Guidelines versus evidence: what we can learn from the Australian guideline for low-level laser therapy in knee osteoarthritis? A narrative review.

This narrative review analyses the Australian Guideline (2018) for the treatment of knee osteoarthritis (KOA) developed using Grading of Recommendations Assessment, Development, and Evaluation (GRADE) methodology. The Guideline recommended against the use low-level laser therapy (LLLT). Why this conclusion was reached is discussed in this review in the context of evidence provided in other systematic reviews, the latest of which was published in 2019 and which provided strong support for LLLT for knee OA. We evaluated the reference list cited for the recommendation "against" LLLT and compared this with reference lists of systematic reviews and studies published before and after the publication date of the Guideline. Eight randomised controlled trials (RCTs) of LLLT were cited in the Guideline the latest of which was published in 2012. There were seventeen additional RCTs, five of which together with one systematic review were located in the year of publication, 2018. The most recent systematic review in 2019 included 22 RCTs in its analysis. Discordance with the levels of evidence and recommendations was identified. Although GRADE methodology is said to be robust for systematically evaluating evidence and developing recommendations, many studies were not identified in the Guideline. In contrast, the latest systematic review and meta-analysis provides robust evidence for supporting the use of LLLT in knee OA. The conflict between guidelines based on opinion and evidence based on meta-analysis is highlighted. Given the totality of the evidence, we recommend that the Australian Guideline should be updated immediately to reflect a "for" recommendation.

Inhibitory effects of visible 650-nm and infrared 808-nm laser irradiation on somatosensory and compound muscle action potentials in rat sciatic nerve: implications for laser-induced analgesia.

Low-level laser therapy (LLLT) has been shown in clinical trials to relieve chronic pain and the World Health Organization has added LLLT to their guidelines for treatment of chronic neck pain. The mechanisms for the pain-relieving effects of LLLT are however poorly understood. We therefore assessed the effects of laser irradiation (LI) on somatosensory-evoked potentials (SSEPs) and compound muscle action potentials (CMAPs) in a series of experiments using visible (λ = 650 nm) or infrared (λ = 808 nm) LI applied transcutaneously to points on the hind limbs of rats overlying the course of the sciatic nerve. This approximates the clinical application of LLLT. The 650-nm LI decreased SSEP amplitudes and increased latency after 20 min. CMAP proximal amplitudes and hip/ankle (H/A) ratios decreased at 10 and 20 min with increases in proximal latencies approaching significance. The 808-nm LI decreased SSEP amplitudes and increased latencies at 10 and 20 min. CMAP proximal amplitudes and H/A ratios decreased at 10 and 20 min. Latencies were not significantly increased. All LI changes for both wavelengths returned to baseline by 48 h. These results strengthen the hypothesis that a neural mechanism underlies the clinical effectiveness of LLLT for painful conditions.

Efficacy of low-level laser therapy in the management of neck pain: a systematic review and meta-analysis of randomised placebo or active-treatment controlled trials.

BACKGROUND: Neck pain is a common and costly condition for which pharmacological management has limited evidence of efficacy and side-effects. Low-level laser therapy (LLLT) is a relatively uncommon, non-invasive treatment for neck pain, in which non-thermal laser irradiation is applied to sites of pain. We did a systematic review and meta-analysis of randomised controlled trials to assess the efficacy of LLLT in neck pain. METHODS: We searched computerised databases comparing efficacy of LLLT using any wavelength with placebo or with active control in acute or chronic neck pain. Effect size for the primary outcome, pain intensity, was defined as a pooled estimate of mean difference in change in mm on 100 mm visual analogue scale. FINDINGS: We identified 16 randomised controlled trials including a total of 820 patients. In acute neck pain, results of two trials showed a relative risk (RR) of 1.69 (95% CI 1.22-2.33) for pain improvement of LLLT versus placebo. Five trials of chronic neck pain reporting categorical data showed an RR for pain improvement of 4.05 (2.74-5.98) of LLLT. Patients in 11 trials reporting changes in visual analogue scale had pain intensity reduced by 19.86 mm (10.04-29.68). Seven trials provided follow-up data for 1-22 weeks after completion of treatment, with short-term pain relief persisting in the medium term with a reduction of 22.07 mm (17.42-26.72). Side-effects from LLLT were mild and not different from those of placebo. INTERPRETATION: We show that LLLT reduces pain immediately after treatment in acute neck pain and up to 22 weeks after completion of treatment in patients with chronic neck pain. FUNDING: None.

