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13.1 Are all the negative studies really negative?

2. Inclusion criteria
In study by Hansen [E18], 40 patients suffering from various "chronic orofacial pains" were tested. The pain had on average lasted 4.9 years (0.5 - 42 years). Twenty-eight patients suffered from “The burning mouth syndrome” (oral dysesthesia), five from toothache in one single tooth, three from tension headaches, etc. There were no objective pathological findings. X-ray examination had revealed nothing. In the headache group, acrylic splints had proved ineffective. A GaAs laser was used, and the initial dose of 2.4 J/cm2 was increased to 4.8 J/cm2 if no effect was observed initially. According to the literature (quoted in the study),The burning mouth syndrome is considered to be either multi-factorial, psychosomatic or purely psychogenic. It is therefore safe to assume that the tissue treated for this study was healthy in every respect. That no pain relief was obtained and that there was an absence of 5-HIAA in the patients' urine is therefore only to be expected.
3. Lack of proper control groups
Seichert [E8] (part1) used a combined GaAs/HeNe laser in a study of patients suffering from various rheumatic complaints. The probes housed five GaAs diodes producing an output of 1.2 mW per diode, while the HeNe laser produced an output of 6.5 mW. One group was given GaAs + HeNe, another HeNe with the GaAs diodes switched off (the placebo group). As both the "verum group" (0.258 J/cm2) and the "placebo group" (0.134 J/cm2) were actually both treated by laser, there is in fact no control group here. The comparison made is not between laser and placebo but between a combination GaAs + HeNe laser and a HeNe laser.
4. Therapeutic technique

Moustsen [E19] did not find any effect of LLLT in sinuitis. This is understandable, because a 30 mW 830 nm laser was used, applying 3J on four skin points close to the nose. While on the low side, such therapy would reduce the sinui-nasal obstruction, but not affect the sinuitis in itself. Successful therapy requires irradiation intraorally over the projections of the sinus, 8-10 J per point, 4-6 points depending on condition and repeated daily for 2-4 days.

5. Systemic effects
The systemic effect of therapeutic laser light has been described by many researchers, such as Braverman [E20], Rochkind [E21], Airaksinen [E22], Inoue [E23] and Schindl [E24]. Essentially, a systemic effect is one such that treatment of a given complaint at one site will also tend to affect a similar complaint elsewhere. It is therefore important to observe caution in interpreting the result of studies in which parts of the test person's/ /animal's body has been treated by laser and another part of the same body has been used as a control, especially in small animal studies.
6. Tissue condition
Persson [E25] observed no effect on angiogenesis in a study of experimental human gingivitis. Although this finding is confirmed in a study by Kusakari [E26], this author does report LLLT as causing an increased flow of blood, which was not studied in Persson's work. Both studies, however, are marred by the fact that healthy humans/animals were used as test subjects. Gingivitis was, for example, induced in young, completely healthy individuals whose immune system was in excellent order. A study by Kozlov [E27] reported that LLLT had a moderate effect on slight periodontitis, a good effect on more manifest periodon-titis, and little effect on advanced periodontitis. The immunological con-dition of the tissue and of the individual is a significant factor in the effectiveness of LLLT, and a "genuine" clinical condition cannot be achieved in a study based on healthy volunteers. This may explain the discrepancy sometimes noted between clinical work and scientific tests.
The significance of the condition of the tissue can clearly be seen in an experiment by Steinlechner [E28] in which keratinocytes, present in 1% and 5% solutions of fetal calf serum, were irradiated with laser light. The cells in the less nutritious solution were stimulated most. The same observation has been made by Yamamoto [E36], irradiating human fibroblasts. There is reason to beleive that the outcome of many in vitro studies has been just as influenced by the nutrient conditions of the cells as by the laser parameters.
7. Power density

According to a study by van Breughel [E29], power density appears to be more important than total dose in wound healing. Lundeberg [E30] used a 6 mW HeNe laser to treat venous leg ulcers. 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 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 another study on venous ulcers by Malm [E37] and Lundeberg, 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 shape of the invisible GaAs beam is also important to know. The distance between diode and wound is not indicated.

