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Photomedicine

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The long way of PBM into established medicine

26.02.2015

Photobiomodulatory medicine has special features that fall through the perceptual grid of common validation processes.

PBM - the way to established medicine
Clinical research on the effects of PBM is based on the usual scientific procedures of human medicine studies. A large number of high-quality meta-analyses and RCTs according to the standards of evidence-based medicine are available for the application areas of pain therapy and wound treatment, proving the pronounced therapeutic efficacy of PBM.
In addition, there are now several studies on the mechanisms of action of photobiomodulation at the molecular and cellular level.
However, many physicians are still unaware of photomedicine and the state of research is hardly acknowledged.

1. State of research

Clinical Research
The available literature on the mechanisms of action of PBM and their effects in various indications in the Pubmed database today comprises more than 4000 studies. While the methodological quality of PBM studies of the last century was often still low, the majority of publications since then have been based on scientific standards. An evaluation of the literature (reviews, meta-analyses) was repeatedly carried out for defined areas of application.
Today, there is considerable study evidence for defined indications for which the pain-relieving and anti-inflammatory effect of PBM is documented in acute and chronic painful-inflammatory musculoskeletal conditions such as neck pain, epicondylitis, arthritis and tendinopathies. There is also a large number of individual studies on a wide variety of clinical pictures, which often describe a benefit, but without being able to make reliable statements on statistical significance due to the usually small number of cases.
For a comprehensive evaluation of the existing literature, great efforts are generally still necessary (Note: In the member area you will also find a research archive).

Example:
Evidence for the effectiveness of PBM in wound healing processes and in pain conditions of the musculoskeletal system
We document studies for two essential claims of PBM: the promotion of wound healing and pain relief. Based on a minimum number of different quality criteria, we selected 2 meta-analyses (2004) and 7 randomized controlled trials (2009-2012) for wound healing and 6 meta-analyses (2004-2012) and 11 RCTs (2009-2012) for pain relief. We found highly significant therapeutic effects for both forms of treatment:

  • PBM can promote and accelerate wound healing in the event of impaired wound healing processes.
  • PBM can reduce the extent and duration of pain in the musculoskeletal system.

For the promotion of wound healing, the best results have been found in chronic wounds with wound healing disorders. In wounds exposed to permanent pressure (e.g. decubitus ulcers), the results were significantly weaker.
The best results for pain relief could be found for pain states of the musculoskeletal system. Thereafter, indications such as neck pain, tendinopathies, epicondylitis, osteoarthritis of the knee or temporomandibular dysfunctions are the main areas of application of PBM.

Mechanisms of action of PBM
The mechanisms of photobiomodulation at the intracellular level have only recently begun to be better understood. Until recently, there were no conclusive explanations as to how weak light, which cannot even lead to a significant warming of the tissue, is able to influence inflammations, infections, edemas or the healing process of chronic wounds.
Particularly in in vitro studies and animal models, the individual primary effects triggered by the low-level laser in the cell interior have recently been described in ever greater detail.

