Tuesday, May 30, 2023
| Study by first author | Year | Method score | Laser wavelength | Application technique | Result | Reason for exclusion |
|---|---|---|---|---|---|---|
| Mulcahy [40] | 1995 | 5 | 904 | Not stated | No significant differences between active and placebo LLLT | Does not satisfy control group criterion: Lacks sufficient patient numbers in placebo control group as only 3 patients had tendinopathy |
| Simunovic [41] | 1998 | 3 | 830 | Tendon + Trigger Points | LLLT significantly better than placebo | Does not satisfy criterion for specific endpoint and standard number of treatments: Only bilateral conditions were given placebo treatment, but data for this group were not presented |
| Vasseljen [42] | 1992 | 5 | 904 | Tendon | Traditional physiotherapy significantly better than LLLT | Does not satisfy blinding criterion: Neither therapist, patients or observers were blinded in the traditional physiotherapy group |
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.
| Study by first author | Method score | Wave-length | Application technique | Result | Reason for exclusion |
|---|---|---|---|---|---|
| Haker [43] | 6 | 904 | Tendon | No significant differences | Photograph in trial report shows that the laser probe was kept in skin contact and thereby violated the manufacturers' recommendation of a keeping the laser head at a distance of 10 cm. This violation caused a central blind spot of ca 3 cm2 which left the tendon pathology unexposed to LLLT (See Figure 2) |
| Siebert [44] | 6 | 904 + 632 | Tendon | No significant differences | Active laser treatment to the placebo group received red 632 nm LLLT, which we calculated to be (2.25J), which again is an adequate LLLT dose. Consequently this trials lacks a placebo or non-laser control group |
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.
| Study by first author | Method score | Patient numbers | Application technique | Control | Trial results |
|---|---|---|---|---|---|
| Basford [53] | 8 | 47 | Tendon | Placebo | 0 |
| Gudmundsen [51] | 6 | 92 | Tendon | Placebo | ++ |
| Haker [46] | 7 | 49 | Acupoints | Placebo | 0 |
| Haker [50] | 6 | 58 | Tendon | Placebo | + |
| Krashenninikoff [54] | 6 | 36 | Tendon | Placebo | 0 |
| Lam [55] | 7 | 37 | Tendon | Placebo | ++ |
| Løgdberg-Anderson [49] | 7 | 142 | Tendon | Placebo | ++ |
| Lundeberg [47] | 6 | 57 | Acupoints | Placebo | 0 |
| Oken [56] | 7 | 59 | Tendon | UL, Brace | ++ |
| Palmieri [57] | 6 | 30 | Tendon | Placebo | ++ |
| Papadoupolos [52] | 4 | 31 | Tendon | Placebo | - |
| Stergioulas [48] | 7 | 62 | Tendon | Placebo | ++ |
| Vasseljen [58] | 8 | 30 | Tendon | Placebo | + |
| Total | 6.5(Mean) | 730 |
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.
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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).
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Figure 1. (click image to zoom) Quorum flow chart. Quorum flow chart of the steps in the reviewing process.
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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 .
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).
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Figure 2. (click image to zoom) 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).
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The five excluded RCTs[40-44] were taken into the publication bias analysis by a graphical plot as advised by Egger.[45] Four[40-42,44] 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[40,46,47] although this group also reported a positive outcome.[50] Three of these trials met the eligibility criteria for this review and were included in the meta-analysis.[46,47,50] The five largest trials[43,48-51] all presented positive results, although Simunovic et al.[43] 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).
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Figure 3. (click image to zoom) 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).
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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.[52] Two trials used the acupoints application technique,[46,47] 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 .
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,[36] and the variance could be within the range of measurement error for this methodological criteria list.[53] In addition, fulfilment of more than 50% of methodological criteria is often considered as a threshold for acceptable quality,[54] 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.[48,55,56] In two of these trials,[55,56] 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.
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,[48-51,55-57] whereas three trials using lasers with 820/30 nm[58,52]and 1064 nm[59] wavelengths found no significant effect of LLLT. A single trial administering LLLT with a wavelength of 632 nm,[60] also found significantly better results for the LLLT group. In the two trials where LLLT was administered to acupuncture points,[46,47] no significant differences between LLLT and placebo were found for any of the outcome measures.
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[48,50,55-57] 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.
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Figure 4. (click image to zoom) 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.
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Seven trials[46,49-51,55,57,58] 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[49-51,55,57] 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.
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Figure 5. (click image to zoom) 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.
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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[60] or 904 nm,[48,49,56,57] 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.
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Figure 6. (click image to zoom) 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.
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Two trials with 904 nm wavelength using application technique with tendon irradiation[50,56] 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.
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Figure 7. (click image to zoom) 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.
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Sick Leave. One trial with 904 nm LLLT administered directly over the tendon insertion, presented sick leave data.[51] 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.[47,48,56,57,59,60] The combined WMD was 11.30 mm [95% CI: 7.5 to 16.1] in favour of LLLT. For global improvement, three trials[46,51,57] 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[48,56,57] 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[60] 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.
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Figure 8. (click image to zoom) 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.
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Figure 9. (click image to zoom) 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.
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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]),[57] respectively. Other outcomes were not significantly different beyond 8 weeks. For the two trials using acupoint irradiation,[46,47] 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.[48,58] One of these trials[48] 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[58] using 830 nm wavelength, an exceptionally high withdrawal/dropout rate of 15% occurred after a single treatment session without any given reason.
