LaserWorld Guest Editorial, Nr 19 - 2001.

8th International Congress of the European Medical Laser Association in Moscow

Miroslav Prochazka, Member of EMLA Parliament, Prague, CZ, Premysl Fryda, Member of EMLA Parliament, Prague, CZ

At the end of May the 8th International Congress of the European Medical Laser Association (EMLA) together with the 1st Congress of the Medical Laser Association of the Russian Federation took place in Moscow. Both basic scientific research in laser medicine and specific aspects of the use of invasive and non-invasive laser techniques in medicine of the 21st century were the main topics of the event, not leaving out also photodynamic therapy, lasers in veterinary medicine and other disciplines.

It was possible to see most of the celebrities of contemporary laser medicine from all over the world among invited guests, but, to the detriment of the cause, some of the invited foreign guests had not managed to arrive. However, some of the papers presented by Russian colleagues and doctors and scientists from countries of former Soviet Union, who only scarcely appear at congresses in Western Europe, counterbalanced this handicap very well. Intellectual potentials of these countries must not be neglected, and neither can be neglected exemplary efforts to bring mathematic analyses of results in their works. Now, when working with experimental animal models becomes often very problematic in the West, a surprisingly high number of papers, containing a good and qualitative as well as quantitative adequate analysis of these valuable experiments, can only be appreciated. Furthermore, some of the works clearly indicated their relation to military science, where laser technology undoubtedly witnesses even a bigger boom than it does in medicine...

The congress was rather demanding as far as financial point of view is concerned, regardless to actual prices of air tickets to Moscow, as participation and other fees represented a high portion of participants' expenditures, which might probably influence the number of foreign guests at the end. However, today's Moscow does not count among the cheapest capital cities. It might also be for financial reasons that made some of the participants to think of not participating in the rather rich social programme, inclusive of, among others, an opera in the Great Theatre (Bolshoi Theater) or an excursion to the Chamber of Diamonds in the Kremlin Armory (Kremlyevskaya Oruzheynaya Palata). Accomodation was on a decent level, even though some of the participants could make slight remarks upon it from time to time. However they mostly recalled their student years in university dormitories. Khorosho.

We could be only positively surprised by Moscow itself, by its clean and good looking streets. When comparing with the old times, the change is just great. Old sights are kept in excellent repair, and visiting some of the recent monuments, such as a giant memorial to Peter the Great on an artificial islet in the middle of the Moscow River or the newly built biggest Orthodox Temple of Christ the Redeemer, on the roof domes and inner decorations of which as much as 56 tons of gold was allegedly used, is a tremendous experience. Moscow Metro has come alive with numerous advertising billboards, old flaking GUM has changed into hypermodern shopping mall with luxury brand stores; close to the Red Square a several-storey underground free time and shopping centre with tens of restaurants has been built, with American fast-food places neighbouring Russian, Chinese, Japanese and Indian restaurants, or even a typical Czech Good Soldier Svejk´s Pub with genuine Czech beer. You can buy quite a few souvenirs at the Old Arbat, in the stands there are Pokémons and Barbie dolls standing on the shelf with classical Russian matryoshkas and busts of Lenin. Vodka is still a traditional drink, young moscovites however walk the streets today with a cellular phone in one hand and a bottle of beer in the other one.

However, let us get back to the Congress itself. Three days of lectures in three separate halls covered the whole spectrum of today's laser medicine. Scientific part of the Congress was opened by a valuable speech of Toshio Ohshiro of Japan, resuming his experience with more than 41 thousand cases treated with laser during the last 27 years. Shimon Rochkind of Israel then addressed the congress with his latest paper on results of double-blind studies on laser treatment of peripheral nerves, evidencing motor and sensory functions improvement after LLLT. The second day was mainly devoted to possibilities of the use of laser in ophtalmology.

There was a series of papers aimed at laser treatment of tinnitus, too. A Swedish dentist, Jan Tunér claimed that tinnitus can also fall into dental pathologies and that the character of the unwanted noise can be, in some cases, changed by LLLT, releasing tension of facial muscles or posture of the jaw. Czech duo Tejnska and Prochazka presented their work on non-invasive laser therapy of tinnitus (see Clinixperience No. 4/2000) enriched with their new findings based on their long-term follow of the patients suffering from this disease. Their way of treatment of tinnitus through massive irradiation of meatus and mastoideus with sufficient amount of laser energy has been supported by experience of Lutz Wilden of Germany, whose paper covered the issue of laser treatment of diseases of inner ear as a whole.