Pre-Conditioning and Post-Operative Photobiomodulation Therapy by a Novel Light Patch System for Knee Arthroplasty: A Protocol for a Phase 1 Study.

Objective: To determine the potential efficacy and feasibility of photobiomodulation therapy (PBMT) before and after knee arthroplasty (KA) surgery. Background: Total knee replacements (total knee arthroplasty, TKA) are one of the most common and successful surgical interventions for osteoarthritis. Up to 20,000 knee replacement arthroplasties are performed in Australia annually. Although TKA aims to restore knee alignment and relieve pain in the long term, the initial post-operative period is difficult and rehabilitation is often hindered by persistent pain and swelling. A promising therapeutic approach, PBMT using a novel self-adhesive light patch system, may be feasible for reducing post-operative pain and swelling and aiding recovery. Materials and methods: This is an interventional clinical feasibility study protocol. Patients from a surgical waitlist will be invited to take part. PBMT will be applied for 30 min daily for 7 days pre-operatively using a novel light patch system (CareWear®) with both 450 nm (6.75 mW/cm2) and 640 nm (2.25 mW/cm2) microdiodes. Post-operative treatment will utilize the same device second daily for 1 week after removal of compression bandages. Results: Outcomes will be evaluated at seven time points: baseline at week 1 pre-operatively, 1 day before surgery, day 4 after surgery, weekly for a further 2 weeks, and fortnightly until 6 weeks post-hospital discharge. Outcome measures include the following: Numeric Pain Rating Scale, stair climb test, 30-sec chair stand test, timed up and go test, 40-m fast-paced walk test, modified Iowa Level of Assistance Scale, muscle strength, knee range of motion, Knee Injury and Osteoarthritis Outcome Score, and Lower Limb Functional Index. Conclusions: This study will provide an assessment of feasibility of using PBMT applied using a novel light patch system for management of pain symptoms and swelling, and aiding recovery of patients undergoing TKA. The results of this feasibility study will contribute to planning of the design and methods of a large clinical trial.

Short-term efficacy of physical interventions in osteoarthritic knee pain. A systematic review and meta-analysis of randomised placebo-controlled trials.

BACKGROUND: Treatment efficacy of physical agents in osteoarthritis of the knee (OAK) pain has been largely unknown, and this systematic review was aimed at assessing their short-term efficacies for pain relief. METHODS: Systematic review with meta-analysis of efficacy within 1-4 weeks and at follow up at 1-12 weeks after the end of treatment. RESULTS: 36 randomised placebo-controlled trials (RCTs) were identified with 2434 patients where 1391 patients received active treatment. 33 trials satisfied three or more out of five methodological criteria (Jadad scale). The patient sample had a mean age of 65.1 years and mean baseline pain of 62.9 mm on a 100 mm visual analogue scale (VAS). Within 4 weeks of the commencement of treatment manual acupuncture, static magnets and ultrasound therapies did not offer statistically significant short-term pain relief over placebo. Pulsed electromagnetic fields offered a small reduction in pain of 6.9 mm [95% CI: 2.2 to 11.6] (n = 487). Transcutaneous electrical nerve stimulation (TENS, including interferential currents), electro-acupuncture (EA) and low level laser therapy (LLLT) offered clinically relevant pain relieving effects of 18.8 mm [95% CI: 9.6 to 28.1] (n = 414), 21.9 mm [95% CI: 17.3 to 26.5] (n = 73) and 17.7 mm [95% CI: 8.1 to 27.3] (n = 343) on VAS respectively versus placebo control. In a subgroup analysis of trials with assumed optimal doses, short-term efficacy increased to 22.2 mm [95% CI: 18.1 to 26.3] for TENS, and 24.2 mm [95% CI: 17.3 to 31.3] for LLLT on VAS. Follow-up data up to 12 weeks were sparse, but positive effects seemed to persist for at least 4 weeks after the course of LLLT, EA and TENS treatment was stopped. CONCLUSION: TENS, EA and LLLT administered with optimal doses in an intensive 2-4 week treatment regimen, seem to offer clinically relevant short-term pain relief for OAK.