  • Anti-inflammatory effects
    Low-energy laser light with a defined wavelength and sufficient energy density has an anti-inflammatory effect by reducing "oxidative stress" such as increased concentrations of ROS (Reactive Oxygen Species). ROS are intermediate products of cellular respiration, which include free radicals and other oxidizing agents. They can alter the molecular structure of proteins and damage the lipid layers of the cell membrane. ROS are also formed by cells of the immune system to fight bacteria and viruses. In very low concentrations, however, they play a physiological role and are important as transmitters in signal transmission in the brain or in the insulin transduction cascade.
    Mitochondria in damaged or ischemic tissue produce nitric oxide (NO), which competes with oxygen for binding to cytochrome C oxidase (COX), the enzyme complex IV of the respiratory chain. Cytochrome C oxidase is a key enzyme for the entire cell metabolism. It can absorb laser light, which displaces nitric oxide from cytochrome C oxidase (COX). This process is called photodissociation and can reverse inhibited mitochondrial respiration by excessive NO binding. The synthesis of ATP subsequently increases and, via the cascade of dependent metabolic downstream effects, leads to a reduction of inflammatory mediators such as prostaglandin E2 (PGE 2), interleukin -1 beta (IL1B) and the tumour necrosis factor alpha (TNF-alpha). The inhibition of proinflammatory signals by the PBM also induces anti-apoptotic effects.
  • Pain-relieving effects
    PBM can inhibit the rapid axon transport in special nociceptors in small diameter fibers and thus the pain transmission. The increase in the pressure pain nerve stimulus threshold is initially reversible. Repeated treatments lead to a decrease in the sensitivity of the pain neurons in the spinal cord. The accumulation of enkephalins and dynorphins inhibits the formation of the neurotransmitter substance P and thus the peripheral and central transmission of stimuli.
    Furthermore, PBM slows down the degranulation of mast cells and thus the release of vasoactive amines and inflammation mediators. By promoting ATP synthesis in the pain receptor, its capacity for hyperpolarisation is strengthened. The stimulus threshold can increase by up to 50% as a result. Opioid peptides (enkephalins, endorphins and dynorphins) can accumulate in the less myelinated nerve fibres for stimulus transmission and also dampen the release of central neurotransmitters in the midbrain (central pain relief).
  • Effects on tissue regeneration/wound healing
    In wound phase I (stage of inflammation and necrosis), PBM promotes antiphlogistic and antiedematous processes. In wound phases II (stage of proliferation) and III (stage of epithelialization), PBM increases the oxygen supply to the cell and the proliferation rate of the fibroblasts for increased formation of collagen and elastin. In the wound phase III it additionally promotes the fusion of the cellular lipid bilayers for a better tensile strength of the tissue and stabilizes the remodeling.
    In addition, the PBM promotes macrophage activity in the area of injury and the regeneration of peripheral nerves after injuries (accelerated build-up of the myelin sheath of the axon).

2. PBM-specific research handicaps

The discrepancy between clinical studies with high evidence and studies which confirm that PBM has only minor effects is enormous in the case of PBM. With PBM, paradoxically, it is precisely the extensive study situation that has led to much confusion.
The project to analyse scientific studies on PBM according to a standardised procedure involves various difficulties and the danger of distortions with regard to effects. The reason for this is the PBM-specific large variability of the study designs, the application techniques, the radiation dosage and the investigated indications in the existing scientific literature on PBM.

Variable intervention modes
Studies with different intervention modes are difficult to compare. The laser-specific treatment parameters and the therapeutic techniques of PBM vary greatly:
Laser therapy is applied (1) with different laser devices, (2) different dosages, (3) different application techniques, (4) different weightings (solitary measure or add-on therapy), (5) a different number of total treatments and with different treatment intervals.
The complexity of the variables makes standardization difficult.

  • (1) Different laser devices

Laser systems work with different wavelengths and output powers. There are HeNe (Helium-Neon), GaAs (Gallium-Arsenide) and GaAlAs (Gallium-Aluminium-Arsenide) which can also be combined in one device. Their effectiveness tends to vary depending on the application. In the 90s lasers had an output power of 1-5 mW, higher powers of up to 30 mW were very rare. Today, lasers have significantly higher output powers of up to 500 mW or even more. Therefore, studies on PBM belong to different "laser generations", the results of which can hardly be compared.

  • (2) Different dosage

The proportion of studies in the scientific literature on PBM for which laser devices with relatively low output powers were used is large. Only in the last 10 years have lasers with up to 100 times higher output power been increasingly used and evaluated. The effectiveness of the PBM for the different indications depends to varying degrees on the power density applied. Higher effective power densities can have an inhibitory effect (e.g. in certain stages of wound healing) or be decisive for an effect (e.g. in painful inflammations of large joints). Over- or underdoses can also be the reason for poor results in studies.

