. In pilot study used as reference for sample size calculation, it was observed that PBMt led to decreased pain (our primary outcome) using visual analog scale (VAS) to 53.90 mm (± 11.50) immediately after PBMt irradiation compared to baseline (68.80 ± 13.30). Thus, the calculation resulted in a sample of 9 volunteers per group, 18 volunteers          
in total.

Eighteen post-surgical THA patients participated in the study. Each patient underwent the same surgical procedure and technique performed by the same surgeon. During surgery, the head and part of the neck of the femur were resected; the acetabulum was prepared to receive high-density polyethylene that fits into a metal hemi-sphere to replace the femoral head which was then connected to a rod inserted in the medullary canal of the femur. The fixing of the femoral head may or may not be cemented. The surgeon used an acrylic plastic polymethylmethacrylate, and the rod was fixed under pressure. The consolidated standard of reporting trials (CONSORT) flowchart summarizing experimental procedures and subjects are shown in Fig.1.

Inclusion criteria and exclusion criteria

Inclusion criteria:

• Patients that were in immediate postoperative period from 8 to 12 h after total hip arthroplasty, due to diagnosis of OA. The diagnosis of OA was conducted by an orthopedic surgeon, based on the previous history of OA in these patients. In addition, the surgeon evaluated radiological images in the anteroposterior profile of the hip of these patients. The surgeon used Dejour’s classification to describe the severity of hip OA;
• Both genders.

Exclusion criteria:

• Any hip surgery that was not due to OA;
• Any hip surgery other than total arthroplasty;
• Neurological and cognitive problems, as dementia, mental retardation, communicative deficit, or any other condition that would make it impossible to understand the study procedures:
• Postoperative complications such as deep vein thrombosis and infections.

Randomization

Prior to initiation of treatment, the 18 patients were randomized into two experimental groups (nine patients per group). Randomization was carried out by a simple drawing of lots (A or B) performed by a participating researcher not involved with the recruitment or evaluation of patients. This same researcher was responsible for programming the PBMt device according to the result of the randomization and was instructed to not disclose          
the identity of the devices to anyone involved in the study. The PBMt device used displayed the same setting and emitted the same sounds regardless of the programmed dose and mode (active PBMt or placebo PBMt). Patient and therapist were blinded throughout the treatment. Randomization labels were created using a randomization table at a central office. Concealed allocation was achieved through the use of sequentially numbered, sealed, and opaque envelopes.

Interventions

A single application of PBMt (active or placebo) was performed within postoperative period from 8 to 12 h, immediately after the baseline evaluation. The active and placebo PBMt were performed using the same device and the irradiated sites were the same in both therapies. To ensure blinding for patients and therapists, the device emitted the same sounds and the same information on the display regardless of the programmed mode (active or placebo). The device in the placebo mode and in the active mode had the brightness of the red light source, but in the placebo mode, the emitted light had only 0.5 mW of power output for each red diode, and both super-pulsed laser, infrared LEDs, and magnetic field were turned off. This amount of power used in placebo mode is negligible but ensures the brightness of the red light without therapeutic effects. In this way, it is impossible to discern between the two PBMt modes (placebo and active). The device was previously coded as active or placebo modes, and only one researcher not involved in the randomization, treatment, and evaluation was aware of these codes. The intervention specifications were as follows:

1. PBMt group: PBMt was applied using a cordless, portable PainAway/PainCure™ device (manufactured by Multi Radiance Medical, Solon-OH, USA) at five sites/points over the full extent of the surgical scar, with a distance of 2 cm between sites (Fig. 2). The cluster style emitter contains 9 diodes comprising 1 super-pulsed laser diode (905 nm, 2.7 mW average power, 8.5 W peak power, and 0.81 J dose for each diode), 4 red LEDs (640 nm, 15 mW average power, and 4.5 J dose for each diode), and 4 infrared LEDs (875 nm, 17.5 mW average power, and 5.25 J dose for each diode). The total irradiation time per site was 300 s and the total energy delivered was 39.8 J. The choice of these parameters was based on a previous study using the same technology. The optical power of the device was checked before irradiation (in each patient) by a researcher that was not involved in data collection and analysis. For such, it was employed a Thorlabs® thermal power meter (Model S322C,          
   Thorlabs®, Newton-NJ, USA). The full description of PBMt parameters is provided in Table 1.
2. Placebo-control group: The placebo PBMt was delivered using the same device that active PBMt but without any emission of therapeutic dose (placebo mode). Patients received a total negligible dose of 0.6 J per point/site in placebo mode. Furthermore, the sources of infrared light and superpulsed are off and the electromagnetic field is          
   inactive.          
   

Outcomes

The outcomes were pain intensity and levels of cytokines (interleukin [IL]-6, IL-8, and tumor necrosis factor alpha [TNF-α]) obtained at baseline (pre-treatment) and immediately (within 10 min) after irradiation with PBMt (post-treatment). These outcomes were collected by an assessor who was not aware of patient allocation to their treatment  groups. 

The primary outcome of the study was pain intensity measured by visual analog scale (VAS). Visual analog scale (VAS) evaluates pain intensity levels perceived by the patient, with assistance of an assessor, on a scale ranging from 0 to 100 mm, with 0 being “no pain” and 100 being “the worst possible pain”.

The secondary outcome of the study was the cytokine levels measured by enzyme-linked immunosorbent assay (ELISA) method. For such, blood samples were collected by a qualified nurse blinded to group allocation and were obtained from the antecubital vein. One hour after collection, each sample was centrifuged at 3000 rpm for 20 min. Pipettes were used to transfer the serum to Eppendorf® tubes, which were stored at − 80 °C until analysis. The levels of IL-6, IL-8, and TNF-α in the blood samples were determined by enzyme-linked immunosorbent assays, using a commercial kit and following the manufacturer’s instructions (BD Biosciences®, USA). Spectrophotometric readings were performed in a SpectraMax® Plus 384 Absorbance Plate Reader (Sunnyvale, CA, USA) with 450-nm wavelength and correction to 570 nm. The results were expressed in pg/ml.

Statistical analysis

The statistical analysis was conducted following the principles of intention-to-treat analysis. Initially, the data was tabulated and evaluated for normality using the Shapiro-Wilk test. As a normal distribution was verified, unpaired, two-tailed, Student’s t test was used to detect difference among groups. The significance level was set at p < 0.05. The data in the graphs are presented as mean and standard error of the mean (±SEM). The researcher that completed the statistical analysis was blinded to randomization and allocation of patients in experimental groups.

Results

Eighteen acute postoperative arthroplasty patients were recruited for this study and completed all procedures with no dropouts. The average age in PBMt group was 69 (± 5.6), height of 165.00 cm (± 11.00), and body weight of 70 (± 9.56), 55.5% were male and 44.4% female. In the placebo-control group, average age was 67 (± 6.4), height of       
169.00 cm (± 5.00), and body weight of 79 kg (± 11.00), 33.3% were male and 66.6% female. There was no difference between experimental groups for demographics’ characteristics (p > 0.05). 

Figure 3 demonstrates that PBMt significantly decreased (p < 0.05) pain compared to placebo-control. At baseline (before treatment), placebo-control group showed 56.70 mm (± 10.00) at VAS scale, while PBMt group showed 65.60 (± 12.40), without difference between groups. Immediately following treatment, PBMt group decreases pain intensity when compared to placebo-control group (p < 0,05), as shown in Fig. 3. 

Fig. 3 Change in pain assessed using 100 mm VAS. Values are mean and error bars are SEM. Asterisk indicates significant difference between placebo/control and PBMt groups (p < 0.05)

As shown in Fig. 4, the levels of IL-6 showed no statistically significant difference between the placebo-control (pretreatment 361.67 ± 29.89 pg/ml and post-treatment 352.88 ± 18.32 pg/ml) and PBMt groups (pre-treatment 350.30 ± 33.38 pg/ml and post-treatment 338.19 ± 28.60 pg/ml) at none time points tested.

The levels of IL-8 in placebo-control and PBMt groups were 191.29 pg/ml (± 15.52) and 190.28 pg/ml (± 15.99), respectively, showing homogeneity between groups at baseline evaluation. At post-treatment evaluation, there was a statistically significant decrease in IL-8 in favor of PBMt group compared to placebo-control group (p < 0,05), as showed in Fig. 5. 

The levels of TNF-α in placebo-control and PBMt groups were 467.73 pg/ml (± 24.47) and 469.88 pg/ml (± 26.50), respectively, showing again homogeneity between groups at baseline evaluation. At post-treatment evaluation, there was a statistically significant decrease in TNF-α in favor of PBMt group compared to placebo-control group (p < 0,05), as shown in Fig. 6.

Discussion

The results of this study support the hypothesis that photobiomodulation therapy applied to the surgical incision in the postoperative period reduces acute pain and inflamma-       
tion in patients after hip arthroplasty. Previous studies using laser therapy and the visual analog scale as a means of evaluation also reported less pain in the post-surgical period, corroborating the results of this study. 

Photobiomodulation therapy has been identified as an effective, safe, and non-invasive modality able to modulate the inflammatory process. The current study adds to this collective body of evidence. It is known that surgical injuries in the hip joint induce immune response mediated by inflammatory cytokines.

Fig. 4 Change in IL-6 levels measured by ELISA immunoenzymatic assay. Values are mean and error bars are SEM 

There was modulation of the inflammatory process in the arthroplasty postoperative period in the group treated with the active phototherapy. These results are in accordance with previous studies in the literature in which authors demonstrated decreased in pain scores and inflammatory markers in patients treated with laser therapy over the surgical incision in tibial fractures postoperative. Decrease in pain and reduced administration of analgesic drugs was also observed in patients treated with laser therapy in distal radius fracture in the immediate postoperative period. 

In order to observe the action of PBMt on serum levels of proinflammatory citokynes IL-6, IL-8, and TNF-α, mediators released during acute inflammation, we performed an analysis using the immunoenzymatic test. In this study, we chose not to perform blood tests before the surgery, since there is a prior consensus in the scientific literature regarding the increase of cytokines and their kinetic behavior, which occur after post-surgical hip arthroplasty, highlighting the acute inflammatory character. 

Our results show reduced IL-6 levels in the group treated with effective PBMt, although this reduction was not statistically significant. The results are consistent with previous studies that investigated the effects of PBMt in decreased IL-6 release. This reduction in IL-6 release may not be significant because of the short time interval chosen between the end of surgery and the application (8 to 12 h after surgery). Several authors report that an increase in peak concentrations occurs on the first day and remains until the third day post-surgery. 

Fig. 5 Change in IL-8 levels measured by ELISA immunoenzymatic assay. Values are mean and error bars are SEM. Asterisk indicates significant difference between placebo-control and PBMt groups (p < 0.05)

Fig. 6 Change in TNF-α levels measured by ELISA immunoenzymatic assay. Values are mean and error bars are SEM. Asterisk indicates significant difference between placebo-control and PBMt groups (p < 0.05)

Regarding the release of IL-8, our results show a statistically significant decrease in serum levels of this cytokine in the group treated with effective PBMt. This allows us to infer that PBMt attenuates the levels of this cytokine. A previous study showed increased IL-8 at the end of surgery with peaks in 6 h and decrease on the first day, indicating its chemotactic character and short duration. The findings of this study also indicate a statistically significant decrease in serum levels of proinflammatory cytokine TNF-α. Since in the early stages of inflammation, an increased presence of TNF-α stimulates IL-6 and IL-8 synthesis attributing the acute inflammatory process in surgical trauma, modulation of this cytokine minimizes this process. Thus, once the action of these mediators is controlled, the patient has a less aggressive inflammatory process due to the surgical procedure. Acute inflammation can lead to functional impairment to the patient. Therefore, modulation, not elimination, of the inflammatory process and its subsequent signs and symptoms is paramount to the success of the tissue repair and quality. 

Our results provide us with evidence that a single application of PBMt added to postoperative treatment attenuates inflammation and significantly reduces acute inflammatory pain. These results point to a possible decrease in the administration of analgesic drugs, which besides having high cost for health systems and have adverse or side effects. Improving pain control may decrease length of stay, decrease costs, enhance functional recovery, and improve long-term functional outcomes. 

The results also provide a better understanding of the role of PBMt with the parameters used on the modulation of inflammatory mediators, as well as in the decrease of pain, being of great value, since it may guide future therapeutic interventions. However, it is important to highlight that the parameters used in the present study were chosen according to previous study and according to instructions provided by the manufacturer. Further studies are important to substantiate the findings described in this study and to investigate if the parameters used are the most adequate for pain control in patients submitted to THA. 

This study has some limitations such as the lack of assessment of cytokines prior to surgery in order to have more data to ensure the homogeneity of groups, which happened due to our full access to patients only after the surgery, making impossible to analyze the inflammatory markers before the surgery. However, it is important to highlight that the analysis of these mediators after the surgery (before treatments) showed homogeneity between the groups. Finally, it is important to report that magnetic therapy may have an effect of reducing pain, and this aspect warrants further investigation.

Conclusion

In this study, PBMt (phototherapy) with the parameters used as the immediate postoperative treatment of hip arthroplasty provided pain decrease and decreased serum levels of proinflammatory cytokines (IL-6, IL-8, and TNF-α). PBMt is a safe       
treatment and without reported side effects, and can be suggested as a possible therapeutic modality in the immediate hip arthroplasty postoperative period.

Funding This study was supported by research grants 2010/52404-0 from São Paulo Research Foundation-FAPESP (Professor Ernesto Cesar Pinto Leal-Junior), 310281/2017-2 from Brazilian Council of Science and Technology Development-CNPq (Professor Ernesto Cesar Pinto Leal-Junior). FAPESP and CNPq had no role in the planning of this study; they had no influence on study design, data collection and analysis, decision to publish,       
or preparation of the article.

Compliance with ethical standards

The present study was submitted and approved by the research ethics committee (process number 066490). All patients voluntarily agreed to participate and signed the informed consent statement.

Competing interests: Professor Ernesto Cesar Pinto Leal-Junior receives research support from Multi Radiance Medical (Solon, OH, USA), a phototherapy/photobiomodulation device manufacturer. Douglas Scott Johnson is an employee and a shareholder of Multi Radiance Medical (Solon-OH, USA). The remaining authors declare that they have no conflict of interests.

Ethical aspects: All experimental procedures were submitted and approved by the Research Ethics Committee of Nove de Julho University (process number 066490). All patients signed an informed consent form prior to enrollment.

The Effect of Low-Level Laser on Postoperative Pain After Tibial Fracture Surgery: A Double-Blind Controlled Randomized Clinical Trial

Sholeh Nesioonpour ; Soheila Mokmeli ; Salman Vojdani ; Ahmadreza Mohtadi ; Reza Akhondzadeh ; Kaveh Behaeen ; Shahnam Moosavi ; Sarah Hojjati

1. Department of Anesthesiology, Pain Research Center, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran
2. Canadian Optic and Laser Center, COL Center, Victoria, Canada
3. Department of Orthopedic, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran
4. Department of Physical Education and Sport Science, Bu-Ali Sina University, Hamedan, Iran

*Corresponding author: Salman Vojdani, Department of Anesthesiology, Pain Research Center, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran. Tel: +98-6112220168, Fax: +98-6112220168, E-mail: Vojdani.s@ajums.ac.ir

Received: January 14, 2014; Revised: February 15, 2014; Accepted: February 24, 2014

1. Background

One of the undesirable complications of surgery is postoperative pain  that  may  result  in  serious  morbidi- ties such as agitation, hypertension, mood changing, tachycardia (1, 2) and delay in wound healing, which can be more dangerous in patients with the underlying  dia- betes mellitus,  hypertension,  or  coronary  heart  diseases as it may lead to fatal complications such as myocardial infarction (3). There is a high variability among patients in tolerance to pain and analgesic requirement (4, 5). The studies show that about 80% of  patients experience a mild to severe pain after surgery (6). There is inadequate post- operative analgesia in the half of all surgeries, can lead to chronic postoperative pain (7). Several methods are avail- able to control and reduce postoperative pain such as ad- ministering opioids or nonsteroidal anti-inflammatory drugs (NSAIDs) and  patient-controlled  analgesia  (PCA). It is established that the use of systemic opioids alone is not sufficient to relieve postoperative pain. 

In most cases inadequate dosage is prescribed to reduce the side effects of these drugs like respiratory depression and therefore, the medication cannot control pain completely (8, 9). An- algesic nephropathy, skin reactions, and peptic ulcers are common side effects of nonsteroidal anti-inflammatory drugs (10). Recent advances present new techniques for prevention and reduction of postoperative pain. One of the most important technologies of this century is the use of low-level laser (LLL) at the site of surgery (11).

Low-level laser therapy (LLLT) was pioneered at Rus- sia and Hungry and then at Europe in early 1960s. It is a branch of  laser treatments that has been indicated for pain killing and wound healing. LLLT uses irradiation with laser light of low intensity and its effects are not due to producing heat. These nonthermal effects are thought to be mediated by a photochemical reaction that alters cell membrane permeability, leading to increased mRNA synthesis and cell proliferation. FDA has started differ-ent investigations on LLLT for 15 years and has approved the use of LLLT for pain relief in carpal tunnel syndrome since 2002 (11, 12). It is also used to treat damages in sport injuries and musculoskeletal disorders. In addition, it is applicable to reduce neck pain and the size of keloid scarring after surgery (13-17). 

Many studies found that LLL stimulates respiratory cycle in mitochondria and increases adenosine triphosphate molecules (14) that reduce swelling and pain (16). In another study, applying LLL directly over painful points was useful in treatment of stress fracture of tibia (18). The LLL is effective in relieving pain of knee osteoarthritis, breast augmentation surgery, and cryosurgical treatment of oral leukoplakia (15, 17).

2. Objectives

Pain following orthopedic surgeries are considered severe pain (19, 20); hence, the aim of this study was to investigate the effect of LLLT on acute pain after tibial fracture surgery.

3. Patients and Methods

This double-blind, controlled, randomized clinical trial was conducted in 2012-2013 in Imam Khomeini Hospital, Ahvaz, Iran. The study was approved by the Ethical Committee of Jundishapur University of Medical Sciences (ETH-654) and all subjects signed an informed consent. Sample size was calculated at 27 in each arm of the study by setting the power at 80% and the values for Z1-α/2, Z 1-β, P1, and P2 at 1.96, 0.84, 0.68, and 0.32, respectively, based on a previous observational study (21). A total of 54 patients aged between 18 and 60 years who were candidate for tibial fracture surgery in American Society of Anesthesiologists (ASA) classes I and II were allocated randomly to two equal groups of control and laser. All subjects were matched based on their age, weight, and height. 

Patients who were pregnant, those with malignant tumors, benign tumors with malignant potential, hypersensitivity to light, e.g. systemic lupus erythematosus, coagulopathies, high intracranial pressure, histo- ry of chronic pain, those on long-term opioids or other painkillers during the preceding month, or those who did not agree to undergo spinal anesthesia were excluded from the study.       
Monitoring equipment including electrocardiograph, pulse oximeter and sphygmomanometer were employed for all patients; they received 10-mL/kg intravenous lac- tated Ringers’ solution and then spinal anesthesia was induced by the anesthesiologist.

Spinal anesthesia was induced by intrathecal adminis- tration of 10-mg 0.5% bupivacaine (Astrazeneca Co., Ger- many) with 25-gauge needle in the sitting position and with the midline technique.

If the systolic blood pressure dropped by 20% or more, 10-mg ephedrine would be injected intravenously. Upon achieving successful anesthesia, pull-tight elasticated tourniquet was clamped and operation was started. The surgical procedures were similar in both groups and in- cluded open reamed interlocking intramedullary nail- ing, which is the preferred approach for treatment of tibial shaft fractures (22).       
After the surgery and before the final bandage in sur- gery room, patients in laser group were treated with a combination of two lasers (Canadian Optic and Laser Center, Canada): (1) GaALAs hand held probe (PLP-IR) with wavelength of 808 nm and 300-mW output power in continuous mode (dose, 6 J/cm2; area, 1 cm2; and time, 20 s/point); and (2) GaALInP hand held probe (PLP-R) with wavelength of 650 nm and 100-mW output pow- er in continuous mode, (dose, 3 J/cm2; area, 1 cm2; and time, 30 s/point).

Each tibial fracture was radiated from four sides in con- tact technique with the combination of IR and R laser in dose of 9 J/cm2 (medial, lateral, anterior, and posterior sides of fracture region and popliteal fossa). For radiation on popliteal fossa, the legs were elevated by 60° angels. In addition, trigger points on muscles and surgical wounds (6-8 points) were radiated with 4 J/cm2 by the same combination of IR and R lasers (ten seconds of each laser; 3 J/point IR plus 1 J/point R laser).       
For placebo laser treatment in control group, all those sites were treated with the lasers in turn-off mode with the same duration.       
One of authors who was blind to the group allocation and did not participate in the laser therapy procedures, filled out the questionnaires. The amount of total analgesic and pain intensity at second, fourth, eighth, 12th, and 24th hours after the surgery were investigated in both groups. Pain intensity was quantified by visual analogue scale (VAS) in which zero and ten represented analgesia and worst possible perception of pain, respectively. If VAS was three or more, 0.3 mg/kg of pethidine was injected intravenously.

3.1. Statistical Analysis

The data are presented as mean ± standard deviation (SD). We performed Shapiro-Wilk test and Levene's test for normality of the data distribution and equality of variances. Independent samples t test, repeated measure test, and Bonferroni post hoc test were used to analyze the data. P Value of less than 0.05 was considered as sta- tistically significant. All the statistical analyses were done by SPSS software version 16 (SPSS Inc, Chicago, IL, USA).