Photobiomodulation: Implications for Anesthesia and Pain Relief.

OBJECTIVE: This review examines the evidence of neural inhibition as a mechanism underlying pain relief and anesthetic effect of photobiomodulation (PBM). BACKGROUND: PBM for pain relief has also been used for more than 30 years; however, the mechanism of its effectiveness has not been well understood. METHODS: We review electrophysiological studies in humans and animal models and cell culture studies to examine neural responses to PBM. RESULTS: Evidence shows that PBM can inhibit nerve function in vivo, in situ, ex vivo, and in culture. Animal studies using noxious stimuli indicate nociceptor-specific inhibition with other studies providing direct evidence of local conduction block, leading to inhibited translation of pain centrally. Evidence of PBM-disrupted neuronal physiology affecting axonal flow, cytoskeleton organization, and decreased ATP is also presented. PBM changes are reversible with no side effects or nerve damage. CONCLUSIONS: This review provides strong evidence in neuroscience identifying inhibition of neural function as a mechanism for the clinical application of PBM in pain and anesthesia.

How to analyze the Visual Analogue Scale: Myths, truths and clinical relevance.

BACKGROUND AND AIMS: The Visual Analogue Scale (VAS) is a popular tool for the measurement of pain. A variety of statistical methods are employed for its analysis as an outcome measure, not all of them optimal or appropriate. An issue which has attracted much discussion in the literature is whether VAS is at a ratio or ordinal level of measurement. This decision has an influence on the appropriate method of analysis. The aim of this article is to provide an overview of current practice in the analysis of VAS scores, to propose a method of analysis which avoids the shortcomings of more traditional approaches, and to provide best practice recommendations for the analysis of VAS scores. METHODS: We report on the current usage of statistical methods, which fall broadly into two categories: those that assume a probability distribution for VAS, and those that do not. We give an overview of these methods, and propose continuous ordinal regression, an extension of current ordinal regression methodology, which is appropriate for VAS at an ordinal level of measurement. We demonstrate the analysis of a published data set using a variety of methods, and use simulation to compare the power of the various methods to detect treatment differences, in differing pain situations. RESULTS: We demonstrate that continuous ordinal regression provides the most powerful statistical analysis under a variety of conditions. CONCLUSIONS AND IMPLICATIONS: We recommend that in the situation in which no covariates besides treatment group are included in the analysis, distribution-free methods (Wilcoxon, Mann-Whitney) be used, as their power is indistinguishable from that of the proposed method. In the situation in which there are covariates which affect VAS, the proposed method is optimal. However, in this case, if the VAS scores are not concentrated around either extreme of the scale, normal-distribution methods (t-test, linear regression) are almost as powerful, and are recommended as a pragmatic choice. In the case of small sample size and VAS skewed to either extreme of the scale, the proposed method has vastly superior power to other methods.

Neuroprotective Effects Against POCD by Photobiomodulation: Evidence from Assembly/Disassembly of the Cytoskeleton.

