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Background and Objective: Low-level laser therapy (LLLT) and cryotherapy are widely used treatments in the acute phase of tendon injury. The aim of this study was to investigate the interaction of these two treatments on tendon inflammation and mechanical properties., Materials and Methods: Six groups of six Wistar rats were used in this study. The Achilles tendons of the healthy control group were not subjected to injury or treatment. The tendons of the injured nontreated group (ING) were injured, but not treated. The remaining four groups were injured and subjected to LLLT, cryotherapy, LLLT first/cryotherapy, or cryotherapy first/LLLT. All treatments were performed at 1 h post-trauma. Inflammatory mediators, tendon histology, and biomechanical properties were assessed at 24 h post-trauma by comparing the treatment groups with the ING., Results: In all treatment groups, the inflammatory process shifted in an anti-inflammatory direction compared with the ING. Significant alterations in cytokine expression were found in only the LLLT group (↓IL-1β) and the combined intervention groups (↓IL-1β, ↓TNF-α, ↑IL-6). It was also found that cryotherapy followed by LLLT was the only treatment that significantly (p < 0.05) improved the biomechanical parameters of force (N) and displacement (mm) at the tendon rupture and corresponded with the best histological scores of all of the treatment groups., Conclusions: Our results demonstrate that cryotherapy in combination with LLLT can produce an anti-inflammatory "add-on" effect. The order of therapy administration seems essential, as superior histology and biomechanical results were found in the cryotherapy first/LLLT group.

Background: The temporomandibular joint (TMJ) is a structure of the craniofacial complex affected by neurological diseases. Orthopedic and musculoskeletal changes can also cause temporomandibular disorders (TMD) and pain. Low-level laser (LLL) therapy has been studied in the treatment of temporomandibular jaw (TMJ) dysfunction, and controversial results were obtained., Objective: The objective of this work was comparing the physiotherapeutic and drug protocol (PDP) to LLL therapy in the treatment of pain associated with TMD., Methods: A sample of 60 female patients, 20-50 years of age, TMD triggering agents (stress, parafunctional habits) controlled, was randomly divided into three groups, group 1 (G1)-LLL (780 nm laser, dose of 35.0 J/cm 2 , for 20 sec, thrice a week, for 4 weeks); group 2 (G2)-PDP (hot packs thrice a day, morning, afternoon, and evening, for 15 min, exercise of opening and closing the mouth, twice a day, myorelaxing and anti-inflammatory drug administration); and group 3 (G3)-Placebo (450 nm halogen lamp, Max LD Gnatus, light curing unit)., Results: Patients were evaluated every return appointment for the presence (P) or absence (A) of pain for 4 weeks and results were statistically analyzed. First week: 60% of G1, 100% G2, and 70% of G3-related pain. Second week: 55% of G1, 15% of G2, and 100% of G3-related pain. Third week: 10% of G1, 15% of G2, and 85% of G3-related pain. Last week: 0% of G1, 0% of G2, and 100% of G3-related pain., Conclusions: Based on obtained data, we concluded that, compared to PDP, LLL treatment is effective to control pain associated with TMD.

Objective: The objective of this study was to evaluate the effect of laser irradiation on dog bone marrow stem cells., Background Data: Low doses of low-level red laser positively affect the viability of mesenchymal stem cells, and also increase proliferation., Methods: Low-level laser (wavelength, 660 nm; power output, 50 mW), was applied to dog bone marrow stem cell cultures (DBMSC). The energy densities delivered varied from 1 to 12J/cm(2). The effect of the laser irradiation was evaluated on cell proliferation measured with the MTT colorimetric test, cell cycle phase, and on lipidic peroxidation (free radical production)., Results: The results indicate that laser irradiation to DBMSC did not change the morphology of the cells, but significantly increased their viability and the number of cells at the G2/M phase with 6, 10, and 12 J/cm(2). On the other hand, malonaldehyde production was significantly enhanced with 8 J/cm(2)., Conclusions: The parameters used to irradiate DBMSC increased significantly proliferation without producing high levels of reactive oxygen species (ROS).