  • (3) Different application techniques

Laser therapy or PBM can be applied "automatically" with the help of "scanners" or tripods - or with hand-guided laser instruments that allow direct skin contact and make the therapy much more effective. Laser therapy can be used for local irradiation (e.g. joints, damaged skin areas etc.) or for stimulation of trigger, pain and/or acupuncture points and other reflex areas. It can target superficial tissue areas (e.g. scratch wounds) or deeper body layers (e.g. transmastoid irradiation of the inner ear). It can also be used invasively (intravenous, interstitial and intraarticular laser therapy). Different treatment techniques are often mixed.

  • (4) Different weightings

The type of intervention with PBM also reflects their different therapeutic weighting in different clinical pictures. In many cases, PBM is not compared with any intervention (placebo). In some meaningful clinical studies, PBM is compared with established conventional interventions. Thus, PBM is not tested against no intervention (placebo), but the effects of PBM are compared with the effects of a standard medical therapy procedure.
In some studies, the effects of PBM are investigated as an add-on therapy to a standard intervention. The standard intervention (e.g. wound therapy according to guidelines) plus co-intervention (simultaneous therapy) with PBM is compared with the standard intervention alone. For example, in severe chronic wounds or severe pain, PBM does not claim "non-inferiority" compared to standard therapies according to the guidelines. It merely claims a highly effective add-on therapy to the standard therapy with additional benefits such as an acceleration and activation of wound healing (endpoint: time until wound closure) and/or a significant additional reduction in pain (endpoint: e.g. VAS).

  • (5) Different number and frequency of treatments

The total number of treatments for a therapeutic effect with PBM can vary greatly depending on the indication. For example, a single treatment for a superficial skin wound can have a noticeable effect. Chronic wounds, on the other hand, usually react only after a few treatments with a noticeable and visible effect and the therapy should be carried out over longer periods of time.
Treatment intervals can also be adequate or inappropriate. In the case of acute complaints or at the start of treatment, for example, a treatment frequency of 1x/week is usually inadequate, whereas in the case of chronic complaints it may be sufficient.
In practice, the number and interval of treatments are adapted to the individual situation. They depend on how well the complaints respond to the treatment in the individual case. In a clinical examination, however, this individualization is not possible because of the necessary standardized intervention protocol.

3. Incomplete studies - Wrong dosage

A key parameter for effective laser therapy is dosage. Especially in the treatment of pain, an effective minimum dose is crucial. The minimum dose is the dose at which a therapeutic effect can be proven. It varies depending on the indication and can be relatively low (e.g. 3-4 J for a herpes wound of the lip) or very high (e.g. 20 J for an alveolitis).
One result of some meta-analyses of pain therapy with PBM around the turn of the century was that it could be deduced from many studies with no proof of efficacy that the cause was too low a dosage. The dose-dependence of the effects of PBM is highly significant.
Nevertheless, studies with negative proof of efficacy are often cited or included in reviews whose lack of evidence can be attributed to underdoses.

4. Conclusions and recommendations of the WALT

Photomedical experts see the decisive cause for the still weak acceptance of PBM among physicians in the often inadequate study protocols. Even though the variability of study parameters in PBM is very complex, the RCTs for PBM with positive evidence can be used to derive precise indication-oriented application protocols with regard to adequate dosage, application technique and duration etc. Jan Tunér (Board member of the World Association of Laser Therapy / WALT) and Lars Hode (President of the Swedish Laser-Medical Society) write in their review of the state of the art in laser photo medicine ("The New Laser Therapy Handbook", Prima Books 2010, ISBN-13 978-91-976478-2-3, p. 580) that "ironically, the most serious shortcoming in many studies on laser therapy was that the therapy itself was not given attention". They believe that by improving study designs and accurately documenting all PBM-specific variables used in an investigation, laser therapy will be recognized to the same extent as laser surgery is today.
The World Association for Laser Therapy (WALT) has published guidance and recommendations on its website to help scientists and physicians design and conduct clinical trials on PBM.

