EVIDENCE-BASED MEDICINE
Joshua G. Bales, MD, Roy A. Meals, MD THE PATIENT A 55-year-old, right-handed man presents with numbness and pain in his right thumb, index, and long fingers that wakes him from sleep. Electrodiagnostic studies are consistent with carpal tunnel syndrome (CTS) with a motor latency greater than 7 ms. He received transient relief from a steroid injection. The wrist brace that prevented night symptoms for years is no longer helpful. The patient prefers to avoid surgery and requests low-level laser therapy (LLLT), which he read about on the Internet. THE QUESTION Is LLLT an effective disease-modifying or palliative treatment for carpal tunnel syndrome? CURRENT OPINION Low-level laser therapy is appealing because it is a painless, noninvasive, office-based application that can be profitable. LLLT is advocated for CTS, enthesopathies (eg, lateral epicondylitis), Raynaud’s disease, rheumatoid arthritis, and osteoarthritis, and to enhance healing of soft tissues and bone. Most hand surgeons are unfamiliar with LLLT and are understandably skeptical. THE EVIDENCE Rationale and basic science The rationale for LLLT is that laser light of the appropriate wavelength can penetrate the skin, activating specific photoacceptors to induce biological healing processes in deeper tissues. For example, some research suggests that stimulation of cytochrome c oxidase (a principal primary photoacceptor in the mitochondrial electron transport chain1) activates a variety of growth FromtheDepartmentofOrthopaedicSurgery,UniversityofCaliforniaatLosAngeles,LosAngeles,CA. Received for publication October 29, 2009; accepted in revised form December 18, 2009. No benefits in any form have been received or will be received related directly or indirectly to the subject of this article. Corresponding author: Joshua G. Bales, MD, Department of Orthopaedic Surgery, University of California at Los Angeles, 757 Westwood Avenue, Los Angeles, CA 90095; e-mail: jbales@ mednet.ucla.edu. 0363-5023/10/35A03-0019$36.00/0 doi:10.1016/j.jhsa.2009.12.029
factors, intracellular intermediates such as procollagen production, and adenosine triphosphate synthesis. The optimal wavelength, power, and duration of therapy are debated. Some research suggests that LLLT leads to increased cell proliferation.1,2 The mitochondrial signaling pathway may preferentially activate tyrosine protein kinase receptors and not tumor necrosis factor alpha.1,3 The downstream products of this activation include various growth factors and cytokines that are associated with inhibition of inflammation.1,4 Thus, LLLT causes proliferation of cell lines important for healing and tissue regeneration: fibroblasts, keratinocytes, and osteoblasts, among others. Depth of penetration through human tissue is influenced by laser power and wavelength, as well as the biological features of the tissue (melanin content, previous scars, etc.). Based on ultrasound measurements, 4 J provides adequate penetration at the acromioclavicular joint, compared with 40 J at the hip for a 780- to 820-nm GaAs laser. The maximum depth of penetration in LLLT is roughly 50 mm.5 Skopin et al. employed LLLT at 980 nm to treat an iatrogenic wound in fibroblast cell cultures. They found that LLLT accelerated cell growth without notably increasing the temperature of the tissue. However, overexposure of LLLT at levels up to 66 J/cm2 inhibits growth.6 The beneficial photobiologic effect of LLLT occurred at 1 to 10 J/cm2. Kazem Shakouri et al. created tibial osteotomies in rabbits and found that LLLT could enhance callus formation at 5 weeks.7 Computed tomography scans of these animals at 5 weeks after osteotomy revealed 297 Hounsfield units for the control group and 691 Hounsfield units for the laser group at the callus site. Despite this radiographic finding, LLLT had no meaningful improvement in the biomechanical properties of healing bone versus control. The power delivered to intended tissues is unpredictable owing to the variety of laser devices employed and the lack of standardization of these devices. For example, Bouvet-Gerbettaz et al. found that the power emitted by the laser was much less than the displayed power on the device.8
© Published by Elsevier, Inc. on behalf of the ASSH. 䉬 469
Evidence-Based Medicine
Low-Level Laser Treatment
470
LOW-LEVEL LASER TREATMENT
Evidence-Based Medicine
Other diseases Low-level laser therapy risks damage to the eye. Laser radiation of 400 to 1400 nm penetrates the eye Tumilty et al. performed a meta-analysis of LLLT for and may cause heating of the retina. The coherence of enthesopathy (epicondylitis, rotator cuff, and Achilles) laser light focused on the retina causes a transient inand de Quervain’s tenosynovitis.19 They found 12 rancrease in temperature, which may destroy retinal phodomized controlled trials with positive outcomes and 13 toreceptors. The end result is the creation of a blind randomized controlled trials with negative outcomes. spot. To prevent any scatter radiation harming the opNonetheless, they are supporterator, goggles are encourive of LLLT on the basis that EDUCATIONAL OBJECTIVES aged during LLLT therapy. the negative trials used wave● List the rationale for treatment using low-level laser treatment. lengths that were outside the CTS ● Describe the potential mechanism of action for low-level laser treatment. guidelines from World AssoThe rationale for LLLT in ● State the factors that effect depth of penetration for low-level laser treat- ciation of Laser Therapy and the treatment of CTS inBjordal et al.20,21 ment. volves facilitation of the ● Discuss the results of randomized studies assessing the effectiveness of Malenfant et al. performed body’s repair of nerve dama literature review and metalow-level laser treatment on carpal tunnel syndrome. age. analysis of complementary Five clinical trials have Earn up to 2 hours of CME credit per JHS issue when you read