Background and Objective: Impaired cell metabolism and increased cell death in fibroblast cells are physiological features of chronic tendinopathy. Although several studies have shown that low-level laser therapy (LLLT) at certain parameters has a biostimulatory effect on fibroblast cells, it remains uncertain if LLLT effects depend on the physiological state., Study Design/material and Methods: High-metabolic immortal cell culture and primary human keloid fibroblast cell culture were used in this study. Trypan blue exclusion and the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) test were used to determine cell viability and proliferation. Propidium iodide stain was used for cell-cycle analysis by flow cytometry. Laser irradiation was performed daily on three consecutive days with a GaAlAs 660-nm laser (mean output: 50 mW, spot size 2 mm(2), power density =2.5 W/cm(2)) and a typical LLLT dose and a high LLLT dose (irradiation times: 60 or 420 s; fluences:150 or 1050 J/cm(2); energy delivered: 3 or 21 J)., Results: Primary fibroblast cell culture from human keloids irradiated with 3 J showed significant proliferation by the trypan blue exclusion test (p < 0.05), whereas the 3T3 cell culture showed no difference using this method. Propidium iodide staining flow cytometry data showed a significant decrease in the percentage of cells being in proliferative phases of the cell cycle (S/g(2)/M) when irradiated with 21 J in both cell types (hypodiploid cells increased)., Conclusions: Our data support the hypothesis that the physiological state of the cells affects the LLLT results, and that high-metabolic rate and short- cell-cycle 3T3 cells are not responsive to LLLT. In conclusion, LLLT with a dose of 3 J reduced cell death significantly, but did not stimulate cell cycle. A LLLT dose of 21 J had negative effects on the cells, as it increased cell death and inhibited cell proliferation.

Background Data and Objective: There is anecdotal evidence that low-level laser therapy (LLLT) may affect the development of muscular fatigue, minor muscle damage, and recovery after heavy exercises. Although manufacturers claim that cluster probes (LEDT) maybe more effective than single-diode lasers in clinical settings, there is a lack of head-to-head comparisons in controlled trials. This study was designed to compare the effect of single-diode LLLT and cluster LEDT before heavy exercise., Materials and Methods: This was a randomized, placebo-controlled, double-blind cross-over study. Young male volleyball players (n = 8) were enrolled and asked to perform three Wingate cycle tests after 4 x 30 sec LLLT or LEDT pretreatment of the rectus femoris muscle with either (1) an active LEDT cluster-probe (660/850 nm, 10/30 mW), (2) a placebo cluster-probe with no output, and (3) a single-diode 810-nm 200-mW laser., Results: The active LEDT group had significantly decreased post-exercise creatine kinase (CK) levels (-18.88 +/- 41.48 U/L), compared to the placebo cluster group (26.88 +/- 15.18 U/L) (p < 0.05) and the active single-diode laser group (43.38 +/- 32.90 U/L) (p < 0.01). None of the pre-exercise LLLT or LEDT protocols enhanced performance on the Wingate tests or reduced post-exercise blood lactate levels. However, a non-significant tendency toward lower post-exercise blood lactate levels in the treated groups should be explored further., Conclusion: In this experimental set-up, only the active LEDT probe decreased post-exercise CK levels after the Wingate cycle test. Neither performance nor blood lactate levels were significantly affected by this protocol of pre-exercise LEDT or LLLT.

Objective: To investigate if development of skeletal muscle fatigue during repeated voluntary biceps contractions could be attenuated by low-level laser therapy (LLLT)., Background Data: Previous animal studies have indicated that LLLT can reduce oxidative stress and delay the onset of skeletal muscle fatigue., Materials and Methods: Twelve male professional volleyball players were entered into a randomized double-blind placebo-controlled trial, for two sessions (on day 1 and day 8) at a 1-wk interval, with both groups performing as many voluntary biceps contractions as possible, with a load of 75% of the maximal voluntary contraction force (MVC). At the second session on day 8, the groups were either given LLLT (655 nm) of 5 J at an energy density of 500 J/cm2 administered at each of four points along the middle of the biceps muscle belly, or placebo LLLT in the same manner immediately before the exercise session. The number of muscle contractions with 75% of MVC was counted by a blinded observer and blood lactate concentration was measured., Results: Compared to the first session (on day 1), the mean number of repetitions increased significantly by 8.5 repetitions (+/- 1.9) in the active LLLT group at the second session (on day 8), while in the placebo LLLT group the increase was only 2.7 repetitions (+/- 2.9) (p = 0.0001). At the second session, blood lactate levels increased from a pre-exercise mean of 2.4 mmol/L (+/- 0.5 mmol/L), to 3.6 mmol/L (+/- 0.5 mmol/L) in the placebo group, and to 3.8 mmol/L (+/- 0.4 mmol/L) in the active LLLT group after exercise, but this difference between groups was not statistically significant., Conclusion: We conclude that LLLT appears to delay the onset of muscle fatigue and exhaustion by a local mechanism in spite of increased blood lactate levels.