The congress also covered topics of oncology, photodynamic therapy, and basic science and theoretical aspects of laser interaction with living tissue. René-Jean Bensadoun of France picked up his earlier study on chemo- and radiation-induced mucositis (see Clinixperience No. 24/2001 and LaserWorld editorial No 1) and informed about new scoring systems allowing better evaluation and comparison between individual studies and protocols on efficacy of LLLT in the overall treatment of cancer. Voinov of Russia informed about research on quantitative tests for individual laser energy doses control through fluorescent albuminous test allowing registration of energy overdose. Proper dosage of laser energy was also the main topics of Jan Bjordal's work, dealing with pain reduction after direct irradiation of chronic joint disorders (see Clinixperience No.13/2000, LaserWorld editorial No 15).

Pain management and treatment of medial and lateral epicondylitis was the main subject of the paper of Zlatko Simunovic and Tatjana Trobonjaca (Laser centres in Switzerland and Croatia). A multicenter, double-blind and placebo controlled study on more than 300 patients has proven the efficacy of LLLT in the management of this disease as well as of many other sport injuries. Simunovic and Trobonjaca also compared results of polarised light and therapeutic laser on lateral epicondylitis. According to their results, over 40 % of the patients irradiated with laser achieved 100 % pain relief and adequately restored functional ability, whilst none of the second group of patients reported total pain relief after repeated treatments with polarised light. Polarised light and its thorough spectral and power analysis was the main subject of Navratil and Kolarova (Czech Republic), being supported by a governmental grant agency. Navratil and Kymplova also highly evaluated the effect of LLLT in combination with systemic enzymotherapy on specific pathologies of locomotive organs.

Russian authors have practically all known invasive and non-invasive lasers at their disposal. There are numerous specialised laser centres in the country, and practising the whole spectrum of laser applications on very extensive numbers of patients brings significantly high value of published papers as far as statistics is concerned. The lecture of the President of the congress, Vladimir Mikhailov of Russia, called "The Past, Present and Future of Laser Therapy in Russia" fascinated all participants with the scope of laser therapy in this country, stating that there are some 1.5 million patients treated with laser every year. Apart from what we would call traditional laser therapy (wound healing, pain management, neurosurgery etc.) there were interesting new LLLT applications reported by Russian authors, such as laser treatment of children suffering from respiratory allergies, or improvement of immunity of the organism by irradiation of blood, raising efficiency of sportsmen by LLLT and others. Furthermore there were numerous applications which some of us could consider either controversial (LLLT on schizophrenic patients) or interesting especially from the point of view of their title, rather than of validity of their results (Laser Therapy of Sexual Disorders in Women and Men).

In the accompanying industrial exhibition visitors could see many Russian firms presenting a pleiad of invasive and therapeutic laser devices, some of them with interesting technical conceptions (for instance a vacuum erection aid combined with a laser). Against strong Russian competition, traditional participants - Swiss Lasotronic with its series of pocket therapy lasers, and Czech MediCom presenting its production line of lasers and laser scanners - were successfully defending the positions of "the rest of the World".

The congress was closed by the meeting of the Board of Directors of EMLA, moderated by EMLA President Tatjana Trobonjaca and EMLA secretary René-Jean Bensadoun. The main topics of the meeting were discussions on new modalities of educational activity of EMLA, unified European training certificate, and the final form and contents of the official EMLA journal. In this context it should be mentioned that Laser Partner has repeatedly offered to become the official paper of the Association. The Board of Directors set the following 9th International Congress of the European Medical Laser Association to take place at the end of October 2002 in Vienna, Austria. Spasibo, dosvidania.

This article is jointly published by LaserWorld and LaserPartner Clinixperience journal.

LaserWorld Guest Editorial, Nr 18 - 2001.

Biostimulatory Windows in Low Intensity Laser Activation:
Lasers, Scanners and NASA's Light Emitting Diode Array System

By Dr. Andrei P. Sommer.
Email
[Short version of the article published in the Journal of Clinical Laser Medicine & Surgery, Vol. 19, Number 1, 2001, Mary Ann Liebert, Inc. Pp. 29-33]

It took 33 years…
The purpose of the international study published in the February 2001 issue of JCLMS was to assess and to formulate physically an irreducible set of irradiation parameters, which could be of relevance in the achievement of reproducible light induced effects in biological systems - in vitro and in vivo. There is ample evidence that the action of light in biological systems depends at least on two threshold parameters: the energy density and the intensity. Depending on the particular light delivery system coupled to an irradiation source, the mean energy density and the local intensity have to be determined separately, by help of adequate experimental methods. The biological independence between the two threshold parameters is of practical importance for the medical application of photobiological effects achieved at low energy density levels, accounting for the success and the failure in most of the cold laser uses since Mester's pioneering work [1,2].