8. Mixed parameters

A study by Hall [E31] is confidently entitled "Low level laser therapy is ineffective in the management of rheumatoid arthritic finger joints". Such a title suggests that all reasonable parameters (wavelengths, doses, pulsing, etc.) have been checked and are kept properly under control. One of the probes used is a so-called cluster probe having a 15 mW GaAlAs laser diode surrounded by 30 non-coherent light-emitting diodes of three different wavelengths. Which wavelength was effective, which was ineffective, and did any particular wavelength have a detrimental effect on the overall result?
Blending coherent and non-coherent light while giving therapy with light of different wavelengths may possibly result in some clinical improvement but may also result in less improvement than if the therapy had been more exactly controlled. Tina Karu, for example, has showed that in cell cultures first irradiated with laser light and showing a clearly demonstrable biological effect, the effect is reduced practically to zero if the cells are then irradiated with broad-band (non-monochrome, incoherent) light [E35]. The main objection to mixed parameters is that they do not result in unequivocal new knowledge.

9. The influence of ambient light
The influence of ambient light is not a clinical problem. In the laboratory, however, it may influence the outcome of a study. As mentioned above Karu [E35] has shown that the effect of laser light may be partly or completely washed out by broadband light. In a study by Lundeberg [E38] the effect of HeNe and GaAs laser on the generation of signals in a sensory receptor was studied. The stretch receptor of Astacus fluviais (crayfish) was mounted over a glass platform. HeNe 1.56 mW and GaAs 0.07 mW, 73 Hz was used, dose not indicated. Disecting the stretch receptor and mounting it is done under the microscope, using very bright broadband ligth. This disturbing factor must be taken into account when evaluating similar trials.
10. Premature conclusions
Some researchers have used titles or conclusions such as "laser therapy is ineffective in...". This is an unscientific approach, since these reports have solely investigated a few of the many possible parameters. The language used reflects an unscientific bias. An example [E42] of this is: "Our results indicate that the analgesic effects reported in humans with similar modes of LLLT might be due to placebo" (comparison of response time on tail-flick between laser acupuncture, morphine and electrical stimulation).
11. Meta-analyses
Two meta-analyses [E32, E33] of the clinical effects of LLLT have been performed. In one, various studies were graded by points on the basis of a number of quality criteria. By this means, a negative study may achieve a high grade even if one of the parameters - though it may be essential to the result of the study - is entirely wrong. In Beckerman's study [E32], for example, Basford's study [E9] has been given the highest score (18 out of a possible 25) in spite of the fact that the dose used is not actually therapeutic. A comparison might be made with a chain: it is no use having 19 perfectly sound links if the 20th is open. The chosen method is important. Bjordal [E41], using a systematic review system, found a higher validity for the same studies than Gam did.
Confusion between groups
I (LH) took part in double-blind study several years ago. When the code was to be broken, the investigator having been entrusted with the envelope could not find it. There was certainly a significant difference between the two groups. However, it is not ethical to decide which group is supposed to be the placebo group just by looking at the outcome of the study, so the whole study had to be cancelled. Knowing how easy it is for codes to be mixed up, for documents to be mixed up and for misunderstandings to arise when several persons are involved in a study, it is not too unlikely for mistakes to occur. This may be the case in the following study by de Bie [E43]:
 
Author: de Bie et al Ref no: [E43]  
Title: Low-level laser therapy in ankle sprains: a randomized clinical trial
Published in: Arch Phys Med Rehabil 1998 Nov;79(11):1415-20
Laser type: GaAs Output: Not stated
Pulsing: Pulsed Pulse frequency: 500, 5 000 Hz
Dose: 0.5 and 5 J/cm2 “on skin”  
Power density: Not stated Treatment distance: Not stated
Laser model: Not stated    
Treated area: 1 cm2  
Treatment time: Not stated No of patientes: 217
No of treatments: 12 Time between treatm: 2-3 days

The investigators : got the following results:

  • Function was significantly better in the placebo group at 10 days (p = 0.01) and 14 days (p = 0.03).
  • Placebo group performed significantly better on days of sick leave (p = 0.02) and at some points for hindrance in activities in daily life and pressure pain.
  • Placebo group performed significantly better on subjective recovery (p = .05).
  • Total days of absence from work and sports were remarkably lower in the placebo group than in the laser groups, ranging from 3.7 to 5.3 and 6 to 8 days, respectively.
  • The total number of relapses at 1 year in the laser group (n = 35) was significantly higher than in the placebo group (n = 13) CONCLUSIONS: Neither high- nor low-dose laser therapy is effective in the treatment of lateral ankle sprains.
Our comments:
de Brie et al came to the conclusion that laser therapy has no effect on ankle sprains. This is an obvious misinterpretation of the presented results. The laser treatment had a clear NEGATIVE effect on all studied parameters. There are several studies showing that laser therapy, on the indication choosen and with the parameters used, had no better effect than placebo. However, among the 2000 studies known to us, no study has reported such a clear negative effect of laser therapy, except for a few studies using doses clearly in the inhibiting dose range. We have the feeling that the two groups might have been mixed up.
Conclusion:
In studying the therapeutic effects of laser light, there are many pitfalls along the way, and many is the researcher who has fallen in. Unfortunately, their work is still cited as evidence that LLLT does not work. In fact, many of these older studies should be disregarded in future discussions on this subject, since they are clearly irrelevant. Meta-analyses, too, may also prove meaningless unless pitfalls of this type can be avoided. In our analysis we have criticised a number of well-known negative studies, and it would be right to insist that a number of positive studies should be subjected to critical scrutiny as well. Positive studies have, however, been the subject of critical comment for many years, whereas only Baxter [E34] and Bjordal [E41] have hitherto made a detailed analysis of the parameters of negative studies.
Litterature: (no cross reference with main index)
[E1] Walker J: Relief from Chronic Pain by Low Power Laser Irradiation. Neuroscience Letters. 1983; 43: 339.
[E2] Snyder-Mackler L et al: Effect of helium-neon laser irradiation on skin resistance and pain in patients with trigger points in the neck or back. Physical Therapy. 1989; 69:
[E3] Snyder-Mackler L et al: Effect of helium-neon laser on musculoskeletal trigger points. Physical Therapy. 1986; 66: 1087.
[E4] Mester E et al: Effects of laser rays on wound healing. Am J Surg. 1971; 122: 532-535.
[E5] Kana J S et al: Effect of low-power density laser radiation on helaing of open skin wounds in rats. Arch Surg. 1981; Vol 116: 293.
[E6] Waylonis G W et al: Chronic myofascial pain: management by low-output helium-neon laser therapy. Arch Phys Med Rehab. 1988; 69: 1017
[E7] Jensen H et al: Infrarø d laser - effekt ved smertende knæ artrose? Ugerskr Læ ger. 1987; 149.
[E8] Seichert N et al: Wirkung einer Infrarot-Laser-Therapie bei weichteilrheumatischen Beschwerden in Doppel-blindversuch. Terapiwoche. 1987; 37: 1375.
[E9] Basford J R et al: Low-energy Helium Neon laser treatment of thumb osteoarthritis. Arch Phys Med Rehab. 1987; 68: 794-797.
[E10] Taube S, Piironen J, Ylipaavalniemi P: Helium-neon laser therapy in the prevention of postoperative swelling and pain after wisdom tooth extraction. Proc Finn Dent Soc 1990; 86: 23-27.
[E11] Lundeberg T, Haker E, Thomas M: Effect of laser versus placebo in tennis elbow. Scand J of Rehab Med. 1987; 19: 135.
[E12] Masse J-F et al: Effectiveness of soft laser treatment in periodontal surgery. Int Dent J. 1993; 43: 121-127.
[E13] Smith R J et al: The effect of low-energy laser on skin-flap survival in the rate and porcine animal models. Plastic and Reconstruct Surg. 1992; 89 (2): 306-310.
[E14] Klein R et al: Low-energy laser treatment and exercise for chronic low back pain: a double-blind controlled trial. Arch Phys Med Rehabil. 1990; 71: 34
[E15] Krikorian D et al: Use of HeNe laser for treatment of soft tissue trauma: evaluation by Gallium-67 Citrate scanning. J Orthop Sports Phys Ther. 1986; 8 (2): 93-97
[E16] Zarkovic N et al: Effect of semiconductor GaAs laser irradiation on pain perception in mice. Lasers in Surgery and Medicine. 1989; 9: 63-66
[E17] Jarvis D et al: Electrophysiologic recording and thermodynamic modeling demonstrate that Helium-Neon laser irradiation does not affect peripheral A? - or C-fiber nociceptors. Pain. 1990. 43: 235-242.
[E18] Hansen H, Thorø e U: Low power laser biostimulation of chronic orofacial pain. A double-blind placebo controlled cross-over study in 40 patients. Pain. 1990; 43: 169.
[E19] Moustsen P et al: Laserbehandling af bihulebetæ ndelse i almen læ gepraxis vurderet ved en dobbeltblind kontrolleret undersø gelse. (In Danish). Ugeskrift Læ ger. 1991; 153(32): 2232. [E"Laser Treatment of Sinuitis in General Medical Praxis Evaluated in a double blind study"]