Objective: This study was designed to study the effect of an infrared low-level laser (GaAs lambda = 904 nm, 4 mW) on inflammatory cell migration in lipopolysaccharide (LPS)-induced peritonitis in mice., Background Data: It has been suggested that red wavelengths of low-level laser therapy (LLLT) can exert anti-inflammatory effects, but little is known about the anti-inflammatory effects of infrared lasers. Peritonitis is a potentially life-threatening inflammatory condition that may be suitable for studying anti-inflammatory effects of infrared lasers., Methods: Sixty male mice were randomly divided into five groups, and one group was given an intraperitoneal sterile saline injection. In the remaining four groups, peritonitis was induced by an intraperitoneal LPS injection. Animals in three of the LPS groups were irradiated at a single point over the peritoneum with doses of 3 J/cm(2), 7.5 J/cm(2), and 15 J/cm(2), respectively. The fourth group injected with LPS was an LPS-control group., Results: At 6 hours after injection the groups irradiated with doses of 3 J/cm(2) and 7.5 J/cm(2) had a reduced number of neutrophil cells in the peritoneal cavity compared with the LPS-control group, and there were significant differences between the number of neutrophils in the peritoneal cavity between the LPS-control group and groups irradiated with doses of 3 J/cm(2) (-42%) and 7.5 J/cm(2) (-70%). In the group irradiated with 15 J/cm(2), neutrophil cell counts were lower than, but not significantly different from, LPS controls (-38%; p = 0.07). At 24 hours after injection, both neutrophil and total leukocyte cell counts were lower in all the irradiated groups than in the LPS controls. The 3-J/cm(2) exposure group showed the best results at 24 hours, with reductions of 77% in neutrophil and 49% in leukocyte counts., Conclusion: Low-level laser therapy (904 nm) can reduce inflammatory cell migration in mice with LPS-induced peritonitis in a dose-dependent manner.

Objective: The aim of this study was to investigate if low-level laser therapy (LLLT) can modulate formation of hemorrhagic lesions induced by immune complex., Background Data: There is a lack of information on LLLT effects in hemorrhagic injuries of high perfusion organs, and the relative efficacy of LLLT compared to anti-inflammatory drugs., Methods: A controlled animal study was undertaken with 49 male Wistar rats randomly divided into seven groups. Bovine serum albumin (BSA) i.v. was injected through the trachea to induce an immune complex lung injury. The study compared the effect of irradiation by a 650-nm Ga-Al-As laser with LLLT doses of 2.6 Joules/cm(2) to celecoxib, dexamethasone, and control groups for hemorrhagic index (HI) and myeloperoxide activity (MPO) at 24 h after injury., Results: The HI for the control group was 4.0 (95% CI, 3.7-4.3). Celecoxib, LLLT, and dexamethasone all induced significantly (p < 0.01) lower HI than control animals at 2.5 (95% CI, 1.9-3.1), 1.8 (95% CI, 1.2-2.4), and 1.5 (95% CI, 0.9-2.1), respectively, for all comparisons to control. Dexamethasone, but not celecoxib, induced a slightly, but significantly lower HI than LLLT (p = 0.04). MPO activity was significantly decreased in groups receiving celecoxib at 0.87 (95% CI, 0.63-1.11), dexamethasone at 0.50 (95% CI, 0.24-0.76), and LLLT at 0.7 (95% CI, 0.44-0.96) when compared to the control group, at 1.6 (95% CI, 1.34-1.96; p < 0.01), but there were no significant differences between any of the active treatments., Conclusion: LLLT at a dose of 2.6 Joules/cm(2) induces a reduction of HI levels and MPO activity in hemorrhagic injury that is not significantly different from celecoxib. Dexamethasone is slightly more effective than LLLT in reducing HI, but not MPO activity.

Objective: We designed an animal pleurisy study to assess if the anti-inflammatory effect of photoradiation could be affected by concomitant use of the cortisol antagonist mifepristone., Background Data: Although interactions between photoradiation and pharmacological agents are largely unknown, parallel use of steroids and photoradiation is common in the treatment of inflammatory disorders such as arthritis and tendinitis., Methods: Forty BALB/c male mice were randomly divided in five groups. Inflammation was induced by carrageenan administered by intrathoracic injections. Four groups received carrageenan, and one control group received injections of sterile saline solution. At 1, 2, and 3 h after injections, photoradiation irradiation was performed with a dose of 7.5 J/cm(2). Two of the carrageenan-injected groups were pre-treated with orally administered mifepristone., Results: Total leukocyte cell counts revealed that in carrageenan-induced pleurisy, photoradiation significantly reduced the number of leukocyte cells (p < 0.0001, mean 34.5 [95% CI: 32.8-36.2] versus 87.7 [95% CI: 81.0-94.4]), and that the effect of photoradiation could be totally blocked by adding the cortisol antagonist mifepristone (p < 0.0001, mean 34.5 [95% CI: 32.1-36.9] versus 82.9 [95%CI: 70.5-95.3])., Conclusion: The steroid receptor antagonist mifepristone significantly inhibited the anti-inflammatory effect of photoradiation. Commonly used glucocorticoids are also known to down-regulate steroid receptors, and further clinical studies are necessary to elucidate how this interaction may decrease the effect size of photoradiation over time. For this reason, we also suggest that, until further clinical data can be provided, clinical photoradiation trials should exclude patients who have received steroid therapy within 6 months before recruitment.