the related and alternative medical treatcompared LLLT with articles and take the online test. To pay the $20 fee and take this month’s ment for Raynaud’s phenomsham LLLT. Naeser et al. test, visit http://www.assh.org/professionals/jhs. ena.22 Although they found noted decreased pain, senLLLT to be the most promsory latency, and Phalen’s and Tinel’s signs after ising (with 3 trials of moderate to good quality), they treatment with LLLT.9 Evcik et al. found no diffound substantial heterogeneity among the studies ferences in the primary outcomes of pain and funcand emphasized that a well-designed trial with adetion.10 Shooshtari et al found no differences in quate power was needed. symptoms or grip strength, but slight improvement Based on 222 patients in 5 placebo-controlled trials in electrophysiology with LLLT.11 Chang et al. of LLLT in rheumatoid arthritis, a Cochrane Systemic noted differences in symptoms and strength, but Review concluded that functional outcomes, range of not electrophysiology 2 weeks after treatment.12 motion, and local joint swelling were largely unaffected Irvine et al. found no differences.13 by LLLT, with perhaps some effect on short-term pain Several trials compared LLLT with other treatrelief and morning stiffness.23 Brosseau et al found that ments for CTS. Yagci et al. performed a prospecLLLT was no better than sham for osteoarthritis of the tive, randomized, unblinded comparison of LLLT hand.24 with splinting alone and found no differences in the primary outcome of symptom relief, and small SHORTCOMINGS OF THE EVIDENCE differences in the secondary outcome of electroThe basic science evidence in support of LLLT is physiological parameters. 14 Dincer et al. perpoor and there is a substantial divide between the formed a prospective, randomized, unblinded combasic science rationale and clinical evidence of parison of ultrasound and splinting versus LLLT 15 efficacy. and splinting versus splinting alone. LLLT and Low-level laser therapy has been evaluated in nusplinting had notably better symptom relief than merous clinical trials, but only a few use sham laser. splinting alone, but it was not superior to ultraStudies that use sham show little or no effect for prisound and splinting. Bakhtiary et al. found that 16 mary outcome measures, which are not clearly specified ultrasound was superior to LLLT. in the study, but can be inferred. In addition, all of the In a systematic review, Piazzini and colleagues studies are small and evaluate only short-term outconcluded that there is limited and conflicting evcomes. There is substantial heterogeneity in the studies, idence that LLLT is an effective treatment for and few use validated outcomes measures. It is not clear CTS.17 Reviewing nearly the same studies, Naewhether the inconsistent results can be ascribed to techser18 stated that the negative studies did not use nical factors. The observation that not all level 1 and 2 appropriate doses of laser treatment for CTS and studies represent good quality science25 is evident in a concluded that LLLT is a promising treatment for review of the trials evaluating LLLT, many of which mild to moderate CTS when the motor latency is less than 7 ms. were published in relatively obscure journals. JHS 䉬 Vol A, March
DIRECTIONS FOR FUTURE RESEARCH An ideal study would be a large, multicenter, prospective, randomized, double blind, sham, laser-controlled study, powered and designed to answer a clear primary study question, using established validated outcomes measures, and evaluating patients at least 2 years after treatment. A comparison of LLLT with CTR could also provide useful information. OUR CURRENT CONCEPTS The available scientific data do not support a role for LLLT as a disease-modifying treatment in CTS. At best it is palliative, and the data on this are inconsistent and conflicting. Because our patient’s electrodiagnostic studies are positive, and his motor latency is greater than 7 ms, his CTS would be considered severe and he is at risk of additional permanent nerve damage without disease-modifying treatment. Even the advocates of LLLT indicate that it is appropriate only for mild to moderate CTS. In the absence of well-designed, randomized, sham-controlled studies that consistently demonstrate meaningful and long-lasting palliation, we do not recommend LLLT. We would counsel our patient not to delay effective disease-modifying surgery. REFERENCES 1. Gao X, Xing D. Molecular mechanisms of cell proliferation induced by low power laser irradiation. J Biomed Sci 2009;16:4. 2. Vinck EM, Cagnie BJ, Cornelissen MJ, Declercq HA, Cambier DC. Increased fibroblast proliferation induced by light emitting diode and low power laser irradiation. Lasers Med Sci 2003;18:95–99. 3. Zhang J, Xing D, Gao X. Low-power laser irradiation activates Src tyrosine kinase through reactive oxygen species-mediated signaling pathway. J Cell Physiol 2008;217:518 –528. 4. Rodrigo SM, Cunha A, Pozza DH, Blaya DS, Moraes JF, Weber JB, et al. Analysis of the systemic effect of red and infrared laser therapy on wound repair. Photomed Laser Surg 2009;27:929 –935. 5. Zhao ZQ, Fairchild PW. Dependence of light transmission through human skin on incident beam diameter at different wavelengths. In: Steven L. Jacques, ed. SPIE Proceedings of Laser-Tissue Interaction IX. Bellingham, WA: SPIE, 1999:354 –360. 6. Skopin MD, Molitor SC. Effects of near-infrared laser exposure in a cellular model of wound healing. Photodermatol Photoimmunol Photomed 2009;25:75– 80. 7. Kazem Shakouri S, Soleimanpour J, Salekzamani Y, Oskuie MR. Effect of low-level laser therapy on the fracture healing process. Lasers Med Sci 2010;25:73–77. Epub 2009 Apr 28. 8. Bouvet-Gerbettaz S, Merigo E, Rocca JP, Carle GF, Rochet N. Effects of low level laser therapy on proliferation and differentiation of murine bone marrow cells into osteoblasts and osteoclasts. Lasers Surg Med 2009;41:291–297.