Energy density
Ameliorated wound closures were achieved at energy densities between 1 and 4 · 104 Jm-2 in the therapy of ulcera cruris with 50mW He/Ne-Lasers [ 3] . This and further evidence has led to the establishment of one basic Arndt-Schultz-curve showing different modes of cell reaction at different energy density levels [ 1,2,3,4,5,6,7,8] . When the levels were too small, there were no observable effects. Higher levels resulted in the inhibition of cellular functions. Energy densities of therapeutically relevant photobiological effects [ 8,9,10,11,12,13,14,15,16,17,18,19,20,21] , were in accordance with the energy density range described in the basic Arndt-Schultz-curve.

Power density
The influence of the power density (light intensity) on irradiated cells was demonstrated in fibroblast cultures [ 22] ; and possibly as well in animal experiments: The mast cells of irradiated mouse tongues showed a progressing degranulation with increasing laser power (4mW, 50mW) where the locally administered energy density was kept at the same level [ 23] .
Observations in patients revealed also that thresholds of light intensity (presumably wavelength dependent) have to be surpassed in order to achieve reproducible biostimulatory effects. A documentation of the precise threshold values was prior to our study lacking. What had been repeatedly found, was that the clinical use of lasers with a power smaller than 4mW in the field of application, induced no reproducible biological effects, independent of the length of the total irradiation time [ 24,25] .

The LILAB-equation

Applications of the LILAB-equation
In practice it is of great importance to apply the laser light to a much greater area than the laser beam cross section itself. Due to the cooperative behaviour of photostimulated cells [ 28,29] , it seems to be important to simultaneously irradiate the application field in order to avoid adverse effects with respect to the intended aims [ 30] . Consequently the application field would have to be irradiated in the shortest possible period, creating a homogenously distributed mean energy density with the necessary local light intensity - as required for activation.
For these practically important cases scanners have been developed. Scanners were used in vivo with satisfactory results. The suitability of conventional scanners for medical applications depends, besides the values of the local light intensity, on the uniformity of the mean energy density in the application field.
In agreement with equation (1), the biologically effective light intensities can also be applied on greater areas by use of high power lasers in combination with optical lenses (beam diverging systems). Beam diverging systems could be adequate with suitable semiconductor lasers, as reported on the successful photobiostimulation of General Motors workers and other patients with carpal tunnel syndrome [31]. Promising for photobiostimulation of extended wound areas with homogenous mean field intensities and energy densities within the activating range [8], appear to us, as potential light sources, light emitting diodes (LED) and NASA's lightweight light emitting diode array systems in particular [17,18].
In contrast to the threshold intensity necessary for activation Istim - a quantity directly calculable from the technical data of the laser - the mean field intensity Ifield in any application field A greater than the cross section of the laser beam, can only be determined accurately by measuring the mean energy density (E/A). The determination of this quantity, is relatively simple in case of the spot surfaces generated by beam diverging systems, and more complicated in case of the light patterns generated by scanners as described in literature [ 8,32,33] . The question whether (E/A) is an activating energy density or not, depends not explicitly on the particular magnitude of the associated Ifield-value, but primarily on the value of the local light intensity Istim and the total duration of the local light stimulus per activated field.
The LILAB-System [37], being an exemplary model to demonstrate the interplay between biologically relevant irradiation parameters - and a relatively simple irradiation system, is based on a fast beam distributor, designed for homogenous irradiation of arbitrarily large application fields [ 8] . Using a prototype LILAB-System based on a 25mW He/Ne-Laser (632.8nm), we could generate various, nearly homogenously spread energy density fields. Representatively for mean field intensities of biological relevance (72Wm-2) [33], we could apply intensities within the range administered via NASA's irradiation system (24Wm-2 to 743Wm-2), found to be effective in fibroblasts, osteoblasts and skeletal muscle cells [16,17,18]. Recent laboratory results observed in murine osteoblasts irradiated with the NASA-LEDs, and the associated exemplary experimental protocol accounting for the irreducible set of the three biologically independent parameters (wavelength, energy density, intensity) necessary for complete characterization of the irradiation, have been recently published [16, 38].