4. Results

Demographic characteristics of participants are pre- sented in Table 1. Two groups were similar in terms of age, weight, height, and body mass index. There was no signif- icant difference between groups regarding the duration of surgery (57.34 ± 3.2 and 56.29 ± 3.4 minutes in control and laser groups, respectively; P = 0.71) and anesthesia duration (84.14 ± 5.21 and 85.02 ± 4.98 minutes in control and laser groups, respectively; P = 0.69).

Table 1.  Demographic Characteristics of the Participants a,b

a Abbreviations: LLLT, low-level laser therapy; and BMI, body mass index. b Data are presented as mean ± SD.

Figure 1. Pain Intensity at Different Hours in lllt and Control Groups

Table 2. Postoperative Pain Intensity a, b

a Abbreviations: LLLT, low-level laser therapy; and VAS, visual analogue scale. b Data are presented as mean ± SD.

Based on VAS, mean scores of pain intensity after opera- tion in different periods are presented in Table 2. Pain reduced considerably at second, fourth, eighth, 12th, and 24th hours after surgery in laser group in comparison with the control group. Although there were no signifi- cant differences in pain intensity between the second and fourth, the fourth and eighth, the eighth and 12th, as well as the 12th and 24th hours in each group (P > 0.999, P = 0.110, P = 0.681, and P > 0.999 in control group; P > 0.999, P = 0.099, P = 0.097, and P > 0.999 in laser group, respectively), there were significant differences between the second and eighth, the second and 12th, the second and 24th, the fourth and 12th, the fourth and 24th, as well as the eighth and 24th in each group (P < 0.001, P = 0.010, P < 0.001, P = 0.009, P < 0.001, and P = 0.002 in control group; P < 0.001, P = 0.002, P < 0.001, P = 0.002, P < 0.001,       
and P < 0.001 in lase group, respectively; Figure 1).       
The mean of total amount of analgesic (pethidine) used in laser group was significantly less than control group

The mean of total amount of analgesic was 51.62 ± 29.52 and 89.28 ± 35.54 mg in laser and control groups, respectively (P = 0.008).

5. Discussion

Pain as a stressor, stimulates the physiological and psy-chological responses. Its outcomes have a direct effect on the postoperative complications, recovery time, and pa- tient’s satisfaction with the health system. The aim of this study was to investigate the effect of LLL with the wave- lengths 650 and 808 nm on pain after tibial fracture sur-gery. The results of this study showed that pain reduction was significant at the second, fourth, eighth, 12th, and 24th hours after surgery (P Value ≤ 0.05). Similarly, Moore et al. showed that low level gallium-aluminum-arsenide laser for four to six minutes at the end of the cholecystectomy had no significant effect on pain reduction at the first and the fourth hours after surgery; however, the effect was signifi- cant at the eighth, 12th, 24th, and 48th hours after surgery (21). 

Hegedus et al. reported that the use of LLL (wavelength, 830 nm; continuous wave; and power, 50 mW) in patients with knee osteoarthritis resulted in pain reduction and im-provement in joint movement (15). Jackson et al. found that laser irradiation with wavelength of 630 to 640 nm at the beginning and at the end of breast augmentation surgery reduced the postoperative pain (23). Moreover, Ribeiro et al. reported that AsGaAl laser (660 nm) could decrease the pain as well as postoperative recurrence rate in patients with oral leukoplakia (17).

The results of our study showed the mean total amount of analgesic use in laser group was significantly lower than the control group (P < 0.05). This finding is consis- tent with the findings of other researchers who reported that LLLT could decrease pain during and after the surgery and had a positive effect on wound healing and edema (12). LLLT is used in muscular fatigue (24), wound healing, and pain reduction in dental procedures in patients with and without diabetes (25-27). The researches showed that LLL could cause analgesia by reducing prostaglandin E2 (28, 29), raising endorphin level, and increasing urinary excretion of serotonin, the pain receptors stimuli. LLLT also has a negative effect on pain neurotransmitters and prevents accumulation of acetylcholine, a pain stimulus in the receptors (30).

The results of this study showed that the combination of laser therapy and analgesic medications had better ef- fect during the 24 hours of recovery after the surgery. La- ser radiation at wavelengths of 650 and 808 nm (R and IR laser) can decrease postoperative pain and analgesic use in postoperative period. LLLT does not have side effects like respiratory depression, skin reaction, and analge- sic nephropathy that are seen with other methods. It is recommended to perform more studies concerning the applications of LLLT in anesthesia field as it is a noninva- sive, safe, and acceptable analgesic method in patients in recovery or surgery room.

Acknowledgements

The paper was issued from thesis of Dr Salman Vojdani. Hereby, we acknowledge the vice chancellor of Deputy of Research and Technology Affairs of Ahvaz Jundishapur University of Medical Sciences, especially Research Con- sultation Center (RCC) for technical support. We wish to thank Bahareh Beshavardi Nejad for her collaboration.

Authors’ Contributions

Study concept and design: Sholeh Nesioonpour and So- heila Mokmeli. Analysis and interpretation of data: Sarah Hojjati and Salman Vojdani. Manuscript preparation: Salman Vojdani, Ahmadreza Mohtadi, Reza Akhondza- deh, Kaveh Behaeen, and Shahnam Moosavi. Collection of data: Salman Vojdani and Sarah Hojjati. Critical revision: Sholeh Nesioonpour.

Funding/Support

The financial support (Grant No. U-91189) was provided by Ahvaz Jundishapur University of Medical Sciences, vice chancellor for research and technology.

Efficacy of Class IV Diode Laser on Pain and Dysfunction in Patients with Knee Osteoarthritis: A Randomized Placebo-Control Trial

Objective

The alm of this study was to investigate the effect of class IV diode laser on knee       
pain and functions in patients with knee osteoarthritis.

Patients and methods

Fifty patients with a mean ± SD) age of 55.68+8.88 years, helght of 173.84±       
4.946 cm, weight of 83.86±5.28 kg, and BMI of 27.78±1.89 kg/cm2 were randomly assigned equally into two groups (25 patients in each group). Group I recelved a multiwave locked system laser plus exercises and group II recelved placebo laser plus exercises three times weekly for 4 weeks. Exercise program was applied for both groups three times weekly for 4 weeks. The exercises included range of motion, stretching isometric, and isotonic resisted exercises to the quadriceps and hamstring muscles. Pain was evaluated using a visual analog scale and knee function by using the Westom Ontario and McMastor Universites index of Osteoarthritis (WOMAC). Statistical analyses were perfomed to compare differences between baseline and post-treatment resuits for both groups.

Results

Visual analog scale and WOMAC were significantly decreased in both groups after 4       
weeks of treatment, with a more significant decrease gained in group I (P > 0.0001).

Conclusion

Class IV diode laser combined with exercise was more effective than exercise alone       
in the treatment of patients with knee osteoarthritis. Mutiwave locked system laser       
combined with exercise effectively decreased pain and WOMAC as compared with       
the placebo laser plus exercises group.

Keyboards:

class IV laser, knee function, knee osteoarthritis, multiwave locked system, pain 

Introduction

Osteoarthritis (OA) is a group of conditions that lead to joint signs and symptoms, which are associated with defective integrity of articular cartilage that can affect the normal daily activities in the elderly with higher social and financial influences on       
either patients or society. 

It is characterized by join inflammation, synovitis, and articular cartilage degeneration with many clinical manifestations such as pain, reduced range of movement, crepitus,       
tenderness, impairment of muscular performance, and functional capability.

The most commonly involved joint is the knee with impaired life quality and associated morbidity. Knee OA commonly affects the elderly, and especially women. One-third of the people aged 65 years and older have knee OA, which is evident by radiography. The incidence of the OA tends to increase with aging, with increasing pain and disability of the       
lower limb, which can seriously affect one the activities. Although OA is commonly seen a progressive pain, and caronic disorder with functional limitation, early therapeutic approach can minimize its symptoms.

The treatment includes several interventions, both pharmacological and nonpharmacological, according to the degree of joint destruction. Treatment of OA aimed a to relieve pain, increase to limited range of motion (ROM), and promote cartilage regeneration. Weight reduction and exercise alone or combined with patient education, electrical stimulation, magnetic field, ultrasound, and low-level laser therapy (LLLT) could relieve pain and improve function. Although these modalities provide only symptomatic relief and cannot modify the degenerated cartilage structure, its side effect is low and comparable to the other NSAIDs. Laser therapy was reported that can relieve both acute and chronic musculoskeletal pain. Moreover, it is commonly used in the treatment of degenerative knees OA in animals and humans. Studies on animals reported       
that LLLT decelerates the arthritic process by altering level of prostaglandin, increasing the levels of proteins, and improving the repair of degenerating cartilages by increasing the number of chondrocytes and the thickness of the articular cartilage.

Researchers investigated the clinical effect of laser in the treatment of knee OA. Some authors reported a positive effect on pain relief, whereas the other authors disagreed with this result. These controversial results may be because of the differences in parameters (wavelength, dose, time, area, technique) used in treatments by different studies. Thus, it is important to choose optimum parameters to achieve therapeutic response in patients with knee OA. In the previous studies, LLLT was used in the treatment of knee OA in specific points, with an average of 6J/point, Scanning of the related area such as the quadriceps, hamstring, and the calf muscles was not easy. Because of the large area of laser radiation and low-power laser generator, the time of application will be too much or even not applicable. Now, the presence ot new types of class IV lasers, which provide a high laser power (<0.5 W), help to deliver an adequate level of fluency (energy density that is sufficient to cover large area of treatment and to stimulate the physiological responses. The safety of new high power laser, which approved by Food and Drug Administration, helps to scan the related area in addition to stimulating specific point on the joint line.

Researchers investigated the clinical effect of laser in the treatment of knee OA Some authors reported a positive effect on pain relief, whereas the other authors disagreed with this result. These controversial results may be because of the differences in parameters (wavelength, dose, time, area, technique) used in treatments by different       
studies. Thus, it is important to choose optimum parameters to achieve therapeutic response in patients with knee OA. In the previous studies, LLLT was used in the treatment of knee OA in specific points, with an average of 6J/point. Scanning of the related area such as the quadriceps, hamstring, and the calf muscles was not easy. Because of the large area of laser radiation and low-power laser generator, the time of application will be too much or even not applicable. Now, the presence of new types of       
class IV lasers, which provide a high laser power (<0.5 W), help to deliver an adequate level of fluency (energy density) that is sufficient to cover a large area of treatment and to stimulate the physiological responses. The safety of new high-power laser, which approved by Food and Drug Administration, helps to scan the related area in addition to stimulating specific on the joint line.

The multiwave locked system (MLS) is a novel treatment used for a variety of diseases causing pain and inflammation. •nie MLS laser is a synchronized laser, which has continuous emission of 808 nm with pulsed emission of 905-nm dickie lasers. In comparison with the LLLT, the synchronization of two laser wavelengths provides a high-Biwer class IV laser (808 nm, with a maximum power 1 W, and nm, with a maximum power of 25 W). advantage of this combination is postulated to have a better penetrability and the possibility of increasing the emitted energy. From the available literature, there was no study that investigated the effect of this combination on the deep articulating pain as in knee OA. Therefore, the objective of this study was to investigate the effect of class IV diode laser on knee pain and functions in patients with knee OA.

Patients and methods

Patients

A single blinded placebo-controlled trial was approved by University's Ethics Research       
Committee. A rheumatologist who performed a baseline evaluation for all patients was blinded to the study purpose or design. Patients were subjected to imaging before the decision of accepting them in the trial. On the basis of radiographic finding, patients with       
grade less than or equal to 3 in the Kellgren and Lawrence grading ofOA were included in the study. The estimated sample size was performed by GPower 3.1 program (Universitat Kiel, Germany) for windows with α errors of 0.05, power (1-β error) of 0.80, effect size of 0.85, and using Wilcoxon—Mann—Whitney test for two groups in the analysis of data to detect changes in pain level. The effect size was based on the previous studies. The estimated sample size was 48 patients. The number of samples was increased to 50 for possible dropout. A total of 50 male patients participated in the study. The patients were recruited from physical therapy and rehabilitation department of A1-Nour Hospital, Mecca, Saudi Arabia. A written consent was collected from the patients for participation in the study and to publish their results.

The inclusion criteria were as follows: (a) anterior or posterior knee pain for at least 3 months, (b) limitation in knee ROM and posterior knee muscle tightness, c) BMI less than or equal to 30 kg/m2, and (d) at least a score of 25 on the Western Ontario and McMaster       
Universities Index of Osteoarthritis (WOMAC) as self-reported disability questionnaire.       
Patients were excluded if they had previous surgery, rheumatoid arthritis, fractures, more than 20° genu valgum or genu varum, previous intra-articular injection of corticosteroid or hyaluronic acid, or any cardiovascular, respiratory, or other musculoskeletal problems that interfere with patient participation in exercise. Patients were assigned randomly into two groups of 25 patients in each group. Group I received MLS plus exercises and group II received placebo laser plus exercises. Randomization was performed by online graphPad program (GraphPad Software, San Diego, California, USA) after assigning a specific number for every patient. Patients did not know which group they were assigned to and which treatment they would be given. The therapists were blinded to the group       
assignment as well, and therefore neither patients nor the therapist knew who was in which group.

Assessment

Patient's age, weight, height, and BIMI were recorded. Pain level was measured by visual analog scale (VAS) and knee function using WOMAC.

Assessment of pain

The VAS was used for evaluation of pain for all patients. It is a line divided into 10 equal sections, with 10 representing 'unbearable pain' and 0 representing 'no pain'. Each participant was asked to indicate the level of his pain by marking on this scale. A ruler was used to measure the distance in centimeters from 0 to the marked point. It is an ordinal scale commonly used by researches, and it was shown to be a reliable and valid measure of pain. Measurement was performed at baseline and 4 weeks after treatment.

Assessment of knee function

The lower limb and knee joint functions were evaluated by using WOMAC. The WOMAC scale could evaluate pain, stiffness, and lower limb and knee function. WOMAC is considered as a reliable and valid measure for evaluation of patients with hip and knee OA. Five items of the WOMAC scale were used to measure pain, two items for stiffness, and 17 items for physical function. Each item was graded on a fivepoint scale of 0-4, where 0, no pain/limitation; 1, mild pain/limitation; 2, moderate pain/limitation; 3, severe pain/limitation; and 4, extreme pain/limitation. After confirmation of its validity and reliability, an Arabic version of WOMAC was used in patients with knee OA.

Treatment       
Multiwave locked system laser therapy

MPhi laser device (ASA, Arcugnano, Italy) was used in this study. It provides synchronized and overlapping continuous and pulsed emissions of Ga—Al—Ar laser emitted in a single handpiece. MPhi has continuous emission of wavelength 808 nm with peak power of       
1000 mW, mean power of 500 mW, spot diameter of 2 cm, and spot area of 3.14 cm2. Pulsed emission has a wavelength of 905 nm, peak power of 25 W, mean power of 54mWat, with a frequency of 1500 Hz, with the same diameter and spot area.

While the patient assumed a supine lying position, the affected knee was slightly flexed and supported with a pillow underneath. Laser was applied into two subphases: scan and trigger point subphases. In the scan phase, both the anterior and posterior knee surfaces were scanned, with an average area of 100cm2, time of application of 6 min and 17 s per session, and a total energy of 214 150J. In trigger point treatment, laser probe was perpendicular and in contact to four points on the anterior knee surface around the patella and two points on the posterior knee surface on the medial and lateral hamstring insertion. The energy, delivered was 2.14J/cm2, 6.175J on each point in an average time of 16s. The total time of laser session was about 9 min. NILS laser was applied to all patients in group I three sessions/week for 4 consecutive weeks. Calibration of laser equipment       
was done by the manufacturing company. For placebo laser, patients in group II attended the physical therapy department and received sham laser with the same equipment, time, area, and points of application before applying exercise program three sessions/week for 4 consecutive weeks.

Exercises

Exercise program was applied thrice a week for 4 weeks for all patients in both treatment groups. The program included (a) 5-min ROM exercise to lower limb joints in pain-free range from nonweight-bearing position, (b) 10 min stretching exercise to the hamstring and calf muscles, and (c) isometric strengthening exercise to the quadriceps muscle using sand bags while the patient raised his leg straight for 10 times for three sets with 5-       
min rest in between each set. The patient performed an isotonic resisted exercise, three sets of 10 times each, to the quadriceps muscle using Multigym device with a variable resistance according to patient tolerance. Hamstring strengthening exercise, three sets of 10 times each, was performed from prone lying position using sandbags. The total time of exercise was about 45 min, plus the rest periods between different exercise modes according to patient tolerance. The patient was instructed to repeat the program of       
exercises at home and a handout prescription of exercises was given for all patients. Hot packs were allowed in case of muscle soreness after exercise.

Data analysis

Unpaired t-test was used to compare the mean values of patient's age, weight, height, and BMI for both treatment groups. Changes in VAS and WOMAC between groups were analyzed by Nlann—Whitney U-test. Each group's results were analyzed by Wilcoxon's signed-rank test to compare between baseline and after 4 weeks. level of statistical significance was set as P less than 0.05.

Results

The aim of the study was to investigate the effect of class IV diode laser on knee pain and functions in patients with knee OA. Fifty male patients participated in the study. Their mean age was 55.68±8.88, weight was 83.86±5.28, height was 173.84±4.946, and BMI       
was 27.78±1.89. were randomly assigned into two groups of 25 patients in either group I or group II. Unpaired t-test was used to compare the demographic data of patients including age, weight, height, and BMI, and revealed nonsignificant changes in their       
means between the two treatment groups, as shown in Table 1.

Wilcoxon's matched-pairs signed-ranks test was used to compare between baseline and post-treatment results and revealed significant decreases in VAS and WOMAC in both group I and group II (Table 2). Mann—Whitney test was used to compare the baseline       
and post-treatment scores of VAS and WOMAC and showed nonsignificant differences in baseline results between both groups, as shown in Table 2. Significant decreases were observed in post-treatment results in either VAS or WOMAC, with a significant decrease gained in group I more than group II, as shown in Table 2.

Discussion

The aim of the study was to investigate the effect of MLS on knee pain and functions in patients with knee OA. MILS combined with exercise was effective more than placebo laser plus exercises in the treatment of patients with knee OA MLS combined with exercise was more effective in decreasing VAS score and WOMAC subscales as compared with the placebo laser plus exercises group.

Te result of the present study was consistent with those of the previous studies, which support the effect of LLLT in the treatment of arthritis. Researchers have found favorable analgesic, anti-inflammatory, and biostimulating effects of laser. Diode laser significantly       
reduces the chronic pain as in rheumatoid arthritis, chronic arthritis, and knee injuries

In knee OA, the main aims of treatment are to relieve pain, to improve lower limb function, and to alleviate joint destruction by changing the inflammatory process. Laser diode can reduce pain indirectly by increasing the microcirculation, and increasing oxygenation to tissues with reduction of knee swelling and the intensity of inflammation.       
Laser reduces the inflammatory process by altering prostaglandin synthesis, decreasing interleukin l, enhancing lymphocyte response, and decreasing C-reactive protein and neopterin levels. Laser therapy can reduce pain at the tissue level by altering the release of chemical mediators such as histamine and bradykinin, which are released from injured tissues, and decreasing the release of substance P, which decreases the threshold of pain. These effects lead to an increase in the knee functional performance, and an improvement in the ambulation duration and quality of life. Laser has a biostimulating effect as it influences the cellular metabolism through stimulation of cytochrome       
oxidase enzyme, which enhances the oxidative phosphorylation and increases production, which in turn regulates other cellular processes leading to normalization of biological functions at the cellular level.

The result of the present study was contradictory to the finding of Gur et al. and Tascioglu et al, who found no significant effect of laser on pain in patients with knee OA. Although they used a semiconductor diode laser, the enerw density delivered to patients (1.5, 2 or 3 J/point) was different from the present study (6 J/point). Laser was delivered at low power       
output of 11-2 or 50mW and with different wavelengths (904 or 830 nm), which showed that the power output and the wavelength are important factors that the laser effect was dqrndent on. In addition, it may provide evidence of the importance of the combination of wavelengths (808—905 nm) that was used in the current study. MLS is considered a       
high-power laser with two synchronized wavelengths (808 and 905 nm) resulting in deeper tissue penetration. This combination may be able to reach a deeper area such as the knee joint and is responsible for pain relief and improving knee and lower limb function. 

As the concentration of chromophores in skin and subcutaneous tissue increased, the absorption of laser is increased. When the wavelengths increased up to 1000 nm, the penetration reaches deeper tissues and can reduce pain and inflammation in the deeper area such as the knee joint [19,35]. The optimum dose of the therapeutic laser is dependent on three factors: power output, wavelength, and time of application.       
Class IV laser with a longer wavelength (up to 1000 nm) over a longer period of time produces a higher therapeutic dosage, which is delivered to the tissue and can stimulate the tissues effectively.

Table 1 Demographic characteristics of patients in both treatment groups

The result of the present study indicates that exercise therapy alone or combined with MLS laser is clinically able to decrease pain and improve function. Exercise, when applied actively, was shown to be safe, economical, and effective in the treatment of patients with knee OA. Home-based isometric exercise of the knee extensor and flexor muscles has shown to have a beneficial effect on the long-term increase in muscle strength. Stretching exercises to hamstring muscle when combined with isotonic muscle strengthening provide a useful treatment combination for middle-aged adult patients with knee OA. Combined use of exercise with MLS laser has shown to have clinical significance in providing a effect in reducing pain and improving lower limb and knee function. The reduction of pain and posterior knee muscles spasm and tightness in addition to the anti-inflammatory effect of laser may help decrease the inflammatory process. Moreover, MLS may recover the exercise muscles through improving muscle conditions, enhancing skeletal muscle contractile function, and postexercise recovery, which is considered as the cause for improving knee and lower limb function, as       
reflected in the improvement in WOMAC score.