471
9. Naeser MA, Hahn KA, Lieberman BE, Branco KF. Carpal tunnel syndrome pain treated with low-level laser and microamperes transcutaneous electric nerve stimulation: a controlled study. Arch Phys Med Rehabil 2002;83:978 –988. 10. Evcik D, Kavuncu V, Cakir T, Subasi V, Yaman M. Laser therapy in the treatment of carpal tunnel syndrome: a randomized controlled trial. Photomed Laser Surg 2007;25:34 –39. 11. Shooshtari SM, Badiee V, Taghizadeh SH, Nematollahi AH, Amanollahi AH, Grami MT. The effects of low level laser in clinical outcome and neurophysiological results of carpal tunnel syndrome. Electromyogr Clin Neurophysiol 2008;48:229 –231. 12. Chang WD, Wu JH, Jiang JA, Yeh CY, Tsai CT. Carpal tunnel syndrome treated with a diode laser: a controlled treatment of the transverse carpal ligament. Photomed Laser Surg 2008;26:551–557. 13. Irvine J, Chong SL, Amirjani N, Chan KM. Double-blind randomized controlled trial of low-level laser therapy in carpal tunnel syndrome. Muscle Nerve 2004;30:182–187. 14. Yagci I, Elmas O, Akcan E, Ustun I, Gunduz OH, Guven Z. Comparison of splinting and splinting plus low-level laser therapy in idiopathic carpal tunnel syndrome. Clin Rheumatol 2009;28:1059 – 1065. 15. Dincer U, Cakar E, Kiralp MZ, Kilac H, Dursun H. The effectiveness of conservative treatments of carpal tunnel syndrome: splinting, ultrasound, and low-level laser therapies. Photomed Laser Surg 2009;27:119 –125. 16. Bakhtiary AH, Rashidy-Pour A. Ultrasound and laser therapy in the treatment of carpal tunnel syndrome. Aust J Physiother 2004;50: 147–151. 17. Piazzini DB, Aprile I, Ferrara PE, Bertolini C, Tonali P, Maggi L, et al. A systematic review of conservative treatment of carpal tunnel syndrome. Clin Rehabil 2007;21:299 –314. 18. Naeser MA. Photobiomodulation of pain in carpal tunnel syndrome: review of seven laser therapy studies. Photomed Laser Surg 2006; 24:101–110. 19. Tumilty S, Munn J, McDonough S, Hurley DA, Basford JR, Baxter GD. Low level laser treatment of tendinopathy: a systematic review with meta-analysis. Photomed Laser Surg Epub 2009 Aug 26. 20. World Association of Laser Therapy. Dosage recommendations and scientific guidelines. Available at: http://www.walt.nu. Accessed December 5, 2007. 21. Bjordal JM, Couppe C, Ljunggren AE. Low level laser therapy for tendinopathy: evidence of a dose response pattern. Phys Ther Rev 2001;6:91–99. 22. Malenfant D, Catton M, Pope JE. The efficacy of complementary and alternative medicine in the treatment of Raynaud’s phenomenon: a literature review and meta-analysis. Rheumatology (Oxford) 2009; 48:791–795. 23. Brosseau L, Robinson V, Wells G, Debie R, Gam A, Harman K, et al. Low level laser therapy (Classes I, II and III) for treating rheumatoid arthritis. Cochrane Database Syst Rev 2005;4:CD002049. 24. Brosseau L, Wells G, Marchand S, Gaboury I, Stokes B, Morin M, et al. Randomized controlled trial on low level laser therapy (LLLT) in the treatment of osteoarthritis (OA) of the hand. Lasers Surg Med 2005;36:210 –219. 25. Cowan J, Lozano-Calderon S, Ring D. Quality of prospective controlled randomized trials: analysis of trials of treatment for lateral epicondylitis as an example. J Bone Joint Surg 2007;89A:1693– 1699.
JHS 䉬 Vol A, March
Evidence-Based Medicine
LOW-LEVEL LASER TREATMENT