Discussion
The existence of an upper limit for the applicable light intensity - as found in cell culture experiments by Lubart [ 22] - could not be observed in clinical practice, presumably because of the change of the intensity with the depth of penetration due to absorption.
Realizing the importance of intensity and energy density, there is no way to circumvent in future laser experiments the specification of the laser beam diameter - and in using scanners - the measurement of the mean energy density. The method for the measurement of the mean energy density generated by scanners and its validation has been published [33]. Besides the light intensity thresholds and the activating mean energy densities - determined in case of the scanners by the cumulation of the duration of local light stimuli -, certain beam repetition frequencies with extended influence on activation seem to exist. There is also evidence from literature for their existence. The biological effect of the pulse frequency received support from the experimental side - from the observation of an additional Ca2+ uptake in macrophages [ 34] and an enhanced chemiluminescence in murine splenocites [ 35] , after irradiation with pulsed semiconductor lasers of suitable pulse duration and repetition frequency - and also from the clinical side [36]. Thus, the periodical stimulation of extended tissue areas with maximum local photon density, uniform energy density and minimum thermal effects - as realized e.g. with the LILAB-System - is regarded to be a powerful method for the achievement of photobiological results with lasers [ 37] .
The suggestion of the present study, holding for most of the medically used laser and related irradiation systems operating at low energy density levels, hence of general interest, is that the irradiation of areas exceeding the cross section of laser beams with homogenous energy densities must be paralleled in practice by the precise measurement of at least two independent threshold parameters: the local intensity of the laser beam, respectively diode field, and the mean energy density in the application field.

