Efficacy of Photobiomodulation Therapy in the Treatment of Pain and Inflammation: A Literature Review

Citation: González-Muñoz, A.; Cuevas-Cervera, M.; Pérez-Montilla, J.J.; Aguilar-Núñez, D.; Hamed-Hamed, D.; Aguilar-García, M.; Pruimboom, L.; Navarro-Ledesma, S. Efficacy of Photobiomodulation Therapy in the Treatment of Pain and Inflammation: A Literature Review. Healthcare 2023, 11, 938. https://doi.org/10.3390/ healthcare11070938 Academic Editor: George A. Koumantakis Received: 3 February 2023 Revised: 17 March 2023 Accepted: 19 March 2023 Published: 24 March 2023 Copyright: © 2023 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https:// creativecommons.org/licenses/by/ 4.0/). healthcare Review Efficacy of Photobiomodulation Therapy in the Treatment of Pain and Inflammation: A Literature Review Ana González-Muñoz 1,2, María Cuevas-Cervera 1, JoséJavier Pérez-Montilla 1, Daniel Aguilar-Núñez 3, Dina Hamed-Hamed 1, María Aguilar-García1, Leo Pruimboom 4and Santiago Navarro-Ledesma 1,4,* 1Department of Physiotherapy, Faculty of Health Sciences, Campus of Melilla, University of Granada, Querol Street 5, 52004 Melilla, Spain 2Clinica Ana Gonzalez, Avenida Hernan Nuñez de Toledo 6, 29018 Malaga, Spain 3 Department of Nursing and Podiatry, Faculty of Health Sciences, University of Malaga, 29071 Malaga, Spain 4Department of Physiotherapy, University Chair in Clinical Psychoneuroimmunology (University of Granada and PNI Europe), 2518 JP The Hague, The Netherlands *Correspondence: [email protected] Abstract: The main objective of this literature review was to analyze the efficacy of (PBM) therapy application on subjects with chronic pain and inflammation, and furthermore, to evaluate the methodological quality of the collected literature. The search was conducted using five databases: PubMed, ProQuest, Scopus, Web of Science, and PEDro. The keywords “low level laser therapy”, “chronic pain”, and “inflammation” provided the selection of RCTs that were published within the last 5 years, conducted in humans, and written in English. The PEDro Internal Validity Scale (IVS) checklist was used to evaluate the risk of bias in the included studies. A total of 11 articles were selected, all of them RCTs. Of the articles, five showed that PBM positively influences chronic pain, while another showed the same but only in the short term. In two other articles, the patient’s inflammation improved markedly. In one article there was no improvement in chronic pain and in another, there was no improvement in inflammation. Four articles demonstrated that PBM is beneficial in acute pain. Furthermore, six studies were given an “excellent” score and the remaining five a “good” score based on the IVS. Photobiomodulation has beneficial effects on chronic pain and inflammation, although more research needs to be completed in this line for this to be clarified as the existence of RCTs on this subject is limited. Keywords: low-level laser therapy; photobiomodulation; chronic pain; inflammation; metabolism 1. Introduction Photobiomodulation therapy (PBM) commonly uses wavelengths of light with an energy density ranging from 1 to 150 J/cm 2 and from 600 to 1070 nm. The effective tissue penetration is maximal in this range with hemoglobin and melanin, as the principal tissue chromophores, having high absorption bands at wavelengths shorter than 600 nm. The treatment of superficial tissue uses wavelengths in the range of 600 to 700 nm, while the treatment of deeper tissue uses wavelengths in the range of 780 to 950 nm [ 1 , 2 ]. Currently, whole-body PBM has shown a systemic response in addition to the local response, with improvements in quality of life, pain, sleep disorders, tiredness, muscle spasm, morning stiffness, psychological factors, elastic properties of tissue, circadian rhythms, tender points, and in fibromyalgia sufferers [3–7]. Furthermore, PBM therapy has also been shown to improve cerebral blood flow, neuronal bioenergetic functions, neuroinflammation, oxidative stress, neural apoptosis, neurogenesis, and neurotrophic factors, and additionally has effects on intrinsic brain networks [ 1 ]. In addition, PBM is also thought to affect the secretion of certain hormones, such as serotonin and endorphins, leading to a reduction in pain signaling [8]. Healthcare 2023,11, 938. https://doi.org/10.3390/healthcare11070938 https://www.mdpi.com/journal/healthcare Healthcare 2023,11, 938 2 of 19 Chronic pain is a problem that has a very notorious impact on society and people’s lives and is one of the most common health problems among older adults (>65 years). It is estimated that 13–50% of adults in the United Kingdom suffer from chronic pain although it is difficult to obtain accurate data since the estimates for the prevalence in the population vary greatly by place, time, and population. It has been estimated to be 8% per year in the UK. On the other hand, the US sets its estimated costs attributable to chronic pain, including disability, loss of work, and treatments, at about USD 600 