Conclusion 

Class IV diode laser combined with exercise was more effective than exercise alone in the treatment of patients with knee OA. MLS laser combined with exercise effectively decreased pain and WOMAC subscales as compared with exercise alone. NILS laser is an       
effective physical therapy mcxlality that may provide better outcomes for patients with knee OA, especially when used in combination with exercise. Further studies may be recommended to investigate the effect of NILS on quadriceps muscle strength and       
recovery, as well as the changes in the inflammatory process inside the knee joint in patients with knee OA. In addition, the effect of MLS in the treatment of other types of painful and arthritic joints such as rheumatoid arthritis should be considered in future studies.

Limitation

All the recruited patients were male patients. All patients were instructed to perform a home exercise program and the exercise compliance was obtained from family members. Although the family members or the participants themselves reported any deficiency in the exercise prescription at home, we considered this a limiting factor in the present study.

Acknowledgements

The authors express their appreciation to all patients who participated in this study with their consent and cooperation, and would like to give special thanks to their colleagues at the Department of Physical Therapy, Faculty of Applied Medical Science, Umm University, Saudi Arabia. 

Financial support and sponsorship        
Nil 

Conflicts of interest       
There are no conflicts of interest.

The Effect of Low-Level Laser in Knee Osteoarthritis: A Double-Blind, Randomized, Placebo-Controlled Trial

Abstract

Introduction: Low-level laser therapy (LLLT) is thought to have an analgesic effect as well as a biomodulatory effect on microcirculation. This study was designed to examine the pain-relieving effect of LLLT and possible microcirculatory changes measured by thermography in patients with knee osteoarthritis (KOA). Materials and Methods:       
Patients with mild or moderate KOA were randomized to receive either LLLT or placebo LLLT. Treatments were delivered twice a week over a period of 4 wk with a diode laser (wavelength 830 nm, continuous wave, power 50 mW) in skin contact at a dose of 6 J = point. The placebo control group was treated with an ineffective probe (power 0.5 mW) of the same appearance. Before examinations and immediately, 2 wk, and 2 mo after completing the therapy, thermography was performed (bilateral comparative thermograph by AGA infrared camera); joint flexion, circumference, and pressure sensitivity were measured; and the visual analogue scale was recorded. Results: In the group treated with active LLLT, a significant improvement was found in pain (before treatment [BT]: 5.75; 2 mo after treatment : 1.18); circumference (BT: 40.45; AT: 39.86); pressure sensitivity (BT: 2.33; AT: 0.77); and flexion (BT: 105.83; AT: 122.94). In the placebo group, changes in joint flexion and pain were not significant. Thermographic measurements showed at least a 0.5°C increase in temperature—and thus an improvement in circulation compared to the initial values. In the placebo group, these changes did not occur. Conclusion: Our results show that LLLT reduces pain in KOA and improves microcirculation in the irradiated area.

Introduction

Since Endre Mester began his pioneering investigations, numerous clinical and basic research studies have demonstrated the physiological effects and medical applicability       
of low-level laser therapy (LLLT). Its application was initiated based on previous work that demonstrated properties of low-level laser that exert a positive influence on fibroblast and osteoblast proliferation, collagen synthesis, and bone regeneration. In vivo examinations have also shown that LLLT significantly stimulates the activity of alcalic phosphatase and calcium accumulation. In addition to cartilage damage and bone metabolism, pathological alterations are also known to exhibit reduced circulation in the vessels of the joint parallel to the degenerative changes. Numerous authors have reported increased microvascularization as a histological effect of the laser beam.       
While examining revascularization—a phase of wound healing—Mester found a significant increase in the number of vascularized areas in laser-treated patients. In light of the domestic and international literature, the aim of this study is to gather evidence of the analgesic effect of low-level laser as well as its possible effect in increasing micro-       
circulation. In order to obtain objective data, thermographic measurements were taken, and follow-up examinations were performed to control for the permanency of the effects obtained.

Patients and Methods

Both female and male patients with mild to moderate knee osteoarthritis (KOA) were recruited to the study. Reasons for exclusion included considerable deformity of the varus or valgus, ankylosis, intense synovitis, or gonitis observed during physical examination; erosive or destructive alterations detected by radiograph (Kellgren-Lawrence stage 4); and the usual contraindications for laser therapy (Table 1). Thirty-five patients were selected for the examinations, but only 27 patients (22 women and 5 men) completed the study, 18 of whom were in the active LLLT group and 9 in the placebo LLLT group. Eight patients from the placebo group who left the experiment provided no reasons for doing so, nor did they return to the institute. The demographic data on the patients included in the study are summarized in Table 2.

Table 1. Participation in the Study

During the study patients received no steroids, antidepressants, or sedatives. A detailed case history and physical status were recorded. Various examinations were conducted       
prior to treatment in order to rule out other diseases and to attain patient homogeneity (Table 3). Those who underwent treatment were given full disclosure and signed an agreement form on participation in the study. 

Permission was granted for this study by the Institute’s Research Ethics Committee. The patients received no other therapies or pain medication.

Treatments were administered on the same days twice a week over a period of 4 wk with an OPTIKOP KLS GaAlAs diode laser (power 50 mW, continuous wave, wavelength       
830 nm) or with a placebo probe (power 0.5 mW) of the same appearance and display. The probes were numbered 1 (active) and 2 (placebo). Randomization was ensured by having patients randomly choose sealed envelopes from a bowl containing an equal number of slips with either number 1 or 2, which corresponded to one of the laser probe numbers. Neither the patients nor the operator knew which was the active or placebo LLLT probe. Treatment was administered in skin contact only over the joint which caused the most explicit complaints. The dose delivered was 6 J/point.

In one session, a patient was given a total dose of 48 J/cm2. The size of the point in the focus of the laser light was nearly 0.5 mm2; that is to say, the power density was approximately 50 mW/0.5 mm2, i.e., 10W/cm2. The laser has European certificate no. CE 0120. The device is self-checked in accordance with European Standards (CE) and requires no special staff. Treatment was administered over the femoral and tibial       
condyles in every case since enthesis is often responsible for the complaints mentioned by the patients. Laser irradiation was aimed at the synovia and cartilage in the joint line. The points that were irradiated were the medial and lateral epicondyle of the tibia and femur, the medial and lateral knee joint gap, and the medial edge of the tendon of the biceps femoris muscle and semitendinosus muscle in the popliteal ditch (Fig. 1).

Valgization was carefully performed on the knee joint when the medial knee joint gap was being treated, and varization was carried out when treatment was administered       
to the lateral knee joint gap. The knee joint was flexed on treating the popliteal ditch. In order to judge the efficacy of the treatment, subjective (pain on a 10-cm scale), semi-       
objective (pressure sensitivity on the Ritchie index scale), and objective (flexion in degrees, circumference in centimeters, and thermography with temperature [°C]) parameters were measured (Table 4). Thermographic measurements were used to observe microcirculatory changes during the treatment period, and a computer system enabled us to digitize the image.

Considering that thermographic measurement is very sensitive but that its specificity is low, an attempt was made to set appropriate standard examination conditions. The examination room was therefore kept at a constant temperature (21–23°C) and free from drafts at a humidity of 70–80%. Prior to measurement, patients rested for 15 min and       
then the affected part of the body was washed with alcohol.

Table 2. Demographic Data

Table 3. Examinations Before Treatment

Patients were told to avoid coffee, alcohol, and cigarettes prior to measurement since these can influence circulatory conditions. In every case, medial and lateral comparative       
measurements were performed from anterior–posterior and posterior–anterior angles.

A basic (or zero) examination was performed prior to treatment; all other measurements were carried out weekly after the second treatment at the same time each week. In order to control for the permanency of the effect obtained, control measurements were performed 2 wk and 2 mo after completing the therapy.

Results

The graph shows changes in the four parameters examined, plotted against time, for treatment with active and placebo LLLT probes. Certain examination times were       
compared to the initial data; a comparison was also made between the two groups for the time of examination. For statistical analysis, t-tests were used for within-group differences and ANOVA for between-group comparison overtime.

Table 4. Outcome Measures

Joint flexion was 105.83° before treatment (BT) in the active laser group (Fig. 2a), and 122.27° immediately after the last treatment session (AT); 124.33° 2 wk AT; and 122.94°       
2 mo AT. For treatment with the placebo probe (Fig. 2b), joint flexion was 107.22° BT, 115.22° AT, 116.11° 2 wk AT, and 112.11° 2 mo AT. For the active LLLT group, a significant change could be detected compared to the initial value at every time examined. This trend could not be observed for the placebo group (p < 0.05).

FIG. 2. (a) The effect of laser treatment on joint flexion. Treatment resulted in significant improvement in joint flexion at all times examined. (b) The effect of placebo laser treatment on joint flexion. We observed no significant change from treatment at any of the times examined. AT, after treatment.

FIG. 3. (a) The effect of laser treatment on pressure sensitivity of the joint. Treatment resulted in significant improvement in joint flexion at all the times examined. (b) The effect of placebo laser treatment on pressure sensitivity of the joint. We observed no significant change from treatment at any of the times examined.

EFFECT OF LLLT IN KNEE OSTEOARTHRITIS

change could be detected compared to the initial value at every time examined. This trend could not be observed for the placebo group (p < 0.05). Pressure sensitivity of the joint for treatment with the active probe (Fig. 3a) was 2.33 BT, 0.83 immediately AT, 0.33 2 
wk AT, and 0.77 2 mo AT as measured using the Ritchie index. For treatment with the placebo probe (Fig. 3b), pressure sensitivity was 2.11 BT, 1.44 directly AT, 1.44 2 wk AT, 
and 1.66 2 mo AT. There was only a significant change at all the times examined for the active LLLT group compared to the initial value, whereas none was detected for the placebo LLLT group (p < 0.05). Pain in the joint for treatment with the active probe (Fig. 
4a) was 5.75 BT, 1.71 immediately AT, 1.05 2 wk AT, and 1.18 2 mo AT on a 10-cm scale. For treatment with the placebo LLLT probe (Fig. 4b), pain was 5.62 BT, 4.13 immediately AT, 4.07 2 wk AT, and 4.12 2 mo AT. A significant change could be detected at all times examined for the active LLLT group compared to the initial value, whereas this trend could not be observed for the placebo LLLT group (p < 0.05).

FIG. 4. (a) The effect of laser treatment on pain in the joint. Treatment resulted in significant improvement in joint flexion at all the times examined. (b) The effect of placebo laser treatment on pain in the joint. We observed no significant change from treatment at any of the times examined.

The circumference of the joint was 40.45 cm BT for treatment with the active probe, 39.61 cm immediately AT,39.58 cm 2 wk AT, and 39.86 cm 2 mo AT. For the group treated with the placebo LLLT probe, circumference was 40.44 cm BT, 39.86 cm immediately AT, 39.87 cm 2 wk AT, and 40.05 cm 2 mo AT. With regard to the examined parameters, no significant changes appeared for the effective or placebo group under the effect of the treatment (p 0.05). 

Increased metabolism and a richer blood supply to tissues beneath the surface represented important factors in the thermographic results. Where tissues have a higher metabolism and there is a richer blood supply beneath the surface skin, more infrared rays are emitted. The opposite also holds true. 

During the treatment period, weekly thermograms showed increasing temperature in previously cold areas and an extension of the warmer area (Fig. 5a and 5b). There was no increase in skin temperature in the placebo LLLT group (Fig. 6a and 6b). 

At follow-up measurements 2 mo after probe (Fig. 7a and 7b) therapy, the thermographic changes remained elevated by at least a 0.5°C in patients who experienced pain relief. An increased temperature was even observed in the nontreated control side in all patients who were treated with the active LLLT.

Discussion

Our measurement results provide evidence that treatment with the active LLLT probe resulted in significant improvement for all evaluated parameters. In the placebo LLLT 
group, we found nonsignificant changes in joint flexion and pain. In the active LLLT group, we found significant improvement with regard to joint flexion, pain, and pressure sensitivity in the active group in comparison with the placebo group at the times examined. The positive effects obtained from active LLLT still persisted 2 mo after treatment. The lack of effect on knee circumference was expected and has not been demonstrated with other therapies. In the placebo LLLT group, three patients gave an account of an explicit reduction in their complaints, which is in line with placebo improvement in studies of other KOA therapies.

It is a weakness of the study that we did not use other validated tools for measurement of KOA pain and disability such as the WOMAC questionnaire or the Lequesne index. 
However, there is a high correlation between pain scores and these tools, and there is little reason to believe that incorporation of these tools would have altered our results.

Over the years more than 100 double-blind, placebo-controlled studies have been published on the effects of LLLT. These articles also showed the favorable anti-inflammatory effect of LLLT. Based on the objective, semi-objective, and 
subjective measurements after laser and placebo treatments in patients with seropositive rheumatoid arthritis, Baraba came to the conclusion that laser treatment exerts a positive influence on the clinical signs and laboratory parameters of this 
disease. Ohshiro also demonstrated a positive effect on microcirculation and verified changes by thermography in parallel with the reduction of pain. 

In studies where the temperature of the skin was measured, it was reported to have risen in the irradiated site. Mester noticed an increase in the migration index of Tlymphocytes after laser irradiation. He observed that this change can be transmitted by pouring the medium of treated cells on nontreated lymphocytes. In patients with bilateral leg ulcer that failed to respond to conservative treatment, while treating the wound of one limb he also noticed slower but unambiguous wound healing on the other side. Other authors have reported effects proximal and distal from the irradiated area.

FIG. 5. (a) Lateral image of a right knee before eight active low-level laser therapy (LLLT) treatments. White and grey colors represent higher temperatures, greyer and black colors represent colder temperatures. (b) Lateral image of a right knee after eight active LLLT treatments.

FIG. 6. (a) Medial thermogram of the left knee before eight placebo LLLT treatments. (b) Medial thermogram of the left knee after eight placebo LLLT treatments.

EFFECT OF LLLT IN KNEE OSTEOARTHRITIS

FIG. 7. (a) Image from posterior–anterior angle before eight treatments of the right knee joint. (b) Image from posterior-anterior angle after eight treatments of the right knee joint.

With qualitative evaluation of the results obtained, we noticed an increase in temperature, suggesting circulatory changes at a good distance from the treated points and on the untreated side. On the other hand, we did not find this clear change in the control group.

In summary, low-level laser represents an effective treatment for short-term improvement in patients suffering from painful KOA.

Acknowledgments

The authors wish to thank Dr. Gabor Deak for the Doppler examinations and Andras Toth for taking taking the numerous thermographic images. 

Disclosure Statement 

No competing financial interests exist.

Efficacy of low-level laser therapy on pain and disability in knee osteoarthritis: systematic review and meta-analysis of randomised placebo-controlled trials.

Abstract

Objectives: Low-level laser therapy (LLLT) is not recommended in major knee osteoarthritis (KOA) treatment guidelines. We investigated whether a LLLT dose–response 
relationship exists in KOA.

Design: Systematic review and meta-analysis.

Data sources: Eligible articles were identified through PubMed, Embase, Cumulative Index to Nursing and Allied Health Literature, Physiotherapy Evidence Database and Cochrane Central Register of Controlled Trials on 18 February 2019, reference lists, a book, citations and experts in the field.

Eligibility criteria for selecting studies: We solely included randomised placebo-controlled trials involving participants with KOA according to the American College of Rheumatology and/or Kellgren/Lawrence criteria, in which LLLT was applied to participants’ knee(s). There were no language restrictions.

Data extraction and synthesis: The included trials were synthesised with random effects meta-analyses and subgrouped by dose using the World Association for Laser Therapy treatment recommendations. Cochrane’s risk-of-bias tool was used.

Results: 22 trials (n=1063) were meta-analysed. Risk of bias was insignificant. Overall, pain was significantly reduced by LLLT compared with placebo at the end of therapy (14.23 mm Visual Analogue Scale (VAS; 95% CI 7.31 to 21.14)) and during follow-ups 1–12 weeks later (15.92 mm VAS (95% CI 6.47 to 25.37)). The subgroup analysis revealed that pain was significantly reduced by the recommended LLLT doses compared with placebo at the end of therapy (18.71 mm (95% CI 9.42 to 27.99)) and during follow-ups 2–12 weeks after the end of therapy (23.23 mm VAS (95% CI 10.60 to 35.86)). The pain reduction from the recommended LLLT doses peaked during follow-ups 2–4 weeks after the end of 
therapy (31.87 mm VAS significantly beyond placebo (95% CI 18.18 to 45.56)). Disability was also statistically significantly reduced by LLLT. No adverse events were reported.

Conclusion: LLLT reduces pain and disability in KOA at 4–8 J with 785–860 nm wavelength and at 1–3 J with 904 nm wavelength per treatment spot.

PROSPERO registration number: CRD42016035587

Strengths and limitations of this study

• The review was conducted in conformance with a detailed a priori published protocol, which included, for example, laser dose subgroup criteria.
• No language restrictions were applied; four (18%) of the included trials were reported in non-English language.
• A series of meta-analyses were conducted to estimate the effect of low-level laser therapy on pain over time.
• Three persons each independently extracted the outcome data from the included trial articles to ensure high reproducibility of the meta-analyses.
• The review lacks quality-of-life analyses, a detailed disability time-effect analysis and direct comparisons between low-level laser therapy and other interventions.

Introduction

Approximately 13% of women and 10% of men in the population aged ≥ 60 years suffer 
from knee osteoarthritis (KOA) in the USA. KOA is a degenerative inflammatory disease 
affecting the entire joint and is characterised by progressive loss of cartilage and associated with pain, disability and reduced quality of life (QoL). Increased inflammatory activity is associated with higher pain intensity and more rapid KOA disease progression.

Some of the conservative intervention options for KOA are exercise therapy, non-steroidal anti-inflammatory drugs (NSAIDs) and anti-inflammatory low-level laser therapy (LLLT). There is evidence that exercise therapy reduces pain and disability and improves QoL in persons with KOA. NSAIDs are recommended in most KOA clinical treatment guidelines and is probably the most frequently prescribed therapy category for osteoarthritis, despite intake of these drugs is associated with negative side effects, which is problematic, especially since the disease requires long-term treatment. Furthermore, a recently published network meta-analysis indicates that the pain relieving 
effect of NSAIDs in KOA beyond placebo is small to moderate (depending on drug type). Likewise, in the first systematic review on this topic, the pain relieving effect of NSAIDs was estimated to be only 10.1 mm on the 0–100 mm Visual Analogue Scale (VAS) better than placebo.

LLLT is a non-invasive treatment modality, which has been reported to induce anti-inflammatory effects. LLLT was compared with NSAID in rats with KOA by Tomazoni et al 
in a laboratory; NSAID (10 mg diclofenac/knee/session) and LLLT (830 nm wavelength, 6 J/knee/session) reduced similar levels of inflammatory cells and metalloproteinase (MP-3 and MP-13). In addition, LLLT reduced the expression of proinflammatory cytokines (interleukin-1β (IL-1β) and IL-6 and tumour necrosis factor α), myeloperoxidase and prostaglandin E2 significantly more than NSAID did.

LLLT has been applied to rabbits with KOA three times per week for 8 weeks in a placebo-controlled experiment by Wang et al. At the end of treatment week 6, they found that LLLT had significantly reduced pain and synovitis and the production of IL-1β, inducible nitric oxide synthase and MP-3 and slowed down loss of metallopeptidase inhibitor 1. Two weeks later, LLLT had significantly reduced MP-1 and MP-13 and slowed down loss of collagen II, aggrecan and transforming growth factor beta, and the previous changes were sustained. These findings indicate that the effects of LLLT increase over time. 

Pallotta et al conducted a study on LLLT in rats with acute knee inflammation, which demonstrated that even though LLLT (810 nm) significantly enhanced cyclooxygenase (COX-1 and COX-2) expression it significantly reduced several other inflammatory makers, that is, leucocyte infiltration, myeloperoxidase, IL-1 and IL-6 and especially prostaglandin E2. Pallotta et al hypothesised that the increase in COX levels by LLLT was involved in a production of inflammatory mediators related to the resolution of the inflammatory process.

LLLT is not recommended in major osteoarthritis treatment guidelines. LLLT for KOA was mentioned in the European League Against Rheumatism osteoarthritis guidelines (2018) but not recommended, and in the Osteoarthritis Research Society International guidelines (2018), it was stressed that LLLT should not be considered a core intervention in the management of KOA.

This may be partly due to conflicting results of two recently published systematic reviews on the current topic. The conflicting results may arise from omission of relevant trials and unresolved LLLT dose-related issues. Only Huang et al conducted a LLLT dose–response relationship investigation in KOA, that is, by subgrouping the trials by laser dose, but they did not consider that World Association for Laser Therapy (WALT) recommends applying four times the laser dose with continuous irradiation compared to superpulsed irradiation. Thus, it was unknown whether LLLT is effective in KOA, and we saw a need for a new systematic review.

The objectives of the current review were to estimate the effectiveness of LLLT in KOA regarding knee pain, disability and QoL, and we only considered placebo-controlled randomised clinical trials (RCTs) for inclusion to minimise risk of bias.

METHODS

This review is reported in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses statement 2009.

Literature search and selection of studies

Any identified study was included if it was a placebo-controlled RCT involving participants with KOA according to the American College of Rheumatology tool and/or a radiographic inspection with the Kellgren/Lawrence (K/L) criteria, in which LLLT was applied to participants’ knee(s) and self-reported pain, disability and/or QoL was reported. There were no language restrictions. 

We updated a search for eligible articles indexed in PubMed, Embase, Cumulative Index to Nursing and Allied Health Literature, Physiotherapy Evidence Database and Cochrane Central Register of Controlled Trials on 18 February 2019. The database search strings contained synonyms for LLLT and KOA, and keywords were added when optional. The PubMed search string is available in the online supplementary material. The search was continued by reading reference lists of all the eligible trial and relevant review articles, citations and a laser book and involving experts in the field.