[E20] Braverman B et al: Effect of Helium-Neon and Infrared Laser Irrradiation on Wound Healing in Rabbits. Lasers in Surgery and Medicine. 1989; 9: 50.
[E21] Rochkind S. et al: Systemic Effects of Low-Power Laser Irradiation on the Peripheral and Central Nervous System, Cutaneous Wounds and Burns. Lasers in Surgery and Medicine. 1989; 9: 174.
[E22] Airaksinen, O et al: Effects of laser irradiation at the treated and non-treated trigger points. Proc. 4th Intern Symposium. Acupunc & Electrother Res. 1988; 13 (4): 238-239.
[E23] Inoue K et al: Suppressed tuberculine reaction in guinea pigs following laser irradiation. Lasers in Surgery and Medicine, 1989; 9: 271-275.
[E24] Schindl L et al: Influence of low-power laser irradiation on "arthus phenomenon" induced in rabbit cornea. Laser Therapy. 1994; 1; 23
[E25] Persson L, Rydé n H, Preber H, Bergströ m J: Effect of low-energy laser on gingival inflammation. Swedish Dental Journ. 1990; 14: 47.
[E26] Kusakari H, Orikasa N, Tani H: Effects of low power laser on wound healing of gingiva and bone. Laser Bologna '92, p. 49. Monduzzi Editore S.p.A., Bologna, Italy.
[E27] Kozlov, V et al: Lasers in diagnostics and treatment of microcirculation disorders under parodontitis. SPIE Proc. 1995; Vol. 1984: 253-264.
[E28] Steinlechner C, Dyson M: The effect of low level laser therapy on the proliferation of keratinocytes. Laser Therapy. 1993; 5 (2): 65.
[E29] van Breughel H et al: Power density and exposure time of HeNe laser irradiation are more important than total energy dose in photo-biomodulation of human fibroblasts in vitro. Lasers in Surgery and Medicine. 1992; 12: 528
[E30] Lundeberg T, Malm M. Low power HeNe laser treatment of venous leg ulcers. Ann Plast Surg. 1991; 27: 537.
[E31] Hall J et al: Low level laser therapy is ineffective in the management of rheumatoid arthritic finger joints. Br J Rheuma. 1994; 33: 142.
[E32] Beckerman H et al: The efficacy of laser therapy for mucoskeletal and skin disorders: a criteria-based meta-analysis of randomized clinical trials. Physical Therapy. 1992; 7 (72): 483

[E33] Gam A N et al: The effect of low-level laser therapy on musculo-skeletal pain: a meta-analysis. Pain. 1993; 52: 63-66
[E34] Baxter C D: Therapeutic lasers. Theory and practice. 1994. Churchill Livingstone.
[E35] Karu T: Photobiological Fundamentals of Low Power Laser Therapy. IEEE Journal of Quantum Electronics. 1987; QE23(10): 1703.
[E36] Yamamoto Y et al. Effect of low-power laser irradiation on procollagen synthesis in human fibroblasts. J Clin Laser Med Surg. 1996; 14 (3): 129-132.
[E37] 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.
[E38] Lundeberg T et al. Low power laser irradiation does not affect the generation of signals in a sensory receptor. Am J Chinese Med. 1998; 16 (3-4): 87-91.
[E39] Siebert W 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
[E40] Mulcahy D. et al. Low level laser therpy: a prospective double blind trial of its use in an orthopaedich population. Injury. 1995; 26 (5): 315-317.
[E41] Bjordal JM, Greve G : "What may alter the conclusions of reviews ?". Physical Therapy Reviews. 1998; 3: 121-132
[E42] Lundeberg T, Hode L, Zhou J. A comparative study of the pain-relieving effect of laser treatment and acupuncture. Acta Physiol Scand. 1987; 131: 161.
[E43] de Bie RA, de Vet HC, Lenssen TF, van den Wildenberg FA, Kootstra G, Knipschild PG, Low-level laser therapy in ankle sprains: a randomized clinical trial. Department of Epidemiology, Maastricht University, The Netherlands. Arch Phys Med Rehabil 1998 Nov;79(11):1415-20

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