References
1. Mester, E., Szende, B., and Gartner, P. (1968). The Effect of Laser Beams on the Growth of Hair in Mice. Radiobiol. Radiother. 9 (5), 621-6.
2. Mester, E., Spiry, T., Szende, B., and Tota, J.G. (1971). Effect of Laser Rays on Wound Healing. Am.-J.-Surg. 122 (4), 532-5.
3. Mester, E. (1981). Über die stimulierende Wirkung der Laserstrahlung auf die Wundheilung, in: Der Laser: Grundlagen und Klinische Anwendungen. K. Dienstl, and P.L. Fischer (eds.). Berlin, Heidelberg, New York: Springer, pp.109-118.
4. Mester, E., Mester, A., and Toth, J. (1983). Biostimulative Effect of Laser Beams, in: New Frontiers in Laser Medicine and Surgery. K. Atsumi (ed.). Excerpta Medica, pp. 481-489.
5. Mester, A.R., Nagylucskay, S., Mako, E., et al. (1998). Experimental Immunological Study with Radiological Application of Low Power Lasers, in: Laser in Medicine. W. Waidelich (ed.). Berlin, Heidelberg, New York: Springer, pp. 502-512.
6. Ohshiro, T. (1988). Low Level Laser Therapy: A Practical Introduction. New York: John Willey and Sons, pp. 30.
7. Mester, E., Mester, A.F., and Mester, A. (1985). The Biomedical Effect of Laser Application. Lasers Surg. Med. 5, 31-39.
8. Sommer, A., and Franke, R.P. (1993). LILAB - a new System for Low Intensity Laser Activated Biostimulation. Biomed. Tech. 38, 168-171.
9. Yamada, K. (1991). Biological Effects of Low Power Laser Irradiation on Clonal Osteoblastic Cells (MC3T3-E1). J. Jpn. Orthop. Assoc. 65, 787-799.
10. Trelles, M.A., and Mayayo, E. (1987). Bone Fracture Consolidates Faster With Low Power Laser. Lasers Surg. Med., 7, 36-45.
11. Wu, W., Naim, J.O., and Lanzafame, R. J. (1994). The effect of laser irradiation on the release of bGFG from 3T3 fibroblasts. Photochem.-Photobiol. 59 (2), 167-170.
12. Rosner, M., Caplan, M., Cohen, S., Duvdevani, R., Solomon, A., Assia, E., Belkin, M., and Schwartz, M. (1993). Dose and temporal parameters in delaying injured optic nerve degeneration by low energy laser irradiation. Lasers Surg. Med. 13 (6), 611-617.
13. Pinheiro, A.L., Cavalcanti, E.T., Pinheiro, T.I., Alves, M.J., and Manzi, C.T. (1997). Low level laser therapy in the management of disorders of the maxillofacial region. J. Clin.-Laser-Med.-Surg. 15 (4), 181-3.
14. Bihari, I. (1994). CO2 Laser in Low Power Applications in Wound Healing. Laser Therapy, 6 (1), 43.
15. Sroka, R., Schaffer, M., Fuchs, C., Pongratz, T., Schrader-Reichard, U., Busch, M., Schaffer, P.M., Duhmke, E., and Baumgartner, R. (1999). Effects on the mitosis of normal and tumor cells induced by light treatment of different wavelengths. Lasers Surg. Med. 25 (3), 263-71.
16. Whelan H.T., personal communication: NASA-LEDs presented in [17,18] were used to irradiate the Osteoblasts.
17. Whelan, H.T., Houle, J.M., Whelan N.T., Donohoe, D.L., Cwilinski, J., Schmidt, M.H., Gould, L., Larson, D.L., Meyer, G.A., Cevenini, V., and Stinson, H. (2000). The NASA light-emitting diode medical program - progress in space flight and terrestrial applications. Space Tech. & App. Int'l. Forum - 2000, 504, 37-43.
18. Whelan, H.T., Houle, J.M., Donohoe, D.L., Bajic, D.M., Schmidt, M.H., Reichert, K.W., Weyenberg, G.T., Larson, D.L., Meyer, G.A., and Caviness, J.A. (1999). Medical applications of space light-emitting diodes technology - space station and beyond. Space Tech. & App. Int'l. Forum - 1999, 458, 3-15.
19. Pinheiro, A.L.B. personal communication: Irradiation of mouth ulcers in 57 HIV-positive patients - in average three ulcers per patient (23 patients with lesions strongly related to the HIV infection) - using 5mW lasers (635 and 670nm, beam cross sections ~ 1mm2) and local light doses between 0.9 and 3.4·104 Jm-2, revealed generally a ca. 50% reduction of the total healing period of the ulcers, when compared to non irradiated cases. In the HIV related cases, the healing times depended upon the actual status of infection of the patients: ARC patients reacted in general better to the laser therapy than patients having developed full AIDS.
20. Pinheiro, A.L.B. personal communication: Laser irradiation of tissues contacting implants improved osteointegration (animal experiment): Laser power 40mW, wavelength 830nm, beam cross section ~ 1mm2, dose per spot 1.2·104 Jm-2 and total dose per session 4.8·104 Jm-2. Abstract in: Martins, P.P.M., Pinheiro, A.L.B., Oliveira, M.A.M., and Gerbi, M.E.M. (2000). P.P.M.M. Implant System Have Osteointegration Improved by LLLT. World Association for Laser Therapy, Third World Congress. Athens, 11-13 May.
21. Tunér, J., and Hode, L. (1999). Low Level Laser Therapy - Clinical Practise and Scientific Background. Sweden: Prima Books, pp. 161-162.
22. Lubart, R., Friedmann, H., Peled, I., and Grossman, N. (1993). Light Intensity Effect on Cell Proliferation. Fifth Congress of the European Society for Photobiology. Marburg/Lahn, September 19-26.
23. Trelles, M.A., and Mayayo, E. (1992). Mast Cells are Implicated in Low Power Laser Effect on Tissue. A Preliminary Study. Lasers in Medical Science, 7, 73-77.
24. Mester, A.R. (1992). Modalities of low power laser applications. Laser Applications in Medicine and Surgery. Laser Bologna 92. Third World Congress - International Society for Low Power Laser Applications in Medicine. Bologna, September 9-12.
25. Mester, A.R. (1994). Low power laser in the complex wound management. Laser Therapy, 6 (1), 39.
26. Sommer, A. (1993). Fast Surface Covering Beam Distributor for Lasers. German Patent Office, Munich, Patent Nr. 4308474/2000.
27. Lubart, R., Friedmann, H., Peled, I., and Grossman, N. (1993). Fibroblasts proliferation and light - a non linear interaction. Lasers Surg. Med. 9 (2), 143.
28. Costato, M. (1992). Laser light and biological response: cooperative phenomena vs. order and disorder. Laser Bologna 92. Third World Congress - International Society of Low Power Laser Application in Medicine. Bologna, September 9-12.
29. Dahle, J., Kaalhus, O., Moan, J., and Steen, H.B. (1997). Cooperative effects of photodynamic treatment of cells in microcolonies. Proc. Natl. Acad. Sci. USA, 94 (5), 1773-8.
30. Longo, L., and Corcos, L. (1992). Defocused CO2 Laser therapy in pathologic wound healing, in: Laser in Medicine. W. Waidelich (ed). Berlin, Heidelberg, New York: Springer, pp. 409-412.
31. Gwynne, P. (1994). Cold Laser Uses Move Beyond Carpal Tunnel. Biophotonics, 1(1), 28-29.
32. Sommer, A., and Franke, R.P. (1993). Evaluation of the Energy Density Distribution in Laser Light Fields generated with the LILAB System. Biomed. Tech. 38, 240-242.
33. Sommer, A., and Franke, R.P. (1995). Determination of the Energy Density of a Periodical Homogenous Laser Light Pattern Used in Medical Applications. Biomed. Tech. 40, 133-136.
34. Young, S.R., Dyson, M., and Bolton, P. (1991). Effect of Light on Calcium Uptake by Macrophages. Laser Therapy, 3, 1-5.
35. Karu, T., Andreichuk, T., and Ryabykh, T. (1993). Changes in Oxidative Metabolism of Murine Spleen Following Laser and Superluminous Diode (660-950nm) Irradiation: Effects of Cellular Composition and Radiation Parameters. Lasers Surg. Med. 13, 453-462.
36. Goldman, J.A., Chiapella, J., Cassey, H., et al. (1980). Laser therapy of rheumatoid arthritis. Lasers Surg. Med. 1 (1), 93-101.
37. Sommer, A., and Franke, R.P., (1994). The Low Intensity Laser Activation Biostimulation (LILAB) System. Laser Therapy, 6 (1), 23.
38. Sommer, A.P., Pinheiro, A.L.B., Mester, A.R., Franke, R.P., Whelan, H.T. (2001). Biostimulatory Windows in Low-Intensity Laser Activation: Lasers, Scanners, and NASA's Light-Emitting Diode Array System. J. Clin.-Laser.-Med.-Surg. 19 (1), 29-33.