Two reviewers (MBS and JMB) each independently selected the trial articles. Both reviewers scrutinised the titles/abstracts of all the publications identified in the search, and any accessible full-text article was retrieved if it was judged potential eligible by at least one reviewer. Both reviewers evaluated the full texts of all potentially eligible retrieved articles and made an independent decision to include or exclude each article, with close attention to the inclusion criteria. When selection disagreements could not be resolved by discussion, a third reviewer (IFN) made the final consensus-based decision. Any retrieved article not fulfilling the inclusion criteria was omitted and 
listed with reason for exclusion.

Risk-of-bias analysis

Two reviewers (MBS and JJ) each independently evaluated all included trials for risk of bias at the outcome level, using the Cochrane Collaboration’s risk-of-bias tool. When risk-of-bias disagreements could not be resolved by discussion, a third reviewer (IFN) made the final consensus-based decision. Likelihood of publication bias was assessed with graphical funnel plots. 

Data extraction and meta-analysis

Three reviewers (MBS, JMB and KVF) each independently extracted the data for meta-analysis. Two of the reviewers (MBS and KVF) each independently collected the other trial characteristics. The data-extraction forms were subsequently compared, and data disagreements were resolved by consensus-based discussions. Summary data were extracted unless published individual participant data were available. The results from the included trials for statistical analysis were selected from outcome scales in adherence to hierarchies published by Juhl et al.

Pain intensity was the primary outcome. As pain reported with continuous, numeric and categorical/Likert scales highly correlates with pain measured using the VAS, the scores of all pain scales were transformed to 0%–100%, corresponding to 0–100 mm VAS. The pain results were combined with the mean difference (MD) method, primarily using change scores, that is, when only final scores could be obtained from a trial, change 
and final scores were mixed in the analysis, since the MD method allows for this without introducing bias.

Self-reported disability results were synthesised with the standardised mean difference (SMD) method using change scores solely. The SMD was adjusted to Hedges’g 
and interpreted as follows: SMDs of 0.2, ~0.5 and >0.8 represent a small, moderate and large effect, respectively. Lack of QoL data prohibited an analysis of this outcome. Random effects meta-analyses were conducted, and impact from heterogeneity (inconsistency) on the analyses was examined using I2 statistics. An I2 value of 0% 
indicates no inconsistency, and an I2 value of 100% indicates maximal inconsistency; the values were categorised as low (25%), moderate (50%) and high (75%). 

SDs for analysis were extracted or estimated from other variance data in a prespecified prioritised order: (1) SD, (2) SE, (3) 95% CI, (4) p value, (5) IQR, (6) median of correlations, (7) visually from graph or (8) other methods. The trials were subgrouped by adherence and non-adherence to the WALT recommendations for laser dose per treatment spot, as prespecified. WALT recommends irradiating the knee joint line/synovia with the following doses per treatment spot: ≥ 4 J using 5–500 mW mean power 780–860 nm wavelength laser and/or ≥ 1 J using 5–500 mW mean power (>1000 mW peak power) 904 nm 
wavelength laser. The main meta-analyses were conducted using two prespecified time points of assessment, that is, immediately after the end of LLLT and last time point of assessment 1–12 weeks after the end of LLLT (follow-up). 

MBS performed the meta-analyses, under supervision of JMB, using the software programme Excel 2016 (Microsoft) and Review Manager Version V.5.3 (Copenhagen: The Nordic Cochrane Centre, The Cochrane Collaboration, 2014).

Figure 1 Flow chart illustrating the trial identification process. CENTRAL, Cochrane Central Register of Controlled Trials; CINAHL, Cumulative Index to Nursing and Allied Health Literature; LLLT, low-level laser therapy; PEDro, Physiotherapy Evidence Database.

Patient and public involvement

Patients or the public were not involved in the conceptualisation or carrying out of this research.

Results

In total, 2735 records were identified in the search, of which 22 trial articles were judged eligible and included in the review (n=1089; figure 1 and tables 1–2) with data for meta-analysis (n=1063). Four included trials were not reported in the English language and one included trial was unpublished (Gur and Oktayoglu). Excluded articles initially judged potentially eligible were listed with reasons for omission (online supplementary material).

At the group level, the mean age of the participants was 60.25 (50.11–69) years (data from 19 trials), the mean percentage of women was 69.63% (0–100%; data from 17 trials), the mean body mass index of the participants was 29.55 (25.8–38; data from 14 trials), the mean of median K/L grades was 2.37 (data from 13 trials) and the mean baseline pain was 63.61 mm VAS (35.25–92) (data from 22 trials). LLLT was used as an adjunct to exercise therapy in 11 trials. The mean duration of the treatment periods was 3.53 weeks with the recommended LLLT doses and 3.7 weeks with the non-recommended LLLT doses (tables 1 and 2). Non-recommended LLLT doses were applied in nine of the trials. That is, Al Rashoudet et al, Bulow et al, Tasciouglu et al and Bagheri et al applied too few (<4) Joules per treatment spot with 830 nm wavelength, Jensen et al, Nivbrant et al and Hinman et al applied too few (<1) Joules per treatment spot with 904 nm wavelength and Youssef et al (one group) and Rayegani et al used continuous laser with too long of a wavelength (880 nm; table 2). No adverse event was reported by any of the trial authors. None of the trial authors stated receiving funding from the laser industry (online supplementary material).

Overall, pain was significantly reduced by LLLT compared with the placebo control at the end of therapy (14.23 mm VAS (95% CI 7.31 to 21.14); I2=93%; n=816; figure 2) and during follow-ups 1–12 weeks later (15.92mm VAS (95% CI 6.47 to 25.37); I2=93%; n=581; figure 3). The dose subgroup analyses demonstrated that pain was significantly reduced by the recommended LLLT doses compared with placebo at the end of therapy (18.71 mm (95% CI 9.42 to 27.99); I2=95%; n=480; figure 2) and during follow-ups 2–12 weeks later (23.23 mm V AS (95% CI 10.60 to 35.86); I2=95%; n=392; figure 3). The dose subgroup analyses demonstrated that pain was significantly reduced by the non-recommended LLLT doses 
compared with placebo at the end of therapy (6.34 mm VAS (95% CI 1.26 to 11.41); I2 =44%; n=336; figure 2), but the difference during follow-ups 1–12 weeks later was not significant (6.20 mm VAS (95% CI −0.65 to 13.05); I2=38%; n=189; figure 3). The between-subgroup differences (recommended versus non-recommended doses) in pain results were significantly in favour of the recommended LLLT doses regarding both time points (p=0.02 and 0.02; figures 2 and 3).

Table 1 Characteristics of the included trials

The values for age and body mass index (BMI) are means and the values for K/L grade are medians. Baseline Visual Analogue Scale (VAS) scores have been extracted or estimated as described in the Method section. Week of assessment in bold denotes time point used for the main meta-analyses.

AQoL-6D, Assessment of Quality of Life 6 Dimensions; DIQ, Disability Index Questionnaire; K/L, Kellgren/Lawrence; LLLT, low-level laser therapy; NRS, Numeric Rating Scale; QoL, quality of life; SKFS, Saudi Knee Function Scale; TENS, Transcutaneous Electrical Nerve Stimulation; VNPS, Visual Numerical Pain Scale; WOMAC, Western Ontario and McMaster Universities Osteoarthritis Index.

Overall, disability was significantly reduced by LLLT compared with placebo at the end of therapy (SMD=0.59 (95% CI 0.33 to 0.86); I2=57%; n=617; figure 4) and during follow-ups 1–12 weeks later (SMD=0.66 (95% CI 0.23 to 1.09); I2=67%; n=289; figure 5). The dose subgroup analyses demonstrated that disability was significantly reduced by the recommended LLLT doses compared with placebo at the end of therapy (SMD=0.75 (95% CI 0.46 to 1.03); I2=34%; n=339; figure 4) and during follow-ups 2–8 weeks later (SMD=1.31 (95% CI 0.92 to 1.69); I2=0%; n=129; figure 5). The dose subgroup analyses demonstrated 
that disability was neither significantly reduced by the non-recommended LLLT doses compared with placebo at the end of therapy (SMD=0.36 (95% CI −0.02 to 0.73); I2=49%; n=278; figure 4) nor during follow-ups 1–12 weeks later (SMD=0.26 (95% CI −0.06 to 0.58); I2=0%; n=160; figure 5). The between-subgroup differences in disability results were in favour of the recommended LLLT doses over the non-recommended LLLT doses but only significantly regarding one of two time points (p=0.11 and <0.0001; figures 4–5).

Table 2 Laser therapy characteristics of the included trials

*Non-recommended low-level laser therapy dose. †1250 Joules per session.

No QoL meta-analysis was performed because this outcome was only assessed in a single trial, that is, by Hinman et al who applied a non-recommended LLLT dose and reported insignificant results.

Figure 2 Pain results from immediately after the end of therapy. LLLT, low-level laser therapy.

The funnel plots indicated that there was no publication bias (online supplementary material). We additionally checked for small study bias by reducing the statistical 
weight of the smallest studies through a change from random to fixed effects models and this led to similar mean effect estimates, indicating that there was no small study bias (online supplementary material).

Methodological quality of the included trials was judged adequate (low risk of bias), unclear (unclear risk of bias) and inadequate (high risk of bias) in 75%, 19% and 6% instances, respectively. Risk of detection bias and reporting bias appeared low in all the trials. There was a lack of information regarding random sequence generation in five trials, allocation concealment in 12 trials, blinding of therapist in four trials and incomplete outcome data in four trials. Therapist blinding was inadequate in seven trials and there was an inadequate handling of data in a single trial (figure 6). However, risk-of-bias subgroup analyses conducted post hoc revealed that there was no statistically significant interaction between the effect estimates and risk of bias, and the analyses did not display a drop in statistical heterogeneity (online supplementary material). Support for our risk of bias judgments is available (online supplementary material).

Neither did the levels of statistical heterogeneity change when we switched from the MD to the SMD method posthoc (online supplementary material). 

Post hoc analyses demonstrated that LLLT was significantly superior to placebo both with exercise therapy (p=0.0009 for pain and p<0.0001 for disability) and without exercise therapy (p=0.01 for pain and p=0.008 for disability) as cointervention (online supplementary material).

Figure 3 Pain results from follow-ups 1–12 weeks after the end of therapy. LLLT, low-level laser therapy.

Figure 4 Disability results from immediately after the end of therapy. LLLT, low-level laser therapy.

Post hoc analyses were performed to more precisely estimate the pain time-effect profile for the recommended LLLT doses by imputing the results of the trials with these doses in subgroups with narrower time intervals. Pain was significantly reduced by the recommended LLLT doses compared with placebo immediately after therapy weeks 2–3 and 4–8 and at follow-ups 2–4, 6–8 and 12 weeks later; the peak point was 2–4 weeks after the end of therapy (31.87 mm VAS beyond placebo (95% CI 18.18 to 45.56); I2=93%; n=322). The 21-week and 34-week follow-up pain results were not statistically significant (figure 7 and online supplementary material). The statistical heterogeneity in the main pain analyses of the recommended LLLT doses was high (I2=95%; figures 2–3) but the mean statistical heterogeneity of the five subgroups covering the same time period was only moderate (I2=58%; figure 7 and online supplementary material).

Discussion

Our meta-analyses showed that pain and disability were significantly reduced by LLLT compared with placebo. We subgrouped the included trials according to the 
WALT recommendations (2010) for laser dose per treatment spot, and this revealed a significant dose–response relationship. Our principal finding is that the recommended LLLT doses offer clinically relevant pain relief in KOA. The non-recommended LLLT doses provided no or little positive effect.

The absolute minimally clinically important improvement (MCII) of pain in KOA has been estimated to be 19.9, 17 and 9 units on a 0–100 scale in 2005, 2012 and 2015, respectively. It is important to note that the MCII of pain is a within-subject improvement and depends on baseline pain intensity. The pain reduction from the recommended LLLT doses was significantly superior to placebo even at follow-ups 12 weeks after the end of therapy, and the difference was greater than 20 mm VAS from the final 4–8 weeks of therapy through follow-ups 6–8 weeks after the end of therapy. Interestingly, the pain reduction from the recommended LLLT doses peaked at follow-ups 2–4 weeks after the end of therapy (31.87 mm VAS highly significantly beyond placebo). 

Disability was also significantly reduced by the recommended LLLT doses compared with placebo, that is, to a moderate extent at the end of therapy (SMD=0.75) and to a large extent during follow-ups 2–8 weeks later (SMD=1.31). More trials with disability assessments are needed to precisely estimate the effect of LLLT on this outcome during follow-up.

Figure 5 Disability results from follow-ups 1–12 weeks after the end of therapy. LLLT, low-level laser therapy.

Figure 6 Risk-of-bias plot of the included trials. The trials are ranked by mean pain effect estimates, that is, more laser positive results in the bottom of the figure; the plot is based on the results from the main pain analyses (immediately after the end of therapy, primarily).

Furthermore, our analyses demonstrated that LLLT is effective in KOA both with and without exercise therapy as cointervention. Strength training was seemingly only used as an adjunct to LLLT in two of the included trials, and thus more trials with this combination of treatments are needed.

Risk of bias of the included trials appeared insignificant and could not explain the statistical heterogeneity (online supplementary material). We find it plausible that some of the statistical heterogeneity of the overall analyses is associated with the dose subgroup criteria (wave length-specific laser doses per treatment spot) since the 
mean levels of statistical heterogeneity of the subgroup analyses were consistently lower than the overall levels. It is unknown to us whether other differences in the LLLT protocols impacted the results.

The statistical heterogeneity in the main pain analyses of the recommended LLLT doses was high, and some of it can be explained by the pooling of results from various time points of assessment given the pain reduction increased and subsequent decreased with time; the pain reduction time profile showed a drop in statistical heterogeneity to a moderate level.

According to WALT, the osteoarthritic knee should be laser irradiated to reduce inflammation and promote tissue repair. One of the discrepancies from our 
review and previously published reviews of the same topic is that we omitted the RCT by Yurtkuran et al, as they solely applied laser to an acupoint located distally from the knee joint (spleen 9).

In line with our findings and the WALT dose recommendations, Joensen et al observed that the percentage of laser penetrating rat skin at 810 and 904 nm wavelength was 20% and 38%–58%, respectively. That is, to deliver the same dose beneath the skin, 2.4 times the energy on the skin surface is required with an 810 nm laser compared with a 904 nm laser device. This may be due to the different wavelengths and/or because 904 nm laser is superpulsed (pulse peak power ≥ 10 000 mW typically), whereas shorter wavelength laser is delivered continuously or with less intense pulsation. The estimated median dose applied with the recommended LLLT was 6 and 3 J per treatment spot with 785–860 and 
904 nm wavelength laser, respectively. Most of the trial authors reported LLLT parameters in detail but did not state whether the laser devices were calibrated. Therefore, in the LLLT trials with non-significant effect estimates, equipment failure cannot be ruled out.

It is important to note that no adverse events were reported by any of the trial authors and the dropout rate was minor, indicating that LLLT is harmless. Our clinical findings that the effect of LLLT progresses over time is in line with in vivo results of Wang et al. The positive effect from LLLT seems to last longer than those of widely recommended painkiller drugs. The effect of using the NSAID tiaprofenic acid, for example, is probably 
gone within a week, unless the treatment is continued. Future trials should investigate whether booster sessions of LLLT can prolong the positive effect. Comparative cost-effectiveness analyses of LLLT and NSAIDs would also be of great interest.

Figure 7 Pain time-effect profile (recommended low-level laser therapy (LLLT) doses versus placebo-control). Values on the y-axis are mm Visual Analogue Scale (VAS) pain results. Positive VAS score indicates that the recommended LLLT doses are superior to placebo. The related forest plot is available (online supplementary material). **The recommended LLLT doses are highly statistically significantly superior to placebo (p≤0.01).

Strengths and limitations of this study

In contrast to previous reviews on the current topic, our review was conducted in conformance with an a priori published protocol, which included a detailed plan 
for statistical analysis (eg, laser dose subgroup criteria). Furthermore, this is the first review on this topic without language restrictions, and this expansion proved 
important since four (18%) of the included trials were 
reported in non-English language. 

We conducted a series of meta-analyses illustrating the effect of LLLT on pain over time. To ensure high reproducibility of the meta-analyses, three persons each independently extracted the outcome data from the included trial articles.

This review is not without limitations. It lacks QoL analyses, a detailed disability time-effect analysis and direct comparisons between LLLT and other interventions.

Conclusions

LLLT reduces pain and disability in KOA at 4–8 J with 785–860 nm wavelength and at 1–3 J with 904 nm wavelength per treatment spot.

Contributors: MBS, JMB and HL wrote the PROSPERO protocol. MBS and JMB selected the trials, with the involvement of IFN when necessary. MBS and JJ judged the risk of bias, with the involvement of IFN when necessary. MBS and IFN did the translations. MBS, JMB and KVF extracted the data. MBS performed the analyses, under supervision of JMB. All the authors participated in interpreting of the results. MBS drafted the first version of the manuscript, and subsequently revised it, based on comments by RÁBL-M, HS and all the other authors. All the authors read and accepted the final version of the manuscript. 

Funding The University of Bergen funded this research. 

Competing interests JMB and RÁBL-M are post-presidents and former board members of World Association for Laser Therapy, a non-for-profit research organization from which they have never received funding, grants or fees. The other authors declared that they had no conflict of interests related to this work. 

Patient consent for publication Not required. 

Provenance and peer review Not commissioned; externally peer reviewed. 

Data availability statement The dataset for meta-analysis is available from the 
corresponding author upon reasonable request. The corresponding author affirms that the manuscript is an honest, accurate and transparent account of the study being reported; that no important aspects of the study have been omitted; and that any discrepancies from the study as planned (and, if relevant, registered) have been explained. 

Open access This is an open access article distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited, appropriate credit is given, any changes made indicated, and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/.

OrCID iD 
Martin Bjørn Stausholm http://orcid.org/0000-0001-9869-0705

Immediate pain relief effect of low level laser therapy for sports injuries: Randomized, double-blind placebo clinical trial

ABSTRACT

Objectives: To determine the immediate pain relief effect of low-level laser therapy on sports injuries in athletes and degree of pain relief by the therapy.  
Design: Double-blind, randomized, comparative clinical study. 
Methods: Participants were 32 college athletes with motion pain at a defined site. Participants were randomized into two groups in which the tested or placebo laser therapy was administered to determine pain intensity from painful action before and after laser irradiation, using the Modified Numerical Rating Scale. The post-therapeutic Modified Numerical Rating Scale score was subtracted from the pre-therapeutic Modified Numerical Rating Scale score to determine pain intensity difference, and the rate of pain intensity difference to pre-therapeutic Modified Numerical Rating Scale was calculated as pain relief rate. 
Results: Low-level laser therapy was effective in 75% of the laser group, whereas it was not effective in the placebo group, indicating a significant difference in favor of the laser group (p <0.001). Pain relief rate was significantly higher in the laser group than in the placebo group (36.94% vs. 8.20%, respectively, < 0.001 with the difference in pain relief rate being 28.74%. 
Conclusions: Low-level laser therapy provided an immediate pain relief effect, reducing pain by 28.74%. 
It was effective for pain relief in 75% of participants.

Introduction

Sports injuries constitute a serious problem for many athletes and others who participate in sports because they cause pain and dysfunction, resulting in the inability to continue sports activities. Various physical therapies, including electrotherapy, thermotherapy, cryotherapy, and phototherapy, have been used to alleviate symptoms of sports injuries such as pain. Low-level laser therapy (LLLT) has been clinically introduced as one of such physical therapies. LLLT has been examined in clinical research and reported to be effective for its long-term effect on many diseases in the general Bjordal et al, reported that a single session adult population. of LLLT relieved tenderness at the affected site in patients with Achilles tendinitis, and they demonstrated both immediate and long-term effects on injuries in the general adult population.

Studies on the effect of LLLT on sports injuries in athletes are limited to the reports of its effect on sprained ankles and Achilles tendinopathy. In both of these studies, the effect of LLLT was the same as was observed in the general adult population. In the study by Stergioulas in patients with sprained ankles, LLLT that was given twice daily significantly alleviated edema at 24-72 h as compared with placebo therapy. In another study by Stergioulas et al. in recreational athletes with Achilles tendinopathy, the combination of eccentric exercise and LLLT for 4-12 weeks alleviated motion pain as compared with placebo therapy. Thus, LLLT has been demonstrated to alleviate edema and pain associated with sports injuries in a few days to weeks. However, these studies did not 
provide any data on the immediate pain relief effect of LLLT on sports injuries in athletes.

Because athletes with sports injuries need earlier functional recovery compared to members of the general population, the immediate effect of LLLT is important. Therefore, this study was designed to evaluate whether LLLT provides an immediate pain relief effect on sports injuries in athletes and to determine the extent of pain relief by LLLT.

2. Materials and methods

A double-blind. randomized, placebo-controlled, parallel-group comparison study was performed. Participants were randomly assigned to the laser or placebo group.

Forty-seven college athletes met the following inclusion criteria: participation in intercollege to athletic activities 5 days/week or more; treatment at Osaka University of Health and Sport Sciences Clinic between July 1, 2013, and January 31, 2015 for sports 
injury; and diagnosis by an orthopedist with an orthopedic sports injury for which LLLT was indicated. LLLT was indicated for sport injuries if the following criteria were met: the injuries were painful in motion; the painful area was defined; LLLT was not contraindicated; and the injuries were not associated with any neurological findings.