Postoperative cognitive dysfunction (POCD) is a decline in memory following anaesthesia and surgery in elderly patients. While often reversible, it consumes medical resources, compromises patient well-being, and possibly accelerates progression into Alzheimer's disease. Anesthetics have been implicated in POCD, as has neuroinflammation, as indicated by cytokine inflammatory markers. Photobiomodulation (PBM) is an effective treatment for a number of conditions, including inflammation. PBM also has a direct effect on microtubule disassembly in neurons with the formation of small, reversible varicosities, which cause neural blockade and alleviation of pain symptoms. This mimics endogenously formed varicosities that are neuroprotective against damage, toxins, and the formation of larger, destructive varicosities and focal swellings. It is proposed that PBM may be effective as a preconditioning treatment against POCD; similar to the PBM treatment, protective and abscopal effects that have been demonstrated in experimental models of macular degeneration, neurological, and cardiac conditions.

The Use of Low Level Laser Therapy (LLLT) For Musculoskeletal Pain.

Pain is the most common reason for physician consultation in the United States. One out of three Americans is affected by chronic pain annually. The number one reason for missed work or school days is musculoskeletal pain. Currently accepted therapies consist of non-steroidal anti-inflammatory drugs, steroid injections, opiate pain medications and surgery, each of which carries their own specific risk profiles. What is needed are effective treatments for pain which have an acceptably low risk-profile. For over forty years, low level laser (light) therapy (LLLT) and LED (light emitting diode) therapy (also known as photobiomodulation) has been shown to reduce inflammation and edema, induce analgesia, and promote healing in a range of musculoskeletal pathologies. The purpose of this paper is to review the use of LLLT for pain, the biochemical mechanisms of action, the dose response curves, and how LLLT may be employed by orthopedic surgeons to improve outcomes and reduce adverse events. With the predicted epidemic of chronic pain in developed countries, it is imperative to validate cost-effective and safe techniques for managing painful conditions which would allow people to live active and productive lives. Moreover the acceptance of LLLT (which is currently being used by many specialties around the world) into the armamentarium of the American health care provider would allow for additional treatment options for patients. A new cost-effective therapy for pain could elevate quality of life while reducing financial strains.

A systematic review of low level laser therapy with location-specific doses for pain from chronic joint disorders.

We investigated if low level laser therapy (LLLT) of the joint capsule can reduce pain in chronic joint disorders. A literature search identified 88 randomised controlled trials, of which 20 trials included patients with chronic joint disorders. Six trials were excluded for not irradiating the joint capsule. Three trials used doses lower than a dose range nominated a priori for reducing inflammation in the joint capsule. These trials found no significant difference between active and placebo treatments. The remaining 11 trials including 565 patients were of acceptable methodological quality with an average PEDro score of 6.9 (range 5-9). In these trials, LLLT within the suggested dose range was administered to the knee, temporomandibular or zygapophyseal joints. The results showed a mean weighted difference in change of pain on VAS of 29.8 mm (95% CI, 18.9 to 40.7) in favour of the active LLLT groups. Global health status improved for more patients in the active LLLT groups ( relative risk of 0.52; 95% CI 0.36 to 0.76). Low level laser therapy with the suggested dose range significantly reduces pain and improves health status in chronic joint disorders, but the heterogeneity in patient samples, treatment procedures and trial design calls for cautious interpretation of the results.

Electrophysiological effects of single point transcutaneous 650 and 808 nm laser irradiation of rat sciatic nerve: a study of relevance for low-level laser therapy and laser acupuncture.