Objective: The aim of this study was to review the biological and clinical short-term effects of photoradiation in acute pain from soft-tissue injury., Background Data: It is unclear if and how photoradiation can reduce acute pain., Methods: Literature search of (i) controlled laboratory trials investigating potential biological mechanisms for pain relief and (ii) randomized placebo-controlled clinical trials which measure outcomes within the first 7 days after acute soft-tissue injury., Results: There is strong evidence from 19 out of 22 controlled laboratory studies that photoradiation can modulate inflammatory pain by reducing levels of biochemical markers (PGE(2), mRNA Cox 2, IL-1beta, TNFalpha), neutrophil cell influx, oxidative stress, and formation of edema and hemorrhage in a dose-dependent manner (median dose 7.5 J/cm(2), range 0.3-19 J/cm(2)). Four comparisons with non-steroidal anti-inflammatory drugs (NSAIDs) in animal studies found optimal doses of photoradiation and NSAIDs to be equally effective. Seven randomized placebo-controlled trials found no significant results after irradiating only a single point on the skin overlying the site of injury, or after using a total energy dose below 5 Joules. Nine randomized placebo-controlled trials (n = 609) were of acceptable methodological quality, and irradiated three or more points and/or more than 2.5 cm(2) at site of injury or surgical incision, with a total energy of 5.0-19.5 Joules. Results in these nine trials were significantly in favor of photoradiation groups over placebo groups in 15 out of 18 outcome comparisons. Poor and heterogeneous data presentation hampered statistical pooling of continuous data. Categorical data of subjective improvement were homogeneous (Q-value = 7.1) and could be calculated from four trials (n = 379) giving a significant relative risk for improvement of 2.7 (95% confidence interval [CI], 1.8-3.9) in a fixed effects model., Conclusion: photoradiation can modulate inflammatory processes in a dose-dependent manner and can be titrated to significantly reduce acute inflammatory pain in clinical settings. Further clinical trials with adequate photoradiation doses are needed to precisely estimate the effect size for photoradiation in acute pain.

Objectives: Some conclusions from the Cochrane Database of Systematic Reviews (CDSR) seem volatile in areas of controversy and have recently changed conclusions. With this perspective in mind we decided to test the validity and sensitivity of negative conclusions in a systematic review of low-level laser therapy (LLLT) for osteoarthritis (OA) from the Cochrane Library was valid and robust., Settings/location: None as this was a systematic review of literature., Design: Validity was tested against a 9-item checklist for systematic reviews. Review selections were analyzed for possible discrepancies between trial and review reports and omissions of relevant trials and data. Data from discrepancies and omissions were then entered into sensitivity and subgroup analyses., Outcome Measures: Continuous and dichotomous data for pain, Subjects: Patients with osteoarthritis., Interventions: LLLT., Results: Only clinicians who had performed LLLT trials, and had negative results were invited into the review group. The review was oblivious to findings published after 1993 about physiologic mechanisms and dose response patterns for LLLT. We found 18 questionable selections that favored a negative review conclusion in 17 of 18 cases. These were largely omissions of relevant positive data and selective inclusion of negative data from trials with small, ineffective doses. When existing and omitted data from relevant trials were combined, results changed from negative to significantly positive for continuous and categorical data. Subgrouping trials by location and recommended doses taken from current guidelines, revealed a highly significant effect of LLLT for treating knee OA., Conclusions: The results of this CDSR was not robust and seems to be colored by questionable selections or omissions. For alternative pain therapies, it should be considered if lack of expertise on therapy mechanisms, or conflicts of interests with competing pain drug manufacturers, may bias conclusions. Review groups should recruit a balanced mix of current views and expertise and expand the use of sensitivity analyses to improve quality of CDSRs in areas of controversy.