Exclusion criteria were the inability to define the painful area and absence of definite motion pain. Of the 47 patients enrolled in the study, 32 with a definite painful area and motion pain were included as participants.

The 32 participants were randomly assigned to one of two groups, in which either LLLT or placebo laser therapy was administered (the laser and placebo groups, respectively) according to an assignment table prepared by the coordinator using computer-generated random numbers. The following additional data were collected for each participant: name and site of injury, and period from injury to therapy (number ofdays after injury). The laser group includes 9 patients with ankle sprain, 1 patient with navicular stress fracture, 1 patient with plantar fasciitis, 1 patient with patella tendinitis, 1 patient with spondylolysis, 1 patient with shoulder arthroscopic surgery, 1 patient with triangular fibrocartilage complex injury, and 1 patient with proximal thumb avulsion fracture. The placebo group includes 5 patients with ankle sprain, 2 patients with meniscal injuries, 2 patients with elbow medial collateral ligament sprain, 2 patients with Achilles tendinitis, 1 patient with low back pain, 1 patient with lumbar facet arthritis, 1 patient with infraspinatus muscle injury, 1 patient with deltoid muscle injury, and 1 patient with shoulder periarthritis.

The sample size of the study was calculated at 15 per group using a statistical power of 0.9, intergroup difference of 30, standard deviation of 25. and significant level of 5% with reference to the results of Malliaropoulos et al.10 EZR statistical software all (Saitama Medical Center, Jichi Medical University, Japan, http://www.jichi.ac.jp/saitamasctlSaitamaHP.files/statmedEN.html) was used for calculating the sample size.

This study was performed with the approval of the Research Ethics Committee of Osaka University of Health and Sport Sciences (Approval No. 12-29). Participants who received oral and written explanation of the study and provided written consent to participate were included in the study. LLLT was performed as one of the therapeutic measures after the experiment was completed. Data were collected in the physiotherapy room of Osaka University of Health and Sport Sciences Clinic. None of the participants prematurely discontinued the experiment.

Participants in the laser group received LLLT from laser therapy equipment (Softlasery JQ-WI , Minato Medical Science Co., Ltd, Japan) with an output of 180 mW, irradiation time of 30 s, and total irradiation time of 10 min (Table 1). Participants in the placebo group received placebo therapy from a placebo device (detuned laser) with an output of OmW, irradiation time of 30s, and total irradiation time of 10 min. The Softlasery used for this study was contact-type laser therapy equipment with an irradiation area of 0.0035cm2. The most painful area during a painful motion was selected as the irradiation site. In order to find the most painful area, participants were asked to explain the most painful motion during their daily or athletic activities. Then participants were asked to identify the most painful area by their index finger during the movement.

Because the study was double-blinded, the measurer and participants were blinded as to whether they used the actual or placebo laser equipment. The output, irradiation time, and total irradiation time of the laser therapy equipment were setup by the coordinator before each participant entered the physiotherapy room. The measurer left the physiotherapy room before the coordinator setup the laser therapy equipment and was call back after the setup. Each participant operated the laser equipment independently after receiving instructions on how to use it by the coordinator. Irradiation site was kept within 1 cm2. Therefore a laser prove was applied on the most painful area within a 1 cm2 area for 30 s each time for time of 10 min. To ensure participant safety and eliminate participant bias, participants were instructed not to look at the laser light during laser irradiation. The measurer observed the therapy procedure and measured pain intensity of the painful motion before and after laser irradiation in both groups. Pain during the painful motion was measured using the Modified Numerical Rating Scale (MNRS), which is a 10-cm scale from 0 to 10 at I-cm intervals in millimeters, with 0 representing no pain and 10 representing the worst pain.

Injury sites were classified into upper limbs, lower limbs, and body trunk. The MNRS score after the therapy (post-MNRS) was subtracted from that before the therapy (pre-MNRS) to determine the pain intensity difference (PID). The rate of PID relative to the 
pre-MNRS was calculated as the pain relief rate (PRR). 
PID = Pre-MNRS - Post-MNRS 
PRR = PID/Pre-MNRS x 100

Statistical analysis was performed using SPSS 21 .OJ for Windows (IBM Corporation, Armonk, NY, USA) and EZR. The mean number of days after injury, mean PRR, and the 95% confidence interval (95% CI) were calculated for each group.

The difference in injury sites between the groups was tested using Fisher's exact test, with a significance level of 5%. The difference in the number of days after injury, pre-MNRS. or PRR between the groups was tested using an unpaired t-test with a significance 
level of 5%. When a significant difference in the PRR was observed between the groups, PRR was classified into poor, fair, good, excellent based on the mean value of the difference and 95% Cl. A PRR value equal to or above the mean value of the difference in 
PRR between the groups was considered to indicate that LLLT was effective, and a PRR value below the mean value was considered to indicate that LLLT was ineffective. The difference in the rate of participants in whom LLLT was effective or ineffective was tested with the 12, test with a significance level of 5%.

3. Results

Their characteristics and comparison are shown in Table 2. No significant difference in injury sites (p =0.556, Table 2) or number of days after injury (p=O.706, t=O.380, Table 2) was observed between the groups. The rate of participants in whom LLLT was effective was 75% in the laser group and 0% in the placebo group, and the rate of participants in whom LLLT was ineffective was 25% in the laser group and 100% in the placebo group, with a significant difference between the groups (p < 0.001, 12 = 19.20, Fig. 1). The PRR was significantly higher in the laser group than in the placebo group (36.94%[95% Cl: 25.81-48.071 vs. 8.20%[95% Cl: 2.43-13.981; p < 0.001 , t = 4.886, Table 2), with an intergroup difference of 28.74% (95% Cl: 16.72-40.75, Table 2).

Table 2 
Participants characteristics with statistical comparison.

4. Discussion

Although an earlier study9 showed that long-term LLLT had a pain relief effect on Achilles tendinopathy in sports injuries, no studies have specifically examined the immediate pain relief effect and PRR of LLLT in injured athletes who need early return to play. Therefore, to examine the immediate pain relief effect of LLLT on sports injuries, this study was performed as a double-blind, randomized, placebo-controlled clinical trial to compare the pain relief effect of one session of LLLT in the laser group with that of placebo therapy in the placebo group. The results showed a significantly higher rate of pain relief effect among participants in the laser group (p < 0.001). Low-level laser has been reported to provide various effects, including inhibition of nerve excitement, anti-inflammation, and tissue repair. The immediate pain relief effect that we observed is more likely related to inhibition of nerve excitement than to chronic effects such as anti-inflammation and tissue repair. In 25% of the laser group in whom LLLT was not effective, no specific characteristics were observed and no specific causal factors could be identified. This is consistent with the results of Malliaropoulos et al.. 10 who reported that 4-weeks LLLT was not effective in 12.5% of patients with meniscal injuries and that no specific causal factors could be determined. In addition to the pain relief effect of LLLT, we examined the PRR to determine the degree of pain relief. The PRR was significantly higher in the laser group than in the placebo group (36.94% vs. 8.2%, respectively, p < 0.001 ), and LLLT immediately relieved motion pain by 28.74% (Table 2). Malliaropoulos et al. reported that 4-weeks LLLT and placebo laser relieved pain by approximately 65% and 22%, respectively, in a randomized controlled trial in patients with meniscal injuries. Bjordal et al. investigated the change in tenderness at the affected site after a single session of LLLT and reported that LLLT significantly relieved tenderness as compared with placebo laser therapy. The results of the present study support the earlier report of Bjordal et al. in terms of the comparable immediate pain relief effect of LLLT although the pain relief effect was lower than that observed with 4-weeks LLLT in the study by the Malliaropoulos et al.  In the present study. no significant difference was noted between the two groups for injury sites, number of days after injury, or pre-MNRS, indicating that the observed pain relief effect was attributable to low-level laser irradiation and that the effect of injury sites, number of days after injury. and pre-treatment pain intensity was limited. Moreover, LLLT relieved the pain associated with the sports injuries by 36.94%. Based on the difference from placebo therapy, the rate of pain relief from low-level laser irradiation was 28.74%, and immediate pain relief occurred in 75% of the participants.

Bjordal et al. reported that a single session of LLLT reduced the accumulation of prostaglandin E2. an inflammatory substance, at 105 min. Thus, LLLT appears to have not only an immediate pain relief effect, but also late anti-inflammatory and tissue-repair promoting effects, and may be useful in combination with active exercise therapy. In fact, Stergioulas reported that the combination of plyometric exercise and LLLT relieved pain more than the combination of the exercise therapy and placebo laser in patients 
with humeral lateral epicondylitis. Furthermore, Stergioulas et al. reported that the combination of eccentric exercise and LLLT resulted in better relief of motion pain than the combination of the exercise therapy and placebo laser in recreational athletes with 
Achilles tendinopathy. Thus, the present study provides important data to demonstrate the uses (e.g., immediate pain relief and promotion of exercise therapy) and efficacy of LLLT. The present study was limited by its failure to cover all sports injuries. LLLT was not shown to be effective for all sports injuries.

Conclusions

To examine the immediate pain relief effect of LLLT on sports injuries. the present study was performed as a randomized, double-blind, placebo-controlled, clinical study comparing the pain relief effect of a single session of LLLT with that of placebo laser therapy. The results revealed that LLLT relieved pain associated with sports injuries by 36.94%. Based on the difference from the placebo therapy, the rate of pain relief from low-level laser irradiation was 28.74%, and significant immediate pain relief occurred in 75% of the participants. These results serve as important data to demonstrate the usefulness of LLLT in combination with active exercise therapy.

Practical implications

• Low-level laser therapy has immediate effect of pain relief for motion pain in sports injuries.
• Low-level laser therapy should be applied to a small treatment area for pain relief.
• Low-level laser therapy should not apply to the patients with inability to define the painful area and absence of definite motion pain.

Acknowledgements

The authors received no assistance, including research grants, except for the placebo laser device lent from Minato Medical Science Co., Ltd. The authors thank the athletes who participated as subjects in this study.

Fig. 1. PRR classification and comparison of ineffective with effective. PRR: pain relief rate (X). 12 test with a significance level of 5%. PRR was classified into poor. fair. good, 
excellent based on the mean value of the difference and 95% Cl. A PRR value equal to or above the mean value of the difference in PRR between the groups was considered 
to indicate that LLLT was effective. and a PRR value below the mean value was considered to indicate that LLLT was ineffective.

A systematic review with procedural assessments and meta-analysis of Low Level Laser Therapy in lateral elbow tendinopathy (tennis elbow)

Jan M Bjordal, Rodrigo AB Lopes-Martins, Jon Joensen, Christian Couppe, Anne E Ljunggren, Apostolos Stergioulas, Mark I Johnson

BMC Musculoskeletal Disorders20089:75       
https://doi.org/10.1186/1471-2474-9-75      
© Bjordal et al; licensee BioMed Central Ltd. 2008      
Received: 29 January 2008      
Accepted: 29 May 2008      
Published: 29 May 2008

Abstract

Background      
Recent reviews have indicated that low level level laser therapy (LLLT) is ineffective in lateral elbow tendinopathy (LET) without assessing validity of treatment procedures and doses or the influence of prior steroid injections.

Methods      
Systematic review with meta-analysis, with primary outcome measures of pain relief and/or global improvement and subgroup analyses of methodological quality, wavelengths and treatment procedures.

Results      
18 randomised placebo-controlled trials (RCTs) were identified with 13 RCTs (730 patients) meeting the criteria for meta-analysis. 12 RCTs satisfied half or more of the methodological criteria. Publication bias was detected by Egger's graphical test, which showed a negative direction of bias. Ten of the trials included patients with poor prognosis caused by failed steroid injections or other treatment failures, or long symptom duration or severe baseline pain. The weighted mean difference (WMD) for pain relief was 10.2 mm [95% CI: 3.0 to 17.5] and the RR for global improvement was 1.36 [1.16 to 1.60]. Trials which targeted acupuncture points reported negative results, as did trials with wavelengths 820, 830 and 1064 nm. In a subgroup of five trials with 904 nm lasers and one trial with 632 nm wavelength where the lateral elbow tendon insertions were directly irradiated, WMD for pain relief was 17.2 mm [95% CI: 8.5 to 25.9] and 14.0 mm [95% CI: 7.4 to 20.6] respectively, while RR for global pain improvement was only reported for 904 nm at 1.53 [95% CI: 1.28 to 1.83]. LLLT doses in this subgroup ranged between 0.5 and 7.2 Joules. Secondary outcome measures of pain free grip strength, pain pressure threshold, sick leave and follow-up data from 3 to 8 weeks after the end of treatment, showed consistently significant results in favour of the same LLLT subgroup (p < 0.02). No serious side-effects were reported.

Conclusion      
 LLLT administered with optimal doses of 904 nm and possibly 632 nm wavelengths directly to the lateral elbow tendon insertions, seem to offer short-term pain relief and less disability in LET, both alone and in conjunction with an exercise regimen. This finding contradicts the conclusions of previous reviews which failed to assess treatment procedures, wavelengths and optimal doses.

Background

Lateral elbow tendinopathy (LET) or "tennis elbow" is a common disorder with a prevalence of at least 1.7% [1], and occuring most often between the third and sixth decades of life. Physical strain may play a part in the development of LET, as the dominant arm is significantly more often affected than the non-dominant arm. The condition is largely self-limiting, and symptoms seem to resolve between 6 and 24 months in most patients [2].

A number of interventions have been suggested for LET. Steroid injections, non-steroidal anti- inflammatory drugs or a regimen of physiotherapy with various modalities, seem to be the most commonly applied treatments [3]. However, treatment effect sizes seem to be rather small, and recommendations have varied over the years. In several systematic reviews over the last decade [4, 5], glucocorticoid steroid injections have been deemed effective, at least in the short-term. But in later well-designed trials evidence is found that intermediate and long-term effects of steroid injections groups yield consistently and significantly poorer outcomes than placebo injection groups, and physiotherapy or wait-and-see groups [6, 7]. Nevertheless, steroid injections have been considered as the most thoroughly investigated intervention, with 13 randomized controlled trials comparing steroid injections to either placebo/local anaesthetic or another type of intervention [5]. Non-steroidal anti-inflammatory drugs (NSAIDs) have been found to achieve smaller short-term effect sizes than steroid injections [8], and topical application seems to be the best medication administration route [8] For oral administration of NSAIDs for LET, evidence is inconclusive from two heterogeneous trials only [9]. The positive short-term results of anti-inflammatory therapies in LET appear to partly contradict the recent paradigm in tendinopathy research, where LET is thought to be mainly a degenerative disorder with minimal inflammation [10, 11].

Exercise therapy and stretching exercises have been used either alone or in conjunction with manipulation techniques or physical interventions. Although the sparse evidence makes it difficult to assess the separate effect of active exercises or stretching [12], four studies have found that either exercises alone [13], or in conjunction with a physiotherapy package, are more effective than placebo ultrasound therapy or wait-and-see controls. Also exercise therapy, particularly eccentric exercises, have been found effective in the intermediate term in tendinopathies of the Achilles, patellar or shoulder tendons [14, 15, 16, 17]. There is some evidence suggesting that joint manipulation or mobilisation techniques either of the wrist, elbow or cervical spine may contribute to short-term effects in LET [18, 19, 20].

Among the physical interventions, ultrasound therapy has been considered to offer a small benefit over placebo from two small trials [12], but a well-designed and more recent trial did not find significant effects of ultrasound therapy in LET [21]. Reviewers have arrived at different

conclusions for the effect of acupuncture [22, 23]. In reviews of physical interventions for LET, conclusions may vary between reviews because of differences in the treatment procedures. A good example of this is the negative conclusion of the LET review for extracorporeal shockwave therapy (ESWT) by Buchbinder et al. [24], where a later review with in-depth assessments of treatment intervention protocols [25], found that a subgroup of trials with proper treatment procedures and adequate timing of outcomes gave a positive result.

Low level laser therapy (LLLT) has been available for nearly three decades, and scattered positive results have been countered by numerous negative trial results. Several systematic reviews have found no significant effects from LLLT, in musculoskeletal disorders in general [26], and in LET in particular [12, 23, 27]. In this perspective it may seem futile to perform yet another systematic review in this area. But none of these reviews evaluated the results separately for the different LLLT treatment procedures, laser wavelengths or doses involved. Neither did they implement evidence of the newly discovered biomodulatory mechanisms which are involved when LLLT is applied. During the last 5–6 years the annual number of published LLLT reports in Medline has increased from 25 to around 200. We recently made a review of this literature, and concluded that LLLT has an anti-inflammatory effect in 21 out of 24 controlled laboratory trials, and a biostimulatory effect on collagen production in 31 out of 36 trials [28].      
Both of these effects were dose-dependent and could be induced by all wavelengths between 630 and 1064 nm with slight variations in therapeutic dose-ranges according to the wavelength used. The anti-inflammatory effect was seen in higher therapeutic dose-ranges than the biomodulatory effect on fibroblast cells and collagen fibre production. Diagnostic ultrasonography of tendinopathies has revealed that partial ruptures and tendon matrix degeneration are underdiagnosed if only physical examinations are made. Consequently, the stimulatory LLLT- effect on collagen fibre production should probably be beneficial for tendon repair. Another interesting feature was that LLLT with too high power densities or doses (above 100 mW/cm2), seemed to inhibit fibroblast activity [29] and collagen fibre production [30]. Six years ago we showed in a systematic review of tendinopathy, that the effect of LLLT is dose-dependent [31]. At the time, the accompanying editoral suggested that the advanced review design could become the new standard for reviewing empirical therapies with unknown optimal doses and procedural differences [32]. Steroids induce a down-regulation of cortisol receptors, and we recently discovered that the cortisol antagonist mifepristone completely diminished the anti-inflammatory effect of LLLT [33]. All these recent findings from the LLLT literature, prompted the World Association for Laser Therapy (WALT) to publish dosage recommendations and standards for the conductance of systematic reviews and meta-analyses last year [34]. One of the issues that has lacked attention is the validity of LLLT-application procedures in tendinopathy. To our knowledge there are only three valid irradiation techniques for LLLT in tendinopathies: a) direct irradiation of the tendon, b) irradiation of trigger points and c) irradiation of acupuncture points.

In this perspective and as our previous tendinopathy review [31] is becoming outdated, there seems to be a need for a new in-depth review of the effects of LLLT in LET where possible confounders are analyzed and subgroup analyses are performed.

Methods

Literature search

A literature search was performed on Medline, Embase, Cinahl, PedRo and the Cochrane Controlled Trial Register as advised by Dickersin et al. [35] for randomised controlled clinical trials. Key words were: Low level laser therapy OR low intensity laser therapy OR low energy laser therapy OR phototherapy OR HeNe laser OR IR laser OR GaAlAs OR GaAs OR diode laser OR NdYag, AND tendonitis OR lateral epicondylitis OR lateral epicondylopathy OR tennis elbow OR elbow tendonitis OR lateral epicondylalgia OR extensor carpi radialis tendonitis.      
Handsearching was also performed in national physiotherapy and medical journals from Norway, Denmark, Sweden, Holland, England, Canada and Australia. Additional information was gathered from researchers in the field.

Inclusion criteria      
The randomised controlled trials were subjected to the following seven inclusion criteria:

1. Diagnosis: Lateral elbow tendinopathy, operationalised as pain from the lateral elbow epicondyle upon finger or wrist extension
2. Treatment: LLLT with wavelengths in the range 632 – 1064 nm, irradiating either the tendon pathology, acupuncture points or trigger points
3. Design: Randomised parallel group design or crossover design
4. Blinding: Outcome assessors should be blinded
5. Control group: Placebo control groups or control groups receiving other non-laser interventions with at least 10 persons per group
6. Specific endpoints for pain intensity or global improvement of health measured within 1 – 52 weeks after inclusion.

Outcome measures       
Primary outcome measures      
Measured after the end of treatment, either as:

1. pain intensity on a 100 mm visual analogue scale (VAS) defined as the pooled estimate of the difference in change between the means of the treatment and the placebo control groups, weighted by the inverse of the pooled standard deviation of change for each study, i.e. weighted mean difference (WMD) of change between groups. The variance was calculated from the trial data and given as 95% confidence intervals [95% CI] in mm on VAS, or
2. improved global health status. This was defined as any one of the following categories: "improved", "good", "better", "much improved", "pain-free", "excellent". The numbers of "improved" patients were then pooled to calculate the relative risk for change in health status. A statistical software package (Revman 4.2) was used for calculations.      
   Secondary outcome measures
3. painfree grip strength (dynamometer, vigorimeter)
4. pain pressure threshold (algometer)
5. sick leave (days)
6. follow-up results at more than 1 week after the end of treatment for pain intensity (WMD) and/or improved global health status (RR) as described for the primary outcome measures

Due to possibility of measurement by different scales, the results for outcomes c) and d) are defined as the unitless pooled estimate of the difference in change between the mean of the treatment and the placebo control groups, weighted by the inverse of the pooled standard deviation of change for each study, i.e. standardised mean difference (SMD) of change between groups. The variance are calculated from the trial data and given as 95% confidence intervals.

Analysis of bias, including methodological quality, funding source and patient selection Positive bias direction, caused by flaws in trial methodology, funding source      
Trials were subjected to methodological assessments by the 10 point Delphi/PedRo checklists . as trials of weaker methodology have been found to exaggerate results in a positive direction. As profit funding has been shown to affect trial conclusions in a positive direction , analysis of funding sources was also performed.

Negative bias direction, caused by poor prognosis or effective co-interventions      
LET patients with long symptom duration and high baseline pain intensity are found to have significantly poorer prognosis in a trial with symptom durations of 8 to 21 weeks . Recent steroid injections have been reported to negatively affect prognosis in LET over a period of 3–12 months after injections . Patient selection of known responders only has been shown to inflate trial results with 38% , and consequently the inclusion of non-responders to treatments is likely to deflate effect sizes. Exercise therapy has been found effective in LET  and other tendinopathies [17], and the use of exercise therapy as a co-intervention may also deflate effect sizes or erase positive effects of LLLT. Consequently, we decided to analyze the included trials for presence of long symptom duration, treatment and treatment failures prior to inclusion, and effective co-interventions.