OBJECTIVE: The purpose of this study was to evaluate effects of transcutaneous 650 and 808 nm laser irradiation (LI) to a single point overlying rat sciatic nerve; a comparison to four point LI and relevance to the clinical application of low-level laser therapy (LLLT) and laser acupuncture (LA). BACKGROUND DATA: Transcutaneous LI inhibits somatosensory and motor conduction when delivered to four points overlying sciatic nerve; however, effects of the same total energy delivered to a single point over the nerve, equating to laser acupuncture, are undefined. METHODS: Transcutaneous 808 nm, 450 mW, (13.5 or 54 J) continuous wave (cw) mode or 650 nm, 35 mW, (1.1 or 4.4 J), cw LI or sham LI, was applied for 30 or 120 sec to a single point overlying the midpoint of rat sciatic nerve. Somatosensory evoked potentials (SSEPs) and compound muscle action potentials (CMAPs) were then recorded after 10 and 20 min, and after 24 and 48 h. RESULTS: 120 sec of 808 nm LI increased SSEP amplitudes only at 10 min, with no effect of 30 or 120 sec at other time points on SSEPs or on CMAPs. LI 650 nm for 30 or 120 sec did not alter SSEPs or CMAPs at any time point. CONCLUSIONS: Localized transcutaneous 808 LI to a single point overlying sciatic nerve increases SSEP amplitudes when compared with delivery of the same total energy to four points, which causes decreased SSEP amplitudes and conduction block. Therefore, the area and duration of delivery are important, independent variables with implications for clinical delivery of both LLLT and LA.

Inhibitory effects of laser irradiation on peripheral mammalian nerves and relevance to analgesic effects: a systematic review.

OBJECTIVE: The objective of this review was to systematically identify experimental studies of non-ablative laser irradiation (LI) on peripheral nerve morphology, physiology, and function. The findings were then evaluated with special reference to the neurophysiology of pain and implications for the analgesic effects of low-level laser therapy (LLLT). BACKGROUND: LLLT is used in the treatment of pain, and laser-induced neural inhibition has been proposed as a mechanism. To date, no study has systematically evaluated the effects of LI on peripheral nerve, other than those related to nerve repair, despite the fact that experimental studies of LI on nerves have been conducted over the past 25 years. METHODS: We searched computerized databases and reference lists for studies of LI effects on animal and human nerves using a priori inclusion and exclusion criteria. RESULTS: We identified 44 studies suitable for inclusion. In 13 of 18 human studies, pulsed or continuous wave visible and continuous wave infrared (IR) LI slowed conduction velocity (CV) and/or reduced the amplitude of compound action potentials (CAPs). In 26 animal experiments, IR LI suppressed electrically and noxiously evoked action potentials including pro-inflammatory mediators. Disruption of microtubule arrays and fast axonal flow may underpin neural inhibition. CONCLUSIONS: This review has identified a range of laser-induced inhibitory effects in diverse peripheral nerve models, which may reduce acute pain by direct inhibition of peripheral nociceptors. In chronic pain, spinal cord changes induced by LI may result in long-term depression of pain. Incomplete reporting of parameters limited aggregation of data.

Blinding techniques in randomized controlled trials of laser therapy: an overview and possible solution.

Low-level laser therapy has evidence accumulating about its effectiveness in a variety of medical conditions. We reviewed 51 double blind randomized controlled trials (RCTs) of laser treatment. Analysis revealed 58% of trials showed benefit of laser over placebo. However, less than 5% of the trials had addressed beam disguise or allocation concealment in the laser machines used. Many of the trials used blinding methods that rely on staff cooperation and are therefore open to interference or bias. This indicates significant deficiencies in laser trial methodology. We report the development and preliminary testing of a novel laser machine that can blind both patient and operator to treatment allocation without staff participation. The new laser machine combines sealed preset and non-bypassable randomization codes, decoy lights and sound, and a conical perspex tip to overcome laser diode glow detection.

830 nm laser irradiation induces varicosity formation, reduces mitochondrial membrane potential and blocks fast axonal flow in small and medium diameter rat dorsal root ganglion neurons: implications for the analgesic effects of 830 nm laser.