Aknowledgement
We are grateful to the American Chemical Society (ACS) for supporting the advance in the investigation of the molecular mechanism of accelerated wound healing processes induced by light, by cosponsoring the 1st International Workshop on Nearfield Optical Analysis.

LaserWorld Guest Editorial, Nr 17 - 2001.

The Cochrane analyses - can they be improved?

Jan Tunér DDS, Grängesberg, Sweden
Jan.tuner@swipnet.se

The aim of the international Cochrane collaboration is to continuously evaluate new and old medical therapies. The basis for their systematic reviews is the recognition of Randomised Controlled Trials as the "gold standard" for scientific evaluation of small and moderate effects from treatment (1). A thorough search is made for the available literature and the most qualified studies are analysed. The purpose of the analysis is to find out whether or not there is any solid support for a specific medical treatment modality. Such analyses are published in medical journals and extended versions are quarterly updated in the Cochrane Library.
Three systematic reviews of the effectiveness of Laser Therapy have been published in the Cochrane Library. These reviews have evaluated the effect of Laser Therapy for Venous ulcers (1), Osteoarthritis (2) and Rheumatoid arthritis (3). However, the Cochrane style of reviewing has been criticised (9) for not taking into account the variability of diagnoses, treatment procedures and dosage of the included trials. Critical comments are, according to the rules of the Cochrane system, supposed to be included into the ongoing updating of the reviews, but the comments on the venous ulcer analysis by the author of this article have not been published, nor commented.
The impact of the Cochrane Library is profound in medicine. It is therefore essential to "evaluate the evaluation", to find out whether or not these analyses can live up to the prestige of the Cochrane Library. The following text is a critical "analysis of the analyses".

Venous ulcers
Four trials are analysed; two comparing laser with placebo, one comparing laser with non-coherent light and one comparing laser with ultraviolet light. The two studies comparing laser with placebo are (4) and (5). In (4) a 6 mW HeNe laser was used. 4 J/cm2 was said to be given to the ulcers. Ulcer size ranged from 3-32 cm2. Treatment technique is not stated. Regardless of technique, it would take between 36 minutes and 6 hours to achieve the stated dose, per wound and session. Using a sweep technique with a focused beam, the power density would be around 0.15 W/cm2. If a defocused beam was used to cover the entire largest wound (32 cm2), energy density would be around 0.00019 W/cm2, which is lower than the energy density of the normal illumination in an operatory, which is extremely low. A dose miscalculation is probable but the authors of the study have been reluctant to reveal the parameters used. In the absence of such parameters, this study cannot be properly evaluated, but very low power density is a probable reason for negative results. In the second study on venous ulcer (5), GaAs was employed. 4 mW was used for 10 minutes on ulcers ranging from 4 to 52 cm2, regardless of ulcer size. The 4-cm2 wound would thus receive 0.6 J/cm2 and the largest wound 0.046 J/cm2, not the 1.96 J/cm2 stated by the authors. Energy density as well as dose for larger wounds are thus low. Treatment technique is not indicated. "The laser was held perpendicular to the surface of the wound". This is not a sufficient description of the treatment method. There is a great difference between following the outer border of the wound (active healing area) and spreading the beam over the open wound area. The distance between diode and wound is not indicated.
In summary, the energy said to be applied in these studies must be questioned. The Cochrane evaluators have not observed the essential contradiction between the actual dose and the dose indicated by the authors. In one of the four studies (Crorus and Malherbe, 1988) the laser wavelength and dose is not stated in the original paper. This makes an evaluation impossible.