Results

Literature search results      
The literature search identified 1299 potentially relevant articles that were assessed by their abstracts. 1119 abstracts were excluded as irrelevant, 180 full trial reports were evaluated, and 18 trials met the inclusion criterion for randomisation (Figure 1).

However a further three randomised trials had to be excluded for not meeting the a priori trial design criteria for sample size in control group, specific endpoints or blinding. The results of this assessment are summarised in Table 1.      
Table 1      
Randomised LLLT-trials excluded for not meeting trial design criteria for diagnosis, blinding or specific endpoints.      
Trial characteristics by first author, method score, laser wavelength in nanometer, laser application technique, trial results and reason for exclusion.

 Analysis of treatment procedures

The remaining 15 trials were then evaluated for adequacy of their treatment procedures for active laser and placebo laser for adherence to either of the three valid application techniques (inclusion criterion 2). This resulted in the exclusion of 2 trials (Table 2, Figure 2).

 Figure 2     
Photograph showing laser therapy procedure with laser head in skin contact in trial by Haker et al. The photograph is taken the trial report in from Archives of Physical Medicine 1991. The drawing of the laser spot sizes at different distances is taken from the manual of Space Mix 5 Mid-Laser (Space s.r.l, Italy).     
Table 2

Randomised LLLT-trials excluded for not meeting criteria of valid procedures for active laser and placebo laser treatment.    
Trial characteristics given by first author, method score, laser wavelength, laser application technique, trial results and reason for exclusion.

Publication bias

The five excluded RCTs were taken into the publication bias analysis by a graphical plot as advised by Egger. Four out of the five excluded trials with grave methodological and procedural flaws, were small and reported negative results. Three trials with negative results for LLLT were performed by the same research group  although this group also reported a positive outcome . Three of these trials met the eligibility criteria for this review and were included in the meta-analysis . The five largest trials  all presented positive results, although Simunovic et al.  was excluded from our meta-analyses for variable timing of endpoints as stated above. Significant asymmetry was noted in the funnel plot, indicating a considerable degree of negative publication bias (Figure 3).

Figure 3

Funnel plot of published trial results given by WMD for pain relief over placebo measured on 100 mm VAS (x-axis), and sample size (y-axis).    
Bias analysis of 13 included trials    
Positive bias detection – poor methodological quality and for-profit funding sources    
The final study sample consisted of 730 patients in 13 trials. The mean and median methodological score was 6.5, and only one trial did not satisfy half or more methodological criteria. Two trials used the acupoints application technique, while the remaining eleven trials used the tendon application technique. None of the trials stated funding from laser manufacturing companies or had authors with affiliations to laser manufacturers. The trial characteristics and the sum methodological scores are listed in Table 3.    
Table 3    
Included randomised LLLT-trials.

 Trial characteristics by first author, method score, laser application technique, control group type, trial results. The abbreviations used are determined by the following categories: (-) means a result in favour of the control group, (0) means a non-significant result, (+) means a positive result for LLLT in at least one outcome measure, and (++) means a consistent positive results for more than one outcome measure.

Subgroup analysis for methodological quality   
The pre-planned subgroup analysis by methodological quality was not performed as all but a single low quality trial were rated fairly similarly with 6–8 criteria fulfilled out of 10 possible criteria. Minor inter-observer differences have been reported for methodological scorings by the Pedro criteria list, and the variance could be within the range of measurement error for this methodological criteria list . In addition, fulfilment of more than 50% of methodological criteria is often considered as a threshold for acceptable quality , and all but one trial with negative results were assessed with scores above this threshold. Consequently, we considered a separate subgroup analysis by methodological quality to be unnecessary to perform.

Negative bias detection – inclusion of patients with poor prognostic factors and effective co- interventions   
Three trials reported details confirming enrolment of patients without poor prognosis   
. In two of these trials , both active and placebo groups received concurrent exercise therapy, which may have deflated effect size. Seven trials reported demographic data affirmative on the inclusion of LET patients with poor prognosis, which are likely to deflate effect sizes. Results for possible confounding factors which may deflate effect sizes are summarized in Table S4, Additional file 1.

Assessment of LLLT procedures and treatment variables   
There was considerable heterogeneity in the treatment procedures and LLLT doses used in the included trials. Treatment characteristics for the 11 trials which used direct irradiation of tendon pathology are listed in Table S5, Additional file 1.

Treatment characteristics for trials which used acupoint irradiation are listed in Table S6, Additional file 1.

Outcomes and effect sizes    
Dichotomized trial results   
Eight out of thirteen trials (62%) reported one or more outcome measures in favour of LLLT over placebo. Eleven trials used the tendon application technique, and eight (73%) of these trials reported positive results for one or more outcome measures (Table 3). All seven trials using 904 nm wavelength and the tendon application technique yielded positive results, whereas three trials using lasers with 820/30 nm and 1064 nm wavelengths found no significant effect of LLLT. A single trial administering LLLT with a wavelength of 632 nm, also found significantly better results for the LLLT group. In the two trials where LLLT was administered to acupuncture points, no significant differences between LLLT and placebo were found for any of the outcome measures.

Meta-analyses of effects Primary outcomes   
Continuous data for pain relief was available from 10 trials in a way which made statistical pooling possible. At the first observation after the end of the treatment period, LLLT was   
significantly better than controls with a WMD of 10. 2 mm [95% CI: 3.0 to 17.5] in favour of LLLT on a 100 mm VAS (p = 0.005). In a subgroup of five trials [48, 50, 55, 56, 57] where 904 nm LLLT was administered directly to the tendon, LLLT reduced pain by 17.2 mm [95% CI: 8.5 to 25.9] more than placebo (p = 0.0001). One trial [60] with 632 nm LLLT, showed significantly better results for LLLT than a wrist brace and ultrasound therapy, but none of the results from trials with wavelengths of 820 nm or 1064 nm, or acupoint application technique were significantly different from placebo. The results are summarized in Figure 4.

Figure 4   
End of treatment results for LLLT measured as the WMD pain reduction on 100 mm VAS. Trials are subgrouped by application technique and wavelengths, and combined results are shown as total at the bottom of the table. Plots on the right hand side of the middle line indicate that the LLLT effect is superior to the control treatment.

Seven trials presented data in a way which allowed us to pool data for global improvement. LLLT was significantly better than placebo with an overall relative risk for improvement at 1.36 [95% CI: 1.16 to 1.60] (p = 0.002). In a subgroup of five trials   
 where 904 nm LLLT was used to irradiate the symptomatic tendon, the relative risk for global improvement was significantly better than placebo at 1.53 [95% CI 1.28 to 1.83] (p < 0.0001). In the remaining two trials [46, 58] where LLLT was administered to acupoints or with 820 nm wavelength, the relative risk for global improvement was not significantly different from placebo at 0.80 [95% CI 0.50 to 1.22]. The results are summarized in Figure 5.

 Figure 5   
End of treatment results for LLLT measured as global improvement. Trials are subgrouped by application technique and wavelengths, and their combined results are shown as total at the bottom of the table. Plots on the right hand side of the middle line indicate that the LLLT effect is superior to the control treatment.

Secondary outcomes

Painfree grip strength showed significantly better results after LLLT than placebo with SMDs of   
0.66 [95% CI: 0.42 to 0.90] [p < 0.0001). When trials were subgrouped by application technique and wavelengths, only trials with irradiation of tendons and wavelengths 632 nm or 904 nm, showed positive results versus control with SMDs at 1.09 [95% CI: 0.42 to 1.76] and 1.30 [95% CI: 0.91 to 1.68], respectively. The results are summarized in Figure 6.

 Figure 6   
End of treatment results for LLLT measured as the SMD for pain-free grip strength. Trials are subgrouped by application technique and wavelengths, and their combined results are shown as total at the bottom of the table. Plots on the right hand side of the middle line indicate that the LLLT effect is superior to the control treatment.

Two trials with 904 nm wavelength using application technique with tendon irradiation reported a small, but significantly elevated pain pressure threshold with SMD at 0.34 [95% CI:   
0.04 to 0.63] (p = 0.02), The results are summarized in Figure 7.

Figure 7   
End of treatment results for LLLT measured as the SMD for pain pressure threshold. Only trials using the tendon application technique and 904 nm wavelength were available, and their combined results are shown as the total at the bottom of the table. Plots on the right hand side of the middle line indicate that the LLLT effect is superior to the control treatment.

Sick leave   
One trial with 904 nm LLLT administered directly over the tendon insertion, presented sick leave data. The relative risk for not being sicklisted after treatment was significantly in favour of LLLT at 2.25 [95% CI: 1.25 to 4.06] (p = 0.0005).

Follow-up   
Six of the trials provided continuous follow-up data on a 100 mm VAS measured between 3 and 8 weeks after the end of treatment. The combined WMD was 11.30 mm   
[95% CI: 7.5 to 16.1] in favour of LLLT. For global improvement, three trials provided data suitable for statistical pooling, and the RR was calculated to 1.68 [95% CI: 1.32 to 2.13] in favour of LLLT. Subgroup analyses showed that three trials administering 904 nm LLLT directly over the tendon, WMD improved to 14.3 [95% CI: 7.3 to 21.3] and RR for improvement to 2.01 [95%CI: 1.48 to 2.73] in favour of LLLT, while a single trial with 632 nm wavelength and the same application procedure reported WMD of 14.0 [95%CI: 7.0 to 20.6]. The results are summarized in Figures 8 and 9.

Figure 8   
Follow-up results at 3–8 weeks after end of treatment for LLLT measured as the WMD for pain reduction on 100 mm VAS. Trials are subgrouped by application technique and wavelengths, and combined results are shown as total at the bottom of the table. Plots on the right hand side of the middle line indicate that the LLLT effect is superior to the control treatment.

Figure 9   
Follow-up results at 3–8 weeks after the end of treatment measured as the relative risk for global improvement for LLLT compared to placebo. Trials are subgrouped by application technique and wavelengths, and combined results are shown as total at the bottom of the table. Plots on the right hand side of the middle line indicate that the LLLT effect is superior to the control treatment.   
Only two trials using the tendon application technique with 904 nm wavelengths reported follow-up results beyond 8 weeks. They reported persisting significant improvement after LLLT for PFS at 3 months (SMD 0.40 [95%CI: 0.05 to 0.75]) [49], and significantly less patients with no or minor pain at work at 5.5 months (RR = 2.1 [95%CI: 1 to 4.3]), respectively. Other outcomes were not significantly different beyond 8 weeks. For the two trials using acupoint irradiation, no significant differences were found at any of the follow-up sessions.

Side-effects and compliance   
Treatment was generally well tolerated and no adverse events were reported. Compliance was high ranging from 100% to 91% in all but two trials. One of these trials had a considerably longer treatment period (8 weeks) than the other trials (median 3 weeks), and all withdrawals were caused by lack of effects. In another trial using 830 nm wavelength, an exceptionally high withdrawal/dropout rate of 15% occurred after a single treatment session without any given reason.

Discussion

In this review, we found that most RCTs of LLLT for LET were of acceptable methodological quality. This finding is in line with previous reviews, although there were some differences between reviewers in methodological scores for individual trials. RCTs of LLLT are of similar methodological quality and include similar sample sizes as RCTS included in recent reviews of corticosteroid injections  and topical or oral NSAIDs. Two of the previous reviews of LLLT for LET found only six RCTs, whereas an earlier review found ten RCTs, and excluded one RCT for methodological shortcomings. We used broader searching criteria in our review and had no language restrictions. This resulted in 18 potentially eligible RCTs. We excluded one RCT for not meeting the inclusion criteria of specific endpoints and another two RCTs for complete lack of blinding and a lack of an LET control group. None of the previous LET reviews assessed the LLLT regimen for procedural errors, while our procedural assessments resulted in exclusion of another two RCTs with grave procedural errors, such as leaving the tendon insertion and acupoints unirradiated [40] and giving adequate LLLT to the placebo group. These exclusions resulted in 13 RCTs being eligible for our review which is twice the number of RCTs included in two of the previously published reviews.

Previous LET-reviews of LLLT and pharmacological interventions like NSAID or corticosteroid injections have not assessed possible bias from for-profit funding sources or publication bias. Our analysis revealed that bias from for-profit funding was largely absent in the available LLLT material and that trials were performed by independent research groups receiving funding from internal sources or non-profit organisations. This feature of the LLLT literature is definitely different from pharmacological pain treatments where up to 83% of trials may be industry-funded. A second feature of the LLLT-literature is that publication bias seems to go in a negative direction. This is distinctly different from the drug trials where positive results have been found to account for up to 85% of the published trials in single journals , although this bias seems to be lesser or absent in high impact journals. 

Our review suggests that LLLT trials reporting negative results are more likely to be published than trials with positive results. To our knowledge we are the first to demonstrate such bias, but such negative publishing bias is probably not unique to LLLT, and it may also be present for other electrophysical agents including TENS and acupuncture. We were surprised to see how large well-designed positive trials of LLLT were published in unlisted journals or journals with low-impact factor, and how small negative trials, often with grave methodological or procedural flaws  were published in higher ranking journals. This may reflect a predominance of RCTs designed using drug-research methodology paradigms without due consideration given to adequacy of the technique used in delivering LLLT, leading to under dosing and negative outcome bias. In addition, it has been that documented drug sponsorship of research activities may influence guideline panels, journal editors and referees  leading to negative views on non-drug treatments such as LLLT as reflected in editorials in pain journals and national medical journals.

Despite these concerns, we believe that the positive overall results of this review need to interpreted with some caution. They arise from a subgroup of 7 out of the 13 included trials. These 7 trials had a narrowly defined LLLT regimen where lasers of 904 nm wavelength with low output (5–50 mW) were used to irradiate the tendon insertion at the lateral elbow using 2–6 points or an area of 5 cm2 and doses of 0.25–1.2 Joules per point/area.   
The positive results for this subgroup of trials were consistent across outcomes of pain and function, and significance persisted for at least 3–8 weeks after the end of treatment, in spite of several factors which may have deflated effect sizes.

For the red 632 nm wavelength which has a poorer skin penetration ability, a single trial with a higher dose (6 Joules) seemed to be equally effective as the lower doses of 904 nm used in the seven positive trials. These LLLT-doses are well within the therapeutic windows for reducing inflammation, increasing fibroblast activity and collagen fibre synthesis, and the dosage recommendations suggested by WALT [71].

The negative results for the 830 nm GaAlAs and 1064 nm NdYag lasers can be attributed to several factors such as too high doses, too high power density or the inclusion of patients with poor prognosis from long symptom duration and prior steroid injections. These wavelengths have previously been found effective in some tendon animal studies and in other locations such as shoulder tendinopathies. At this time it is not possible to draw firm conclusions about the clinical suitability of wavelengths 820, 830 and 1064 nm in LET treatment, but the lack of evidence of effects indicates that they cannot be recommended as LET treatment before new research findings have established their possible effectiveness. The lack of effect for these lasers may also serve as a reminder that higher doses is not always best. We have been witnessing a tendency where newly developed lasers with these wavelengths are being marketed with ever- increasing power and power densities. This may be inappropriate because current knowledge about LLLT mechanisms and dose-response patterns at higher powers is inconsistent or lacking.

The positive results for combining LLLT of 904 nm wavelength with an exercise regimen, are encouraging. We would have thought that exercise therapy could have erased possible positive effects of LLLT, but the results showed an added value in terms of a more rapid recovery when LLLT was used in conjunction with an exercise regimen. This may indicate that exercise therapy can be more effective when inflammation is kept under control. Adding LLLT to regimens with eccentric and stretching exercises reduced recovery time by 4 and 8 weeks in two trials. For this reason, LLLT should be considered as an adjunct, not an alternative, to exercise therapy and stretching.

Based on the above findings, LLLT should be considered as an alternative therapy to commonly used pharmacological agents in LET management. Cochrane-based reviews of NSAIDs and corticosteroid injections [5] have found evidence of short-term effects within 4 and 6 weeks, respectively. The short-term reduction in pain intensity after corticosteroid injections may appear to have a more rapid onset and may also be larger in effect size than after LLLT. But on the other hand, the available LLLT-material is confounded by factors capable of deflating effect sizes. In this perspective, there is a need for more high quality trials with head-to-head comparison of short-term effects between LLLT and corticosteroid injections. In the longer term, NSAIDs seems to be ineffective and corticosteroid injections seem to be harmful both at 26 and at 52 weeks. For LLLT there are some significant long-term effects found at 8, 12 and 24 weeks after the end of treatment.

Conclusion

The available material suggests that LLLT is safe and effective, and that LLLT acts in a dose- dependent manner by biological mechanisms which modulate both tendon inflammation and tendon repair processes. With the recent discovery that long-term prognosis is significantly worse for corticosteroid injections than placebo in LET, LLLT irradiation with 904 nm wavelength aimed at the tendon insertion at the lateral elbow is emerging as a safe and effective alternative to corticosteroid injections and NSAIDs. LLLT also seems to work well when added to exercise and stretching regimens. There is a need for future trials to compare adjunctive pain treatments such as LLLT with commonly used pharmacological agents.

Magnetic Resonance Imaging and Clinical Outcomes of Laser Therapy, Ultrasound Therapy, and Extracorporeal Shock Wave Therapy for Treatment of Plantar Fasciitis: A Randomized Controlled Trial

Aslihan Ulusoy, MD 1, Lale Cerrahoglu, MD 2, Sebnem Orguc, MD 3

1 Physiatrist, Department of Physical Medicine and Rehabilitation, Celal Bayar University Medical School, Manisa, Turkey 2 Professor, Department of Physical Medicine and Rehabilitation, Celal Bayar University Medical School, Manisa, Turkey 3 Professor, Department of Radiodiagnostics, Celal Bayar University Medical School, Manisa, Turkey

A B S T R A C T  

We determined and compared the effectiveness of low-level laser therapy (LLLT), therapeutic ultrasound (US) therapy, and extracorporeal shock wave therapy (ESWT) using magnetic resonance imaging (MRI). We per- formed a randomized, prospective, comparative clinical study. A total of 60 patients with a diagnosis of chronic plantar  fasciitis  were  divided  randomly  into  3  treatment  groups:  group  1  underwent  15  sessions  of  LLLT (8 J/cm2; 830 nm); group 2 underwent 15 sessions of continuous US (1 mHz; 2 W/cm2);  and  group  3  un- derwent 3 sessions of ESWT (2000 shocks). All patients were assessed using the visual analog scale (VAS), heel tenderness index (HTI), American Orthopaedic Foot and Ankle Society (AOFAS) ankle-hindfoot scale,  Roles–   
Maudsley score, and MRI before and 1 month after treatment. The primary efficacy success criterion was the percentage of decrease in heel pain of >60% from baseline at 1 month after treatment for �2 of the 3 heel pain (VAS) measurements. Significant improvement was measured using the mean VAS, AOFAS scale, and HTI   
scores for all 3 groups. The thickness of the plantar fascia had decreased significantly on MRI in all 3 groups. The treatment success rate was 70.6% in the LLLT group, 65% in the ESWT group, and 23.5% in the US group. LLLT and ESWT proved significantly superior to US therapy using the primary efficacy criterion (p ¼ .006 and p ¼ .012, respectively), with no significant difference between the LLLT and ESWT groups (p > .05). The treatment of chronic plantar fasciitis with LLLT and ESWT resulted in similar outcomes and both were more   
successful than US therapy in pain improvement and functional outcomes.   
© 2017 by the American College of Foot and Ankle Surgeons. All rights reserved.

Plantar fasciitis is the most common diagnosis (10% to 15%) for patients with foot and ankle pain (1). Plantar fasciitis has a multi- factorial etiology. It was previously thought to be an inflammatory syndrome; however, recent studies have emphasized that a degen- erative process is more dominant (2–4). The factors thought to be associated with the disease include biomechanical dysfunction, me- chanical overload, obesity, overuse, Achilles tendon strain, decreased ankle dorsiflexion, atrophy of the intrinsic muscles, and a pronated foot type (5,6). The patient’s history and physical examination find- ings are usually sufficient to diagnose plantar fasciitis. Patients typically present with a throbbing, burning, or piercing type of infe- rior heel pain, especially with the first few steps in the morning. However, the pain will decrease after a few steps but will return during the day with prolonged weightbearing activity.  Sometimes, the pain will persist for months or even years (4).   
Although not routinely necessary, imaging can be used to verify recalcitrant plantar fasciitis or to rule out other foot pathology. Magnetic resonance imaging (MRI), although expensive, is very sen- sitive and has been accepted as the standard imaging method to evaluate plantar fascia morphology and bone marrow edema. The MRI findings of plantar fasciitis include thickening of the plantar fascia, perifascial and intrafascial edema pattern at T2-weighted images, intrafascial T1-weighted signal enhancement, and a limited bone marrow edema pattern at the calcaneal tuberosity (7,8).   
The treatment options include numerous methods focusing on the anatomic and biomechanical problems and pain management. The recommended first-tier treatment options are nonsteroidal anti- inflammatory drugs, therapeutic orthotic insoles, limitations of extended physical activities, and Achilles and plantar fascia stretching

exercises (4,9). Patients will usually have a clinical response within 6 weeks. However, if the symptoms persist, second-tier treatment, including physical therapy, orthotic devices, steroid injections, and night splints be added to the ongoing first-tier treatment. Extracor- poreal shock wave therapy (ESWT) and surgery are recommended as the third tier of treatment for patients with chronic (6-month) plantar fasciitis recalcitrant to treatment (4).   
Low-level laser therapy (LLLT) can be used to accelerate wound healing and reduce pain and inflammation (10). The studies investi- gating the molecular effects of LLLT have focused on the photo- biomodulation and photobiostimulation phenomena, which promote cell proliferation and tissue regeneration (11). An important factor associated with the effectiveness of LLLT is tissue penetration capa- bility and the optimum dosage of energy. Therefore, standardization of the treatment protocols and dosages according to the disease directly affects the success of the treatment (12). In that context, the World Association for Laser Therapy group published disease-specific dosage recommendations for LLLT (13). Another treatment modality   
used for >60 years extensively in the treatment of acute and chronic   
pain is therapeutic ultrasound (US). Therapeutic US is used to produce thermal or nonthermal effects by high-frequency acoustic energy (14). US therapy is usually used in combination with the other con- ventional therapies for the treatment of the plantar fasciitis in daily practice. ESWT is another treatment recommendation for chronic plantar fasciitis approved in 2000 by the Food and Drug Adminis- tration. The possible effect of ESWT is stimulation of the wound healing cascade, allowing chronic damage to become acute damage and initiate the normal wound healing process by application of high- intensity pressure waves into the body. Previous studies reported a success rate for ESWT for plantar fasciitis  ranging  from  34%  to 88% (15).   
Despite the increasing popularity of LLLT and ESWT, randomized controlled trials comparing the efficacy of the treatment modalities are lacking. The aims of the present study were to determine and compare the clinical effects of LLLT, ESWT, and therapeutic US objectively using MRI at 1 month of follow-up for patients with chronic recalcitrant plantar fasciitis.   
Patients and Methods

Participants

From December 2012 to December 2014, the present study included 60 patients with chronic recalcitrant plantar fasciitis. All patients agreed to participate in the study and freely signed an informed consent statement after being informed about  the purpose of the study, examination, and treatment application. The local medical ethics committee approved the present study, which was supported by University Scientific Research Project Coordination.