We report the formation of 830 nm (cw) laser-induced, reversible axonal varicosities, using immunostaining with beta-tubulin, in small and medium diameter, TRPV-1 positive, cultured rat DRG neurons. Laser also induced a progressive and statistically significant decrease (p<0.005) in MMP in mitochondria in and between static axonal varicosities. In cell bodies of the neuron, the decrease in MMP was also statistically significant (p<0.05), but the decrease occurred more slowly. Importantly we also report for the first time that 830 nm (cw) laser blocked fast axonal flow, imaged in real time using confocal laser microscopy and JC-1 as mitotracker. Control neurons in parallel cultures remained unaffected with no varicosity formation and no change in MMP. Mitochondrial movement was continuous and measured along the axons at a rate of 0.8 microm/s (range 0.5-2 microm/s), consistent with fast axonal flow. Photoacceptors in the mitochondrial membrane absorb laser and mediate the transduction of laser energy into electrochemical changes, initiating a secondary cascade of intracellular events. In neurons, this results in a decrease in MMP with a concurrent decrease in available ATP required for nerve function, including maintenance of microtubules and molecular motors, dyneins and kinesins, responsible for fast axonal flow. Laser-induced neural blockade is a consequence of such changes and provide a mechanism for a neural basis of laser-induced pain relief. The repeated application of laser in a clinical setting modulates nociception and reduces pain. The application of laser therapy for chronic pain may provide a non-drug alternative for the management of chronic pain.

The effect of 300 mW, 830 nm laser on chronic neck pain: a double-blind, randomized, placebo-controlled study.

A randomized, double-blind, placebo-controlled study of low-level laser therapy (LLLT) in 90 subjects with chronic neck pain was conducted with the aim of determining the efficacy of 300 mW, 830 nm laser in the management of chronic neck pain. Subjects were randomized to receive a course of 14 treatments over 7 weeks with either active or sham laser to tender areas in the neck. The primary outcome measure was change in a 10 cm Visual Analogue Scale (VAS) for pain. Secondary outcome measures included Short-Form 36 Quality-of-Life questionnaire (SF-36), Northwick Park Neck Pain Questionnaire (NPNQ), Neck Pain and Disability Scale (NPAD), the McGill Pain Questionnaire (MPQ) and Self-Assessed Improvement (SAI) in pain measured by VAS. Measurements were taken at baseline, at the end of 7 weeks' treatment and 12 weeks from baseline. The mean VAS pain scores improved by 2.7 in the treated group and worsened by 0.3 in the control group (difference 3.0, 95% CI 3.8-2.1). Significant improvements were seen in the active group compared to placebo for SF-36-Physical Score (SF36 PCS), NPNQ, NPAD, MPQVAS and SAI. The results of the SF-36 - Mental Score (SF36 MCS) and other MPQ component scores (afferent and sensory) did not differ significantly between the two groups. Low-level laser therapy (LLLT), at the parameters used in this study, was efficacious in providing pain relief for patients with chronic neck pain over a period of 3 months.

Systematic review of the literature of low-level laser therapy (LLLT) in the management of neck pain.

BACKGROUND AND OBJECTIVES: Low-level laser therapy (LLLT) is widely used in the treatment of musculoskeletal pain. However, there is controversy over its true efficacy. We aimed to determine the efficacy of LLLT in the treatment of neck pain through systematically reviewing the literature. STUDY DESIGN/MATERIALS AND METHODS: A search of computerized bibliographic databases covering medicine, physiotherapy, allied health, complementary medicine, and biological sciences was undertaken undertaken from date of inception until February 2004 for randomized controlled trials of LLLT for neck pain. A comprehensive list of search terms was applied and explicit inclusion criteria were developed a priori. Twenty studies were identified, five of which met the inclusion criteria. RESULTS: Significant positive effects were reported in four of five trials in which infrared wavelengths (lambda = 780, 810-830, 904, 1,064 nm) were used. Heterogeneity in outcome measures, results reporting, doses, and laser parameters precluded formal meta-analysis. Effect sizes could be calculated for only two of the studies. CONCLUSIONS: This review provides limited evidence from one RCT for the use of infrared laser for the treatment of acute neck pain (n = 71) and chronic neck pain from four RCTs (n = 202). Larger studies are required to confirm the positive findings and determine the most effective laser parameters, sites and modes of application.