Objective: The aim of this study was to investigate if low-level laser therapy (LLLT) can modulate acute inflammation and tumor necrosis factor (TNFalpha) levels., Background Data: Drug therapy with TNFalpha-inhibitors has become standard treatment for rheumatoid arthritis, but it is unknown if LLLT can reduce or modulate TNFalpha levels in inflammatory disorders., Methods: Two controlled animal studies were undertaken, with 35 male Wistar rats randomly divided into five groups each. Rabbit antiserum to ovalbumin was instilled intrabronchially in one of the lobes, followed by the intravenous injection of 10 mg of ovalbumin in 0.5 mL to induce acute lung injury. The first study served to define the time profile of TNFalpha activity for the first 4 h, while the second study compared three different LLLT doses to a control group and a chlorpromazine group at a timepoint where TNFalpha activity was increased. The rats in LLLT groups were irradiated within 5 min at the site of injury by a 650-nm Ga-Al-As laser., Results: There was a time-lag before TNFalpha activity increased after BSA injection. TNFalpha levels increased from < or =6.9 (95% confidence interval [CI], 5.6-8.2) units/mL in the first 3 h to 62.1 (95% CI, 60.8-63.4) units/mL (p < 0.001) at 4 h. An LLLT dose of 0.11 Joules administered with a power density of 31.3 mW/cm(2) in 42 sec significantly reduced TNFalpha level to 50.2 (95% CI, 49.4-51.0), p < 0.01 units/mL versus control. Chlorpromazine reduced TNFalpha level to 45.3 (95% CI, 44.0-46.6) units/mL, p < 0.001 versus control., Conclusion: LLLT can reduce TNFalpha expression after acute immunocomplex lung injury in rats, but LLLT dose appears to be critical for reducing TNFalpha release.

Objective: The aim of this study was to test if a conclusion in a systematic review of low-level laser therapy (LLLT) for osteoarthritis from the Cochrane Library was valid and robust., Background Data: Health policy decisions often rely on conclusions from the Cochrane Database of Systematic Reviews for approval of new therapies, although their validity for controversial non-pharmacological treatment has been questioned., Methods: Validity was tested against a nine-item checklist for systematic reviews. Review selections were analyzed for possible discrepancies between trial and review reports, and omissions of relevant trials and data. Alternative data from discrepancies and omissions were then imputed in a sensitivity analysis, to test if review conclusions were robust., Results: Only clinicians who had performed LLLT trials with negative results were invited into the review group. Review quality was sound in areas of literature search and methodological assessments, and some of the limitations were mentioned. The statistical analysis held 18 questionable selections such as omissions of trials, data, and subgroup analyses. These selections systematically favored the negative review conclusion. Without altering the review protocol, the sensitivity analysis of combined results changed to significantly positive for continuous and categorical data when data from all included trials were combined. Further sensitivity analyses with inclusion of valid non-included trials, performance of missing follow-up, and subgroup analyses revealed consistent and highly significant results in favor of active LLLT., Conclusions: In this example, the Cochrane review conclusion was neither robust nor valid. Representation of experts and different views on efficacy in the review group and extensive use of sensitivity analyses could probably improve quality control of reviews in areas of controversy.

Objective: Our aim was to investigate the effect of low-level laser therapy (LLLT), 650-nm wavelength, on acute inflammatory pleurisy., Background Data: There is only scattered evidence of anti-inflammatory effects from LLLT and dosage characteristics, and the effect on pleurisy inflammation has yet to be investigated., Methods: A classical experimental model of pleurisy was used in a sample of 40 Balb male mice, randomly divided into five groups. Inflammation was induced by carrageenan (0.5 mg/cavity) administered by intrathoracic injections. Four groups received the inflammatory agent, and one received injections of sterile saline solution. At 1, 2, and 3 h after injections, LLLT irradiation was performed, with the same power (2.5 mW), but different irradiation times. The energy densities at each of the three treatment sessions were 0 J/cm(2) (placebo), 3 J/cm(2), 7.5 J/cm(2), and 15 J/cm(2), respectively., Results: Total and differential cell analysis at 4 h after induction of pleurisy showed a significant reduction of inflammatory cell migration for all groups treated with active laser. However, at 4 h after injection, the most significant (p < 0.001) reduction of leukocyte cell migration was seen in the 7.5 J/cm(2) group, at 2.7 (95% CI: 2.5-2.9) x 10(6), versus 7.9 (95% CI: 6.7-9.1) x 10(6) in the placebo control group. The greatest reduction of inflammatory cells was registered for neutrophils., Conclusions: LLLT administered at 1-3 h after the induction of inflammatory pleurisy significantly reduces the inflammatory cell migration measured. Under these conditions and at 2.5 mW, 7.5 J/cm(2) was more effective than 3 J/cm(2) and 15 J/cm(2).