The inclusion criteria were the presence of symptoms of a chronic recalcitrant plantar painful heel of �6 months duration that was unresponsive to 6 weeks of first- tier conservative treatment (nonsteroidal anti-inflammatory drug, home exercise program, and standard insoles). The diagnosis was confirmed clinically by the physical   
examination finding of tenderness to palpation with local pressure at the origin of the plantar fascia on the medial tubercle of the calcaneus and an indication of significant   
pain by a score of �5 for �1 of 3 visual analog scales (VASs; intensity of pain measured   
by the VAS for the first few steps in the morning, during daily activities, and during exercise) before treatment.   
The exclusion criteria were previous local trauma, foot surgery, local steroid injection within  the  previous  3  months,  local  infection,  abnormalities  in  the  knees or ankles, vascular disease, diabetes mellitus, malignancy, peripheral neuropathy, pacemaker, metal implants, rheumatic inflammatory disease, and plantar fascial rupture.   
The trial design was a prospective, randomized, comparative, clinical study with the investigators kept unaware of the treatment groups. The patients were advised to continue their standard home exercise program (plantar fascia stretching, calf muscle stretching, Achilles tendon stretching, and strengthening of the intrinsic muscles of the foot) previously implemented during the treatment course (2,4). Sixty patients were randomized into 3 treatment groups using the stratified block randomization method according to gender and body mass index by one of us (A.U.). The 3 groups were the LLLT group, US therapy group, and ESWT group. All patients were assessed using the VAS for heel pain (first steps in the morning, during daily activities, and during exer- cise), foot functionality (pain and range of motion domains) using the American Or- thopaedic Foot and Ankle Society (AOFAS) ankle-hindfoot scale and Roles–Maudsley score (RMS; patient-administered scoring system regarding activity limitations), and the sensitivity of the heel using the heel tenderness index (HTI) before and after   
1 month of treatment. The same investigator (L.C.) administered these measures and was kept unaware of the treatment groups. MRI was performed using a SIGNA™ HDXT   
1.5 Tesla MRI system (GE Healthcare, Chicago, IL) before and 1 month after treatment. The maximum thickness of the proximal plantar fascia where it attaches to the calca- neus was measured using electronic calipers on fluid-sensitive MRI sequences in the sagittal and coronal planes (Fig. 1). The intrafacial and perifacial soft tissue edema and calcaneal bone marrow edema were assessed in the sagittal plane on short tau inver- sion recovery sequences, and the presence of the calcaneal spurs was evaluated on T1- weighted sequences. After all the patients had completed therapy, the pre- and post- treatment MRI scans were interpreted simultaneously by a radiologist (S.O.), who was unaware of the treatment groups.   
LLLT, US therapy, and ESWT were performed by the same investigator (A.U.) using the BTL-5000 SWT combined device (BTL Turkey, Ankara, Turkey). All subjects were placed in the prone position during treatment.   
Group 1 underwent LLLT. All patients in group 1 received a total of 15 LLLT sessions (5 sessions each week during a consecutive 3-week period). All patients were treated with a gallium-aluminum-arsenide (GaAlAs) laser, with 830 nm of laser light with 50 mW. The laser probe was scanned into the areas of the painful heel, insertion of the plantar fascia on the medial calcaneal area, and the myofascial junction at the dorsum of the heel, for a total dose of 8 J/cm2 for 200 seconds.   
Group 2 underwent US therapy. All the patients in group 2 received a total of 15 US sessions (5 sessions each week during a consecutive 3-week period). US therapy was applied using the following parameters: continuous mode, base frequency of 1 MHz to produce a deeper penetration, power of 2 W/cm2 into the areas of the painful heel, insertion of the plantar fascia on the medial calcaneal area, and the myofascial junction at the dorsum of the heel for 5 minutes using an ultrasound gel.   
Group 3 underwent ESWT. All the subjects in the ESWT group received 3 sessions of ESWT weekly for 3 weeks. Ultrasound gel was applied for better transmission between the ESWT head and the skin. The patients received 2000 shock waves with a 2.5-bar

 Fig. 1. Evaluation of the plantar fascia thickness by magnetic resonance imaging on sagittal (5.4 mm) and coronal (5.6 mm) planes. Arrows indicate measurement location.

pressure, 10-Hz frequency during sessions into the areas of the painful heel, insertion of the plantar fascia on the medial calcaneal area, and myofascial junction at the dorsum of the heel.

Outcome Measures

The primary efficacy success criterion was defined as a �60% decrease in heel pain for �2 VAS measurements (16,17). The secondary outcome measures were a functional response to treatment as defined by the RMS (1 indicating  excellent; 2,  good; 3,  fair; and 4, a poor response), HTI (0 indicating excellent; 1, good; 2, fair; and 3, a poor response), and improvement in the AOFAS scale score and a reduction in plantar fascial   
thickness on MRI.

Statistical Analysis

In the present study, we calculated that the required minimum number of patients would be 45 for 3 groups, with an effect size of 0.48, an a of 0.05, and power of 0.80. Allowing for withdrawals, we determined that the number of participants should be 60.   
Statistical analyses were performed using the SPSS for Windows, version 15.0, software (IBM Corp., Armonk, NY). Descriptive statistics and frequency analysis were performed for categorical variables using counts and percentages, and the minimum, maximum, mean, and standard deviation are presented for the numerical variables. We performed the Wilcoxon test to compare the pretreatment and post-treatment findings within the groups; the McNemar test was used for categorical data. The Kruskal-Wallis test was used to assess the differences among the 3 groups and the crosstab chi-square test for categorical data. The Mann-Whitney U test used for pairwise comparisons. Correlations between  continuous  variables  were  analyzed  using  the  Pearson  correlation  test.   
A p value of < .05 was considered statistically significant.   

Results

Sixty patients fulfilled the inclusion criteria and were included in the present study. Of the 60 patients, 2 withdrew from the study during the treatment period (both from group 2), 4 were unable to complete the follow-up examination by 1 month after treatment (3 from group 1 and 1 from group 2), and 2 patients refused the second MRI examination at the follow-up visit because they reported their symptoms had completely improved (1 from group 1 and 1 from group 3; Fig. 2). Thus, the data from 54 patients were analyzed for the primary outcome and 52 for the MRI evaluations. Side effects were not observed in any patient. No significant differences were found in age, body mass index, or symptom duration in months among the 3   
groups (p > .05) before treatment (Table 1). Also, no significant dif-   
ferences were found in the initial clinical parameters as determined using the VAS (pain intensity), HTI, AOFAS scale, and RMS among the 3 groups (p > .05).   
In all 3 groups, significant differences were found between the pre-   
and post-treatment clinical values. The VAS score had significantly decreased and the AOFAS scale scores had significantly improved after treatment in all 3 groups (p < .05; Table 2).   
The primary efficacy measure of success (decreasing heel pain   
>60% for 2 of the 3 heel pain VAS measurements) was detected in 70.6% of the LLLT group, 65% of the ESWT group, and 23.5% of the US   
 

Fig. 2. Flowchart of the study design. Abbreviations: ESWT, extracorporeal shock wave therapy; LLLT, low-level laser therapy; MRI, magnetic resonance imaging; US, ultrasound.

Table 1   
Patient characteristics at enrollment stratified by treatment group

Abbreviations: BMI, body mass index; ESWT, extracorporeal shock wave therapy; LLLT, low-level laser therapy; SD, standard deviation; US, ultrasound.

group (Table 3). In the comparison of the 3 groups, LLLT and ESWT were found to be more effective than US therapy, with no significant difference found between LLLT and ESWT (group 1 versus 2, p .006; group 2 versus 3, p  .012; group 1 versus 3, p   .717) in the success rate (VAS score 60%).  
The RMSs for the functional responses are listed in Table 4. The RMSs improved in all 3 groups. The comparison showed that 2 treatment modalities (LLLT, p  .03; ESWT, p  .014) were more effective than US therapy, with no significant differences found be- tween LLLT and ESWT (p .82).  
The HTI score changes before and after treatment are listed in Table 5. In the comparison of the 2 groups, ESWT was found to be more effective than US therapy (p   .004). No significant difference was found between LLLT and ESWT (p .115) or between LLLT and US therapy (p .106).  
The initial MRI findings and measurements are listed in Table 6. Soft tissue edema was present in 88.3% and bone marrow edema in 36.7%. The fascia thickness was 4 mm in 86.7% on 1 plane. A sig- nificant decrease was revealed in the thickness of the fascia in all 3 groups after treatment (LLLT, p  .001; US, p < .001; ESWT, p < .001;  
Table 7). No statistically significant difference was found between the  
groups in the reduction of the fascia thickness measured on MRI. The reduction in plantar fascia thickness correlated moderately with the reduction in the pain with the first steps in the morning after treat- ment (p .027; r 0.306). Soft tissue edema persisted in 32 of the 52 patients at the 1-month follow-up MRI. Also, in these patients, the

Table 2  
Results for mean values of American Orthopaedic Foot and Ankle Society scale  and visual analog scale scores before and after treatment

Abbreviations: AOFAS, American Orthopaedic Foot and Ankle Society; ESWT, extra- corporeal shock wave therapy; LLLT, low-level laser therapy; US, ultrasound; VAS, vi- sual analog scale.    
*  Statistically significant.

Table 3    
Primary efficacy success rate* for the 3 groups

 apy; US, ultrasound.   
Data presented as n (%).   
* Decreasing in heel pain of >60% for �2 of the 3 heel pain (visual analog scale) measurements.

reduction in the VAS score for morning first step pain (p .040) and VAS score for pain with daily activity (p .037) was lower than that of the patients with complete regression of soft tissue edema. However, no significant differences were found in pain reduction with (n   13) or without (n   39) ongoing bone marrow edema after treatment (p > .05). The reduction in plantar fascia thickness in the excellent-   
good group using the RMS score was significantly greater than that   
in the fair-poor group on the sagittal (p .042) and coronal (p .023) planes.   
When the patients were invited to attend the follow-up clinic at the first year, they reported no serious symptoms that would require the patients to undergo physical therapy again.

Discussion

Plantar fasciitis is the most common cause of plantar heel pain in adults. The goals of treatment are pain relief and restoration of function (17). However, many different treatment strategies have been recommended, and limited evidence are available to support any of the common treatments (18). The findings from the present investigation showed that LLLT, US therapy, and ESWT all significantly reduced the pain with no side effects and provided an objective reduction in fascial thickness on MRI. However when we evaluated the effectiveness and functionality of the 3 treatment modalities, we found  that ESWT and  LLLT were  more  effective than US therapy at 1 month after the intervention.   
LLLT has gained popularity in recent years and has been supported by new evidence resulting from the standardization of dosing rec- ommendations according to the disease being treated. The first study of the effectiveness of LLLT in plantar fasciitis was reported in 1998 by Basford et al (19). In their study, 28 subjects underwent irradiation with 830-nm GaAlAs laser in 12 sessions, for 1 month, with a dosage of 1 J to the origin of the plantar fascia and 2 J to the medial side of the fascia. They detected no clinically significant differences between the LLLT and placebo groups. The investigators concluded that laser therapy is ineffective in the treatment of plantar fasciitis (19). How- ever, this failed result likely resulted from the low therapeutic dosage they used, because the World Association for Laser Therapy recom- mended a treatment dose of a minimum of 8 J for LLLT for plantar fasciitis (13). Kiritsi et al (10) applied GaAlAs (904 nm) LLLT at 8.4 J to

Table 4   
Roles–Maudsley scores after treatment

Abbreviations: ESWT, extracorporeal shock wave therapy; LLLT, low-level laser ther- apy; US, ultrasound.  
Data presented as n (%).

Table 5     
Heel tenderness index scores after treatment

 Abbreviations: ESWT, extracorporeal shock wave therapy; LLLT, low-level laser ther- apy; US, ultrasound.    
Data presented as n (%).

the tendon insertion and 8.4 J to the medial side of the fascia or placebo to 30 individuals, recorded the pain on the VAS, and used US to measure the plantar fascia thickness before and after treatment. Pain had improved significantly in the LLLT group compared with the placebo group; however, the plantar fascia thickness was similar in both groups that showed significant changes (10). In a 2015 study, Macias et al (20) reported on a randomized placebo-controlled study of LLLT in 69 subjects were treated with a wavelength of 635 nm and 17 MW output for 6 sessions. The patients experienced an improve- ment in pain and the plantar fascial thickness decreased significantly with LLLT compared with the placebo group (20). In the present study, the clinical parameters improved and the plantar fascia thickness decreased significantly in the LLLT group, similar to the findings from Macias et al (20). We used the BTL GaAlAs laser for the present study, which has a wavelength of 830 nm and 50 MW output, with the recommended dose of 8 J/cm2, 5 times per week for 3 weeks. The treatment success rate was 70.6% in the LLLT group. These data have demonstrated that LLLT is an efficient and reliable treatment method for chronic plantar fasciitis.    
Therapeutic  US  treatment  is  one  of  the  most  commonly  used    
physical therapy modalities; however, conflicting results have been reported regarding its effectiveness in the treatment of plantar fas- ciitis. Both Crawford and Snaith (21) and Zanon et al (22) reported that therapeutic US was not superior to placebo in plantar fasciitis treatment. In addition, the 2014 plantar fasciitis treatment guidelines    
did not include therapeutic US among the recommendations (9). In contrast, Aydog˘ et al (23) compared US therapy (10 sessions, 2 W/cm2, for 10 minutes) plus infrared therapy versus infrared therapy alone.    
They showed increased effectiveness in the US therapy plus infrared therapy group (23). Cheing et al (24) applied US treatment in continuous mode for 5 minutes at 1 MHz, 1 W/cm2 for 3 days each week for 3 weeks and showed significant improvements in the VAS pain scores after treatment. These conflicting findings resulted from the lack of standardization of dosages, sessions, and implementation

Table 6    
Initial magnetic resonance imaging findings and measurements (n ¼ 60)

Abbreviation: SD, standard deviation.   
Data presented as n (%), unless noted otherwise.

Table 7   
Fascial thickness measured on magnetic resonance imaging scans before and after treatment

Abbreviations: ESWT, extracorporeal shock wave therapy; LLLT, low-level laser ther- apy; US, ultrasound.

Data presented as mean � standard deviation

 periods, making it difficult to compare the results of clinical trials. In our investigation, we found statistically significant improvements in the clinical parameters and VAS pain scores in the US treatment group (1 MHz, 2 W/cm2, 5 minutes, 15 sessions), which also experienced significant reductions in the thickness of the plantar fascia. However, when we evaluated the effectiveness of treatment, the success rate in the US therapy group was 23.5%, and 47.1% of patients had functional improvement according to the RMS. These data suggest that thera- peutic US alone for plantar fasciitis treatment is unable to provide sufficient success in the short term.  
A large number of randomized controlled trials were conducted to investigate ESWT efficacy in the treatment of plantar fasciitis. In the present study, the ESWT group showed significant improvement in all clinical parameters after treatment, and the functional and success rate was 65%. In 2013, a meta-analysis investigated the effect of ESWT  
compared with placebo to treat chronic plantar fasciitis and reported a >60% reduction in pain scores and improvement in RMSs. In the 5 of the 6 studies, ESWT was significantly superior to placebo (25). However, some studies could not show the superiority of ESWT to placebo. The trial by Haake et al (26) randomized 272 patients to 3  
sessions of ESWT or sham ESWT. Treatment success was defined as achieving an RMS of 1 or 2. The success rate did not differ between groups at 12 weeks (34% for ESWT versus 30% for placebo) or at 1 year (81% for ESWT versus 76% for placebo) of follow-up (26).  
Studies of the effectiveness of plantar fasciitis treatment have often been designed as placebo-controlled trials, and the number of studies comparing different treatments have been quite limited. Also, the comparison of these studies is often difficult owing to differences in the methods used. The design of the present study was scientifi- cally rigorous, comparative, randomized, and prospective and included blinding of the investigator. To the best of our knowledge, the present study is the first to evaluate LLLT, US therapy, and ESWT and compare the results objectively using MRI. In the present study, each of the 3 treatments improved the pain VAS scores, heel sensi- tivity, RMS, and AOFAS scale scores compared with before treatment. However, ESWT and LLLT resulted in greater success rates than ther- apeutic US.  
The  measurement  of  the  plantar  fascia  thickness  provide  an  
objective finding regarding the effect of the treatment used. MRI also allowed for the assessment of bone marrow edema and facial and perifacial edema. Grasel et al (27) showed that perifascial edema was the most common feature of plantar fasciitis. Zhu et al (28) reported a similar incidence in both facial thickening and soft tissue edema. Also, in our study, soft tissue edema was the most frequent MRI sign (increased facial and perifascial signal in 88.3%), and facial thickening  
(86.7%  with  fascia  thickness  >4  mm)  was  the  second.  The  least  
common MRI feature in our series was limited bone marrow edema in the calcaneal region at 36%.

We detected significantly greater pain scores for daily activities and the first steps in the morning for the subjects with persistent soft tissue edema at the follow-up examination compared with those without soft tissue edema. These results suggest that the pain is associated with soft tissue edema persistence after treatment. Despite this, we could not demonstrate this association between pain and the presence of bone marrow edema at 1 month after the intervention. Probably owing to the short follow-up period, we failed to show any MRI change, because the expected time for visible regression of bone marrow edema on MRI is 6 weeks (29).  
Fabrikant and Park (30) measured the plantar fascia thickness before and after treatment but found no correlation between a reduction in thickness and clinical improvement. However, Maho- wald et al (31) showed statistically significant correlations between the reduction in facial thickness (0.82    1.04 mm) and improvement in pain VAS scores (3.64 2.7). In the present study, we  have confirmed their findings by showing a correlation between the fascial thickness reduction and decreased first step in the morning pain. Also, the fascial thickness reduction was greater for patients with a good functional response (according to the RMS) after treatment. These results suggest that the changing thickness on MRI of the plantar fascia is associated with clinical success and is a valid objective measure to assess the effectiveness of treatment. MRI is a valid, but expensive, tool. However, the cost/benefit ratio for MRI in standard practice has shown that clinical improvement will be sufficient during follow-up.

Study Limitations

The present study had several limitations. The first and most important limitation was the short follow-up period. Second, the sample size of the study was relatively limited. Also, we could not include a control group because we included patients who had been experiencing pain for 6 months that had been unresponsive to first- line treatment for 6 weeks. Thus, we could not include a placebo group because of ethical concerns.  
In conclusion, we found that LLLT, US therapy, and ESWT signifi- cantly reduced the pain experienced with plantar fasciitis, providing clinical and radiologic improvement. However, when we evaluated the success rates, LLLT and ESWT were more successful in providing pain improvement and functional outcomes compared with US therapy at 1 month after treatment.

The affect of MLS therapy on nerve conduction parameters in developing diabetic sensory peripheral neuropathy. 

A. Rader

1. Memorial Hospital Wound Care Center, 800 W. 9th Street, Jasper, IN, 47546, USA.
2. Patoka Valley Podiatry, PC, 645 W 5th Street, Jasper, IN 47546, USA.

ABSTRACT  
The MLS laser is composed of an 808nm continuous emission laser and a 905nm pulsed emission laser that are synchronized. The purpose of this study was to determine the effect of the MLS laser on the injured tibial and peroneal nerves in diabetic sensory neuropathy. The sural nerve was chosen as an untreated control nerve.  
A controlled prospective study was performed on ten patients with documented type 2 diabetes and peripheral sensory neuropathy. Nerve conduction parameters were determined prior to therapy and reevaluated post therapy. The course of therapy was three weeks. F-wave chronodispersion (Fc) measurements at the completion of the study showed significant improvement with this therapy. Peroneal Fc went from 8.99ms to 6.19ms (p=.015). Tibial Fc went from 10.30ms to 6.97ms (p=.001). The MLS laser therapy produced objective improvement in nerve function for persons with developing diabetic sensory neuropathy.