million annually, with an incidence of 28.4% in the adult population. Treatment in these older adults is complex since it must have a multifactorial focus that includes pharmacological interventions, physical rehabilitation, and procedures to eradicate the cycle of pain [ 9 – 12 ]. By definition, chronic pain is pain that persists for at least 3 months. It is a factor in premature death and accelerated cognitive deterioration. In turn, this deterioration and dementia make treatment decisions difficult since the patient’s ability to perceive pain and report it is impaired [11]. Inflammation is present in many chronic pain conditions and its reduction is usually related to a decrease in pain. Oxidative stress is known to contribute to this inflammation [ 12 ]. Prolonged inflammation can lead to chronic hypersensitivity and perpetuate chronic pain. Several factors have been identified that influence inflammation induced by oxidative stress, chemokines, transcription factors, microRNAs, and inflammatory cytokines [ 12 ]. It has also been proven that, if widespread inflammation in neurological tissue, which has been caused by a failure of the immune system to promote homeostasis, lasts beyond a certain time, it can result in the onset of chronic pain. When this failure continues, lowgrade inflammation (LGI) and existing damage develop, and its perpetuation indicates the development of chronic musculoskeletal pain, in addition to peripheral hypersensitization, which evolves into central hypersensitization. Therefore, LGI is thought of as a risk factor for chronic diseases. Photobiomodulation has been used in pain and inflammation treatment; nevertheless, a synthesis of its effects and the quality analysis of the studies have never been studied. The goal of this study was to analyze the scientific evidence that currently exists on PBM’s effectiveness when used in the treatment of chronic musculoskeletal pain and inflammation. Secondly, to evaluate the methodological quality of the collected literature. 2. Methodology 2.1. Study Design The present study is a literature review on randomized clinical trials (RCTs). In order to achieve a high methodological quality, a methodology characteristic of a systematic review, including the methodological quality of the selected RCTs, was carried out in accordance with the PRISMA criteria for the development and preparation of meta-analysis and systematic reviews [13]. 2.2. Sources of Information and Search Strategies The literature search was carried out between March, April, and May 2022 using the following five electronic databases: PubMed, ProQuest, Web of Science, Scopus, and PEDro (see Table 1). Healthcare 2023,11, 938 3 of 19 Table 1. Search strategy in the different databases used. PubMed •“Low-Level Light Therapy” (MeSH) AND “chronic pain” (MeSH) •“Low-level Laser Therapy” (MeSH) OR “photobiomodulation” AND “physiotherapy” •“Low-level Light Therapy” (MeSH) AND “inflammation” (MeSH) ProQuest •“Low-Level Light Therapy” AND “chronic pain” •“Low-level Light Therapy” OR “photobiomodulation” AND “physiotherapy” •“Low-level Light Therapy” AND “metabolism” •“Low-level Light Therapy” AND “inflammation” Scopus •“Low-level light therapy” AND “chronic pain” •“Low-level light therapy” AND “inflammation” Web of Science •“Low-level light therapy” AND “chronic pain” •“Low-level light therapy” AND “inflammation” PEDro •“Low-level light therapy” AND “chronic pain” •“Low-level light therapy” AND “inflammation” The PICO strategy components were followed to develop the research questions and were based on the following elements: • Population: patients older than 18 years of age and with inflammation or pain lasting for more than 3 months. • Intervention: reduction in the symptomology of pain or inflammation after a PBM intervention. •Comparison: the use or not of PBM. • Results: effectiveness of the PBM application strategies on chronic pain and inflammation. 2.2.1. PubMed The search for articles in PubMed used Medical Subject Headings (MeSH), as well as key terms not included in MeSH such as “photobiomodulation”. The keywords were “Low-level laser therapy”, “metabolism”, “inflammation”, “physiotherapy”, “chronic pain” and “photobiomodulation”. The Boolean operators were: AND/OR. The following parameters were used to limit the search strategy of this study: •Text accessibility: open-access or accessible to the University of Granada, Spain. •Type of articles: RCTs and observational studies. •Date of publication: 2017–2022. •Species: human. •Language: English. 2.2.2. ProQuest The keywords “low-level laser therapy”, “metabolism”, “photobiomodulation”, “inflammation”, “physiotherapy” and “chronic pain” were used for the search. The Boolean operators were: AND/OR. The following parameters were used to limit the search strategy of this study: •Text accessibility: open-access or accessible to the University of Granada, Spain. •Type of articles: RCTs and observational studies. •Date of publication: 2017–2022. •Language: English. 