Osteoarthritis
Five trials were included out of 142 potentially relevant articles. Six abstracts are awaiting assessment, after having contacted the authors for further details. These are our comments on the evaluation:

• a. Bülow (1994) (negative outcome) is a good study with a reasonable energy (22.5 J/session) for painful knee osteoarthritis. However, see discussion on this study in the text on RA.
  
• b. Basford (1987) (negative outcome) used 0.007 J per point for thumb arthritis. Meaningless dosage.
  
• c. Jensen (1987) (negative outcome) used 0.2 J in total for painful knee arthrosis. Clearly a meaningless dosage.
  
• d. Stelian (1992) (positive outcome) used around 11 J per session, twice daily, so 22 J per knee and day, 10 consecutive days. This study has a dose that is acceptable even in the light of to-days experiences, although it was published already in 1992. The outcome of this study is in sharp contrast to the rather similar study by Bülow. Dose is the same, number of sessions is almost the same (10/9). However, Bülow treated 2-4 times a week, Stelian daily.
  
• e. Walker (1983) (positive outcome) is a classical positive study, but the use of a less-than 1 mW HeNe laser clearly puts this study in doubt. In our opinion it should not be used as anything but a purely historical reference.

The crucial criticism of the evaluation of the studies above is that there is no discussion about dosage! On the Jadad quality scale (1-5), Basford is given 3 and Bülow 2. However, Basford has used a non-significant dosage for a finger joint, while Bülow has a reasonable dose for knee osteoarthritis. Johansen (see RA below) has been over the generally accepted dosage window. In retrospect, the Bülow trial has been criticised for overlooking a significant short-term effect of active laser treatment by only testing the statistical significance at follow-up (Marks & de Palma 2000). Stelian used 55 times higher energy than Jensen, for knee osteoarthritis! The Jadad quality scale is applied correctly to the studies. But without inclusion of the laser parameters in the scale, the evaluation rather becomes a "study design beauty contest" instead of an evaluation of therapeutical significance.

3. Rheumatiod arthritis
8 out of 191 articles met the inclusion criteria, five were RCT:s. Five studies are waiting assessment, pending answers from the authors. Comments:

• a. Johansen (1994) (negative outcome) used 11.9 J per finger joint, which is a high dose, maybe too high.
  
• b. Heussler (1993) (negative outcome) used 1.5 J per finger, which is on the low side.
  
• c. Walker (1987) (positive outcome), see above for relevance. Although Johansen has used 1700 times higher a dose, both studies are "put in the same basket", although a low/high dose evaluation is performed. The wide gap in dosages does not justify a subgroup analysis of merely two groups.
  
• d. Hall (1994) and Goats (1996) used combined coherent and non-coherent light. Combined single wavelength coherent light and multi-wavelengths non-coherent light is a poorly studied area and there is no ground for postulating that they produce the same biological effects when used in combination or alone.
  
• e. The authors quote Seichert (1991): "The laser light loses its coherency completely after only a few tenths of mm in depth". This is not in accordance with laser physics, but a tall tale. Fact is that the length of coherence is considerably reduced but remains within the laser speckles, which can penetrate considerable depth in the infra-red.
  
• f. The meta analysis by Gam (one of the Cochrane co-authors) (8) is referred to. This analysis did not find any effect of Laser Therapy for musculoskeletal pain. The re-evaluation of the same studies made by Bjordal (9) found a clear effect, since an analysis of the dosage and therapeutic techniques was included. This later meta- analysis is not mentioned. As stated above, critical comments on the Cochrane reviews are supposed to be included.