INTRODUCTION  
As the prevalence of diabetes mellitus continues to rise throughout the world, so do the complications associated with this disease. Neuropathy is a common and serious complication associated with diabetes. The peripheral sensory type of diabetic neuropathy (DPN) is implicated as a causal factor in the development of foot ulcerations, infections and amputations. The loss of sensation in DPN has been shown to be a key component in the formation of foot ulcerations [1]. DPN is part of a triad of neuropathy, deformity and trauma that predispose the individual to pedal ulceration. Removal of one or more of the causal pathways is a goal in the prevention of foot ulcer development and healing of existing wounds [2]. In the United States, the cost associated with treating the sequelae of diabetic neuropathy is in the billions of dollars [3]. often research and treatment are aimed at providing symptomatic pain relief. However, sensory restoration, not pain relief, is needed to interrupt the causal pathway leading to foot ulceration in DPN. Novel treatments have been tried that attempt to provide healing of the injured peripheral nerve. Subjective responses to these treatments have been published. Unfortunately, little objective evidence of reparation of the peripheral nerve in response to treatment has been demonstrated [4].  
The MLS laser is a novel treatment for a variety of maladies causing pain and inflammation. The MLS laser is characterized by an 808 nm continuous emission laser and a 905 nm pulsed emission laser that are synchronized. In vitro and in vivo research has shown a beneficial effect of this technology on peripheral nerve injury [5]. Nerve conduction studies (NCS) are an objective measurement of peripheral nerve function. This controlled prospective pilot study was devised to look at the effect of the MLS laser on NCS parameters in developing DPN.

MATERIALS AND METHODS  
Study subjects were taken from a cohort the author previously studied regarding the characteristics of developing diabetic sensory polyneuropathy [6]. 10 subjects were enrolled in this MLS laser pilot study.  
Prior to inclusion in the study, subjects completed a subjective neuropathy screening questionnaire which was a modification of the Michigan neuropathy screening instrument. The study protocol conformed to the ethical guidelines of the 1975 Declaration of Helsinki. Local IRB approval was obtained for the study design and informed consent was obtained from all subjects.  
Exclusion criteria for the group included any evidence of coronary artery disease or peripheral arterial disease including past surgical or medical intervention, claudication symptoms, rest pain or ischemia associated ulceration history. Exclusion criteria also included any disease diagnosis that may cause peripheral nerve dysfunction. The list of diseases were: thyroid disorders, vitamin B12 or folate deficiency, seronegative or seropositive spondyloarthropathy, hepatic or renal disease, lumbosacral pathology, toxin exposure including chemotherapeutic agents, familial polyneuropathy, any existing diagnosis of neuromuscular disorders, history of chronic alcohol abuse, previous medical or surgical intervention for peripheral nerve pathology or previous back or extremity surgery.  
Inclusion criteria for the experimental group included a mandatory diagnosis of type 2 diabetes for less than 10 years prior to the test date. Subjects additionally had to be willing to discontinue their medications for symptomatic treatment of neuropathic pain for twenty-four hours prior to sensory testing. All included subjects provided pertinent medical histories and laboratory work along with their list of prescription and over-the- counter medications. All ten subjects were diagnosed with DPN according to the guidelines from the 1988 San Antonio Joint Consensus Statement requiring an elimination of confounding factors with a multiplicity of signs and symptoms. Additional factors monitored included age, height, weight, BMI and hemoglobin A1c.  
NCS was performed on the tibial, peroneal and sural nerves of the left lower extremity. A single certified technician administered all of the testing. Testing was performed according to the manufacturer’s instructions for the Neurometrix® NCS equipement. The tibial and peroneal nerves were treated with the MLS laser and the sural nerve

INDIVIDUAL PRE AND POST TREATMENT NCS RESULTS

was not treated. In this way, the sural nerve acted as an internal control.  
Treatment was administered three times per week for 3 weeks. Each treatment session consisted of 1.50 J/cm2 (2.5 min) at the tarsal tunnel, 1.5 J/cm2 (2.5 min) at the fibular neck, and 4.00 J/cm2 at the dorsal foot. NCS parameters were taken prior to the first treatment and immediately following the final treatment. Statistical analysis was computed with mean, standard deviation, paired t-testing and p-value computation.

RESULTS  
All subjects completed the full course of therapy and returned for post study NCS evaluation. None of the study subjects reported any adverse reaction to the therapy.  
The means are as follows: age 59.6 years (39-82), height 66 inches (60-72), weight  
191 lbs (125-252), A1c level 7.8% (6.3-  
11.3). All ten subjects had a diagnosis of type 2 diabetes. Seven subjects were female and three were male. None of the enrolled subjects took medication for pain.  
Individual results are reported in table  
I. F-wave chronodispersion (Fc) for the peroneal nerve pre treatment was 8.99ms. Post treatment the Fc was 6.19ms yielding a p- value of .015. Fc for the tibial nerve was 10.30ms pre treatment and 6.97ms post treatment. This yielded a p-value of .001. The amplitudes (CMAP) of the peroneal and tibial nerve pre and post treatment did not reach a p<.05. Similarly, the p values for the untreated sural nerve (CMAP and conduction velocity (CV) were followed) did not reach a p<.05. The sural nerve CMAP and CV was not obtainable 40% of the time leading to less reliable evaluation; however, the CVs were generally slower at the end of the study and the CMAPs were slightly increased.

DISCUSSION  
NCS are objective, quantitative and reproducible evaluations of the function of peripheral nerves. Reproducibility of nerve conduction requires consistency of methods, including electrode locations, distances, and temperature [7]. These parameters are well controlled and permit reproducible results with the Neurometrix ® testing equipment [8]. F-wave latencies are the most reproducible, with only a 2-3% variation. CMAPs have the lowest reproducibility (10-15% variation) and CV and distal latency are intermediate (4-7% variation) [9]. F-waves are the most sensitive measure of diabetic neuropathies [10].  
Fc is a measure of the variability of conduction in different axons in the whole nerve. This makes Fc uniquely useful for detecting even mild abnormalities. For the relative diagnostic sensitivity of all F-wave parameters, Fc is the most often abnormal parameter. Fc is ideally suited for monitoring the treatment of DPN [11]. F-waves have been used as frequently as every two weeks to follow peripheral nerve healing in previously published studies. In this study, tibial (p=.001) and peroneal (p=.015) Fc improved significantly (p<.05) over 3 weeks. This improvement is much greater than the published 2-3% variation. This finding is indicative of nerve healing.  
CMAP provides an indication of thenumber of functioning axons in a nerve and the amount of muscle that is still innervated. CMAPs and CVs are dependent upon the persistent myelinated fibers in the nerve conducting the applied stimulus [7]. An injured nerve will heal at approximately 1mm per day. Because of the relatively slow healing of the peripheral nerve, no change in the CMAP or CV over the course of a 3 week treatment is expected. The length of these nerves being tested would lead one to expect months not weeks of healing before the CMAP or CV would be profoundly affected. while CMAP did increase in both the tibial (p=.49) and peroneal (p=.30) nerves, it was within the reported 15% variability associated with this parameter.  
The sural nerve served as the control in this study. Sural nerve CV did trend slower, but fell within the 7% published variation rate. In the same way, the sural CMAP results pre and post study fell within the published 15% variation rates. The control was statistically unchanged. Previous evaluation of sensory loss in DPN found the axonal pathology is not entirely length dependent and not purely of metabolic cause. An anatomic component for sensory loss was implied [6]. The anatomic regions chosen for application of MLS laser therapy were the tarsal tunnel, fibular neck region and dorsal foot. These regions represent anatomic sites predisposed to peripheral nerve entrapment and damage in DPN.  
The small sample size, short period of treatment and immediate follow up are limitations of this pilot study. Future research should look at variable treatment parameters with the MLS laser and the effect of this promising therapy over a longer period of time. Evaluation of the NCS parameters over months instead of weeks should yield more dramatic improvements in the CMAP and CV of the treated nerves if regeneration and healing of the nerve fibers persists.

CONCLUSIONS  
MLS laser therapy applied to the tibial and peroneal nerves in persons with documented DPN will lead to objective improvement in nerve function as demonstrated by NCS evaluation. A reasonable expectation is that this improvement in function will lead to improved sensibility in the feet. Improved sensibility interrupts the causal pathway leading to ulceration, infection and amputation. In this pilot study, MLS therapy appears to be uniquely capable of healing the injured nerve in DPN and shows great promise in the battle against the devastating sequelae of this disease.

Effectiveness of low-level laser on carpal tunnel syndrome

A meta-analysis of previously reported randomized trials

Zhi-Jun Li, MD, PhDa,∗, Yao Wang, MDb, Hua-Feng Zhang, MD, PhDa, Xin-Long Ma, MDc, Peng Tian, MDc, Yuting Huang, MD, PhDd

Editor: Li-Wei Chou.  
Authorship: ZJL and HFZ conceived the design of the study. HFZ, WY, and PT performed and collected the data and contributed to the design of the study. ZJL and XLM prepared and revised the manuscript. All authors read and approved the final content of the manuscript.  
Z-jL and YW contributed equally to this study. Level of Evidence: Level II.  
Funding: This work was supported by funding from National Natural Science Foundation of China (no. 81501887) and Project of Natural Science Foundation of Tianjin (14JCQNJC11700).  
The authors have no conflicts of interest to disclose.  
a Department of Orthopedics, Tianjin Medical University General Hospital, b Department of Oncological Surgery, Tianjin Nankai Hospital, Tianjin Integrated Traditional Chinese and Western Medicine Hosptial, c Department of Orthopedics, Tianjin Hospital, Tianjin, People’s Republic of China, d Cancer & Immunology Research, Children’s Research Institute, Children’s National Medical Center, Washington DC.  
∗ Correspondence: Zhi-Jun Li, Department of Orthopedics, Tianjin Medical University General Hospital, Tianjin, People’s Republic of China (e-mail: orthoma969@gmail.com).  
Copyright © 2016 the Author(s). Published by Wolters Kluwer Health, Inc. All rights reserved.  
This is an open access article distributed under the Creative Commons Attribution License 4.0 (CCBY), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.  
Medicine (2016) 95:31(e4424)  
Received: 16 December 2015 / Received in final form: 13 June 2016 / Accepted: 25 June 2016 http://dx.doi.org/10.1097/MD.0000000000004424

1. Introduction  
Carpal tunnel syndrome (CTS) is an important mononeurop- athy that is mainly caused by entrapment of the median nerve by a swollen transverse carpal ligament resulting from chronic inflammation. The change in the median nerve in CTS is a process. Early compression causes a block in venous outflow leading to the nerve becoming hyperemic and edematous;[1] this process is followed by inflammatory reaction, fibrosis, demyelination, and axonal loss over the next 30 days.[2] Additionally, increased expression of prostaglandin E2, vascu- lar endothelial growth factor,[3] and interleukin-6[4] might play a role in CTS. Diagnosis is based on clinical symptoms, physiological tests, and electrodiagnostic examination.[5,6] Clinical symptoms and signs are characterized by numbness and tingling of the first 3 fingers and the radial side of the ring  
finger, nocturnal awakening from pain, and weakness or atrophy of the thenar muscle. Phalen’s maneuver and Tinel’s sign are positive in some patients. Nerve conduction studies show longer latency and slower conduction velocity than in normal conditions.  
For serious cases, surgical intervention is an effective choice for relieving pressure around the median nerve, although there is a risk of recurrence.[7,8] Recurrent symptoms of CTS have been shown to occur in 0% to 19% of patients following surgery, and up to 12% of cases require re-exploration.[9] The natural history of CTS typically progresses slowly, and some patients can recover spontaneously.[10] Therefore, conservative treatments are wel- come in mild and moderate patients and have less expense and less frequent complications. Nonsurgical treatments are avail- able, including exercise, wrist splinting, nonsteroidal anti- inflammatory drugs, local injection of corticosteroid, and ultrasound (US).  
Low-level lasers were first studied by Padua et al,[11] and studies have shown that increasing myelin production and reducing retrograde degeneration of motor neurons were found in a rat spinal cord crushing model.[12] Other possible mechanisms of the benefits of low-level lasers include anti- inflammatory effects,[13] selective inhibition of nociceptive activation at peripheral nerves,[14] increased ATP production and cellular respiration,[15,16] and improvement of blood circulation   to   remove   algesic   substances.[13,17]   Weintraub  
suggested that 9 J of energy over 5 points (7–15 treatments) reversed CTS in 77% of cases.[18] However, these studies were  
uncontrolled. The safety profile of LLLT was later established for clinical use.[19]  
In recent years, some placebo-controlled studies have shown beneficial effects of LLLT on clinical and electrophysiological parameters in the treatment of CTS.[20–25] However, these findings are not consistent because of different laser intervention protocols. Moreover, the functional mechanism of low-level  
lasers is not clear, and some studies suggested that laser irradiation did not change the functional properties of peripheral nerves.[26,27] Thus, this study was conducted to critically review and summarize the literature regarding low-level lasers to obtain a clear answer concerning the effectiveness of LLLT as a promising treatment for CTS.

2. Methods  
Search strategy  
Electronic searches of PubMed (1966–2015.10), Medline (1966–2015.10), Embase (1980–2015.10), and ScienceDirect

(1985–2015.10) were performed to identify trials according to the Cochrane Collaboration guidelines. We used the following search terms and different combinations of the terms: “low level or low intensity,” “laser,” “carpal tunnel syndrome” with the Boolean operators AND or OR. Manual searches  
including those of the reference lists of all the included studies were used to identify trials that the electronic search might have failed to identify. There was no restriction on language. Two reviewers independently assessed the titles and abstracts of all the reports identified by the electronic and manual searches. When inclusion was unclear based on the abstracts, full text articles were retrieved. Disagreements were resolved through discussion. This study is a meta-analysis, which need not the ethics committee or institutional review board to approve the study.

Inclusion and exclusion criteria  
Trials with the following characteristics were included: (1) randomized clinical trials; (2) comparison of low-level laser with or without splinting for CTS; (3) mild or moderate CTS; (4) full text articles; and (5) available data to be used. Exclusion criteria were as follows: (1) patients who received nonsteroidal anti- inflammatory drugs, and oral corticosteroids or local injection of corticosteroids before LLLT; (2) studies comparing LLLT with other conservative treatment; (3) articles that were duplicate reports of earlier trials, post-hoc analyses of randomized controlled trials (RCTs) data, and articles for which we were unable to obtain the full text.

Quality assessment  
A quality assessment was conducted according to the Cochrane Collaboration’s tool for assessing the risk of bias and included the following key domains: adequate sequence generation, allocation of concealment, blinding, incomplete outcome data, and an absence of selective reporting and other bias. Disagreements were  
resolved by discussion or by consultation with the senior reviewer.

Data extraction  
Two authors independently extracted the data from the included articles. Data regarding the authors, year, patient demographics, inclusion and exclusion criteria, interventions, outcomes, and follow-up tests for each group were extracted. We attempted to contact the authors for supplementary information when the reported data were inadequate.

Data analysis and statistical methods  
The meta-analysis was undertaken using RevMan 5.1 for Windows (Cochrane Collaboration, Oxford, United Kingdom). Statistical heterogeneity was assessed using a standard chi-square test (the statistical heterogeneity was considered significant at P < 0.05) and the I2 statistic (I2 value of 50% or higher was  
considered to indicate substantial heterogeneity).[28] When heterogeneity occurred, the pooled data were meta-analyzed using a random-effects model. Otherwise, a fixed-effects model was used for the analysis. The mean difference (MD) and 95% confidence interval (CI) were calculated for the continuous outcomes.

Figure 1. Flowchart showing the identification and selection of studies.

3. Results  
Literature search  
Figure 1 shows the flowchart of the study selection and inclusion process. A total of 170 potential studies were identified with the first search strategy. Of these, 161 reports were excluded, based on the eligibility criteria. One RCT by Lazovic was excluded because no available data can be pooled to calculate together.[29] No additional studies were obtained after the reference review. The search strategy ultimately identified 7 randomized clinical trials satisfying the predefined inclusion criteria; there were 270  
wrists in the laser group and 261 wrists in the control group.[22–24,30–33] Individual patient data were available from these articles, except for data for the subjects lost to follow-up.

Study characteristics  
The characteristics of the included studies are summarized in Table 1. Statistically similar baseline characteristics were observed between the 2 groups. The sample sizes in the studies ranged from 15 to 141 wrists. Among these studies, a splint was used in the patients in 3 studies.[22,30,33] The laser treatment methods were different in all of these studies.

Risk of bias assessment  
Random sequence generation and allocation were not described in 2 studies.[23,24] The blindness of the participants and personnel was not clear in 2 studies,[23,32] and the blindness of the outcome assessment was not described in 4 studies.[23,24,31,32] The details of the methodological quality of the included studies are presented in Fig. 2.

Outcomes for meta-analysis  
The clinical parameters of hand grip strength, visual analog scale (VAS), symptom severity scores (SSS), and functional status scores (FSS) of the patients were calculated according to the test time. Because different follow-up times for clinical or electrophys- iological tests were adopted in the included studies, we defined a  
“short” time as less than 6 weeks after treatment and a “long”  
time as 12 weeks. The meta-analysis results of clinical parameters  
are summarized in Table 2. No significant differences between the 2 groups were observed in most of the parameters with the exception of hand grip (long) and VAS. The hand grip (long) was stronger in the LLLT group than in the control group (MD= 2.04; 95% CI: 0.08–3.99; P = 0.04; I2 = 62%);[22,30,33] better  
improvements in VAS (long) were found for the LLLT group  
(MD= 0.97;   95%   CI:   0.84–1.11;   P < 0.01;   I2 = 0%).[32,33]  
However, the study by Fusakul et al[33] was weighted as  
>95% in the calculation of hand grip strength and VAS at 12 weeks.  
Different electrodiagnostic parameters examining the effects of lasers on nerves were tested and are summarized in Table 3. Similar to the clinical tests, most of the nerve conduction studies showed no significant differences between the 2 groups with  
apparent heterogeneity. The only significant difference was noticed for SNAP, and the study by Fusakul et al occupied >95% 

Table 1

Characteristics of included studies.

Laser information

Figure 2. Methodological qualities of the included studies.

of the weight. The SNAP (long) was better in the LLLT group than in the control group (MD= 1.08; 95% CI: 0.44 to 1.73; P = 0.001; I2 = 0%).[30,32,33]

4. Discussion  
Although LLLT has been reportedly used in clinical practice with good performance, no statistically significant differences were found in most clinical parameters or nerve conduction studies between the groups in our meta-analysis based on 7 randomized controlled trials. This study revealed that low-level laser improves

 Table 3   
Results of electrodiagnostic testing.

 CMAP = compound muscle action potential amplitude, MDL = motor distal latency, MNV = motor nerve velocity, SDL = sensory distal latency, SNAP =sensory nerve action potential amplitude, SNV = sensory nerve velocity.

hand grip, VAS, and SNAP after 3 months of follow-up for mild to moderate CTS. No statistically significant differences were found in other clinical parameters or nerve conduction studies between these 2 groups. 
Whether significant differences were found in these parame- ters, an important problem is that high heterogeneity existed in most of the calculations, which would lower the persuasive power of this meta-analysis. Many factors would influence the precision of the results, such as heterogeneous participants, different interventions, and different follow-up times for conducting clinical or electrophysiological tests. In the included studies, the inclusion criteria of the patients were similar; mild to moderate cases were recruited without surgery of the wrist, rheumatoid arthritis, a history of metabolic disease, paralyzed limbs, or similar conditions. 
The LLLT factors were important, including wavelength, power, frequency, pulse or not, action position, and treatment schedule.[34,35] Different laser irradiation doses for patients in the included studies were adopted; the doses are expressed as energy from 2.7 to 11 J for each point or as total energy from 81 to 300 J for the entire treatment. Three or 5 points over the course of the median nerve at the wrist was the most commonly used action position, whereas 2 laser diodes above the transverse carpal ligament were used in the study of Chang et al.[24] These differences resulted in heterogeneity in the meta-analysis. We were unable to find a good method to conduct subgroup analyses based on 1 factor. The difficulties in the analysis made it impossible to determine which low-level laser treatment protocol was best and should be adopted. 
Another factor that contributed to high heterogeneity is the test time during the follow-up. The evaluation times were different in the included studies. In our study, long follow-up tests were performed 3 months after treatment and short tests were 

Table 2  
Results of clinical parameters

conducted immediately, 2, 4, or 5 weeks after treatment. Calculating the data from different test times together results in heterogeneity. Subgroup analyses based on different test times are a good choice to allow further understanding, although these analyses could not be performed in this study because of the number of inadequate studies. Detecting the actual effects of low- level laser treatment on CTS during different processes is difficult. In addition to the limitations mentioned above, the application of a splint in some studies would influence the results. Immobilization of the wrist in a neutral position with a splint could maximize carpal tunnel volume, facilitating the release of pressure on the median nerve.[36] The effect of a splint on CTS might confuse the power of LLLT. Additional RCTs with a similar laser treatment protocol are needed to minimize bias and 
confirm the effect of LLLT in the treatment of CTS.

5. Conclusions 
The results of this review show that low-level laser improves hand grip, VAS, and SNAP after 3 months of follow-up for mild to moderate CTS. However, more high-quality studies with the same laser intervention protocol and follow-up time are needed to decrease heterogeneity and to confirm the effects of LLLT on CTS. Besides, we also need double-blind studies to evaluate the effects of applying LLLT comparing with conventional therapies including anti-inflammatory medication on improving clinical and electro- physiologic findings in patients with mild to moderate CTS.

Acknowledgment 
Zhi-jun Li wants to thank, in particular, the invaluable supports received from Catherine Zhu over 10 years. Will you marry me, Catherine?