5. Other handicaps

The weak response to the progress made in photomedicine by orthodox doctors is also due to their incorrect location. What is popular, simple and risk-free to use and helps with many complaints is often viewed sceptically and it is assumed that there is little evidence. The following special features of PBM are certainly unusual for many orthodox physicians:

  • Wide range of applications
    The PBM is versatile. Since it is applied at primary cell biological switching points, it can influence a wide variety of complaints. A distrust of "all-rounders" is justified.
    At first it can be difficult to accept that the low-level laser should help with such different clinical pictures as arthritis of the knee, zoster (both are very well investigated indications of PBM) or allergic rhinitis.
    Even if the healing processes triggered by PBM can be transferred to many clinical pictures, effect statements should not be generalised. These can only be provided by clinical studies for clearly defined indications with precise endpoints.
  • Mechanisms of action at the edge of quantum mechanics
    Another reason is the complexity of the primary local reactions at the molecular and cellular level triggered by PBM irradiation. How light can influence biochemical cell processes is not part of the academic standard knowledge of a physician.
  • Use in complementary medicine
    The low level laser is very common in complementary medicine. Here it often belongs to a "naturopathic" therapy spectrum, which also includes controversial procedures such as homeopathy. Scientific evidence on the effectiveness of therapy methods is often not so important here.
    In fact, the use of the low-level laser in complementary medicine is as old as the invention of the laser. Here, the laser light not only serves as an alternative source of stimulation - as is the case with laser acupuncture - but also established new, original therapy techniques. Frequency-modulated ear acupuncture according to Nogier, for example, is hardly feasible without a low-level laser.
    The reputation that the low-level laser enjoys in non-evidence-based naturopathy stains off and makes it more difficult for the photomedicine specialists, who are exclusively investigating the direct effects of photobiomodulation.
  • No risks
    PBM does not pose any risks when used properly (e.g. to protect the eyes) and is only occasionally associated with mild, transient side effects, which can almost always be attributed to an overdose. We are used to the fact that the most potent remedies and procedures are associated with frequent side effects. That is why it is hard for many to believe that laser photo therapy can have such significant positive effects.
    Due to the absence of risk, laser therapy is also non elitist. The patient can apply PBM - after a detailed training designed for his complaints! - also by himself. However, this potential was and is also a major handicap for serious laser therapy, as the market for ineffective, cheap fake lasers is also large.
  • Pseudo laser instruments
    Last but not least, the widespread dubious use of pseudo laser devices for scientific photomedicine is ruinous. Laser medicine is a business and light-emitting pseudo-instruments can be screwed together quickly. Instruments are sold as laser instruments that do not contain lasers but cheap LEDs, if not simple light bulbs. Or laser diodes are mixed with LEDs, of which the therapist usually has no knowledge. For this purpose, cheap so-called "lasers" for domestic use are advertised in paramedical leaflets. Most of these cheap variants do not even have a CE mark and very few know that even a CE mark is not a seal of quality (in the sense that the promised effect has been proven) but an administrative mark that is intended to document compliance with the statutory minimum requirements. The inferior cheap "lasers" usually resemble slide pointers - and the effects are correspondingly poor or do not occur at all.
  • Lack of basic know-how
    Although laser therapy does not pose any risks when properly applied, this does not mean that it can be used without basic knowledge to show effects.
    Incorrect use and lack of consideration of dosage questions - i.e. generally poor preparation - often lead to blurred, diluted and inadequate results. This does not only apply to everyday practice. Even in some studies, laser and treatment parameters that are decisive for therapy success are often poorly documented or reflect a lack of understanding of their significance.
    Training for the promising use of laser therapy is not regulated. Here the manufacturers still bear the greatest responsibility. Only serious manufacturers do not spare the effort to ensure that their laser systems are used correctly and keep their therapists up to date with the help of training courses and information services.

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