Review conclusions
The evaluators of the Cochrane groups have been successful in finding many of the relevant studies in the literature. Several interesting observations have been made and a skilful analysis of the design parameters has been performed.
Evaluation of effects is a universal problem for all empirically developed therapies, where consensus of a clearly defined optimal dose range and adequate treatment procedure is lacking. For clinicians practising laser therapy it is hard to understand that the reviewers have disregarded which locations for laser exposure and which laser doses that are being used. The methodology used seems to be that of drug studies. But drugs and LLLT are quite different. While the oral intake of the drug is the only procedure, LLLT has several, such as local irradiation, trigger point irradiation, acupuncture irradiation and irradiation over peripheral nerves. All these methods must be evaluated separately.
The biggest problem has been the fact that most of the reviews have included a variety of diagnoses, doses and treatment procedures and then been "put into the same basket". New treatment methods are often subject to trials where clinicians include all their non-responder patients, and the early laser literature is no exception. The laser literature involves around 100 double blind trials (12). They include a heterogeneous sample of around 20 different diagnoses, which vary widely in pathology, tissue involved and prognosis. Adding to this are all the inadequate treatment procedures and doses that have been employed in clinical LLLT trials, so we should be very careful about putting all the trial results together, to see if they add up to an effect that is significantly better than placebo. Under such circumstances the majority of these trials will find no effect of active treatment. Future reviews are suggested to analyse the positive studies in order to find out what kind of parameters seem to work. Subgroup analyses are of particular importance. Dosage analysis cannot be limited to the groups "high" and "low" because of the great variations in dosage.
So what have these new Cochrane reviews brought us? Three distinct steps of progress can be identified. The first is the new review limitation to specific diagnosis (2) (3). The second is that in the RA review, attempts have been made to evaluate effects separately for high and low dose. And thirdly, but not least they even give a (conditioned) recommendation: "Low level laser therapy could be considered for treatment of rheumatoid arthritis for its short term effect and lack of side effects".

Future directions
In my opinion both laser researchers and reviewers have common responsibilities in enhancing our understanding of LLLT. The three existing Cochrane reviews on Laser Therapy have drawn a conclusion to which I can subscribe: The literature on the evaluated indications is ambiguous, the average quality of the studies is not high and the number of relevant studies is low. It can therefore be postulated that there is still insufficient scientific support for the general use of Laser Therapy for these indications and that only moderate and short-term effects can be confirmed. However, I would appreciate if reviewing methodology included validity criteria for doses and targets for laser irradiation (synovia, triggerpoints, acupuncture points, peripheral nerve, etc.).
I would also appreciate if the effect calculations were performed for subgroups of different doses, treatment frequencies and laser types. And there is still room for improvement of the literature search. Further, reviewers must make their own dosage calculations, not taking the doses quoted in the studies for granted. Too many of the negative LLLT studies contain serious flaw (11) and such flaw must be firmly investigated in the evaluation of studies. My main impression is that reviewing methodology slowly is improving, but there is still a long way to go before the Cochrane Collaboration can claim propriety over the term "evidence-based medicine" in this field of medicine.

References:

1. Flemming K, Cullum N. Laser Therapy for venous leg ulcers (Cochrane review). In: The Cochrane Library, 4, 2000.
   
2. Brosseau L, Welch V, Wells G et al. Low level laser therapy (Classes I, II and III) for treating Osteoarthritis. The Cochrane Library. Issue 4, 2000.
   
3. Brosseau L, Welch V, Wells G et al. Low level laser therapy (Classes I, II and III) for treating rheumatoid arthritis. The Cochrane Library. Issue 4, 2000.
   
4. Lundeberg T, Malm M. Low power HeNe laser treatment of venous leg ulcers. Ann Plast Surg. 1991; 27: 537.
   
5. Malm M, Lundeberg T. Effect of low power gallium arsenide laser on healing of venous ulcers. Scand J Plast Reconstr Hand Surg. 1991; 25: 249-251.
   
6. Siebert W, Seichert N et al. What is the efficacy of "soft" and "mid" lasers in therapy of tendinopathies? A double blind study. Archives of Orthopaedic & Traumatic Surgery 1987;106 (6): 358-63
   
7. Seichert N et al: Wirkung einer Infrarot-Laser-Therapie bei weichteilrheumatischen Beschwerden in Doppel-blindversuch. Terapiwoche. 1987; 37: 1375.
   
8. Gam A et al: The effect of low-level laser therapy on musculo-skeletal pain: a meta-analysis. Pain. 1993; 52: 63-66
   
9. Bjordal JM, Greve G: "What may alter the conclusions of reviews?". Physical Therapy Reviews. 1998; 3: 121-132
   
10. Beckerman H et al: The efficacy of laser therapy for muscoskeletal and skin disorders: a criteria-based meta-analysis of randomized clinical trials. Physical Therapy. 1992; 7 (72): 483
    
11. Tunér J, Hode L. It´s all in the parameters - a critical analysis of some well-known negative studies on low-level laser therapy. J Clin Lasers Med Surg. 1998; 16 (5): 245-248.
    
12. Tunér J. What is in the LLLT literature? In: Lasers in Medicine and Dentistry, Ed. Simunovic Z. European Medical Laser Ass. 2000, p.217-226.
    

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