2.2.3. Scopus The keywords used for the search were: “Low-level laser therapy”, “chronic pain”, “photobiomodulation” “physiotherapy, “metabolism” and “inflammation”. The Boolean operator used was: AND. Healthcare 2023,11, 938 4 of 19 The following parameters were used to limit the search strategy of this study: •Text accessibility: open-access or accessible to the University of Granada, Spain. •Type of articles: articles. •Subject: medicine and health professions. •Date of publication: 2017–2022. 2.2.4. Web of Science The keywords for the search were: “Low-level laser therapy”, “chronic pain”, “photobiomodulation”, “metabolism”, “physiotherapy” and “inflammation”. The Boolean operator was: AND. The following parameters were used to limit the search strategy of this study: •Text accessibility: open-access or accessible to the University of Granada, Spain. •Type of articles: articles (RCTs). •Subject: medicine and health professions. •Date of publication: 2017–2022. 2.2.5. PEDro The keywords for the search were: “Low-level laser therapy”, “chronic pain”, “physiotherapy”, “photobiomodulation”, “metabolism” and “inflammation”. The Boolean operator was: AND. The following parameters were used to limit the search strategy: •Text accessibility: open-access or accessible to the University of Granada, Spain. •Subject: chronic pain. •Method: RCTs. •Date of publication: 2017–2022. 2.3. Study Selection 2.3.1. Criteria for Inclusion •Publication between January 2017 and May 2022. •International publication in English and peer-reviewed. •Designed as RCTs. •Access to the complete text available. •Conducted in humans over the age of 18. •Suffer from acute pain or chronic pain. •Suffer from some type of pathology that causes chronic pain. •Suffer from edema/inflammation. 2.3.2. Exclusion Criteria •Not meeting the inclusion criteria. •Repeated in the databases. •Does not assess chronic pain, inflammation or pathology or symptom prevention. •Lack of PBMT implementation in people with pain or inflammation. •No results were shown or no interpretation of the data. 2.4. Article Selection This literature review aimed at focusing on photobiomodulation therapy in general. For this reason, the scope of the search included all areas of low-intensity laser research and the impact it has on various facets within the health fields of medicine and physiotherapy. These studies encompassed the effect of a low-intensity laser on diseases such as fibromyalgia to articles that revealed the part these lasers play in impairments in our temporomandibular joint or teeth. The first searches resulted in 59 eligible studies, which either proved or linked PBM and the benefits it can bring to health regarding the most important areas we wanted to cover in this study. Healthcare 2023,11, 938 5 of 19 In order to increase the search quality, more focused searches were carried out on the influence PBM has on chronic pain, at all levels, without neglecting the impact it has on the diseases and injuries in the subjects studied. Although the search terms were further limited and reflected scientific evidence for PBM in subjects over 18 years of age, studies that did not fall within the scope of our study continued to appear. Photobiomodulation therapy has been classified as a safe, non-invasive treatment modality. Several possible mechanisms have been attributed to PBM such as an increased thermal threshold, improved blood circulation, increased oxygen consumption by accelerating the redox reaction rate, and increased production of ATP and proinflammatory cytokines [14]. Therefore, the scope of this literature review was reduced to studies that researched any link between PBM and the benefits it can bring to our health, with the primary focus on its influence on pain and inflammation. 2.5. Methodological Quality Assessment of the RCTs The assessment of the methodological quality of the selected RCTs followed the PEDro scale, which was adapted and translated to the Spanish language and allowed the items to be both validated and evaluated. Each item, excluding the first, raises the overall score by 1 point. Eleven items can be included, resulting in a global score of 0 to 10 points [15]. Subsequently, the Internal Validity Score (IVS) was used to evaluate the internal validity of the RCTs. This scale contains the items that are indicated to be the most representative in ascertaining the internal validity of an article. The selected items are 2, 3, 5, 6, 7, 8, and 9, so the internal validity will have a score of up to 7 points [15]. 2.6. RCTs Qualitative Synthesis The score given by the scale determined the quality of the study. Hence, a score of 9–10 points is accepted as having excellent methodological quality, a score of 6–8 points has a good methodological quality, those in the 4–5 point range have a regular quality, and finally, those trials that obtain less than 4 points have a poor methodological quality. Studies that fall within this last range were discarded from this study [15]. The IVS classification of the studies is as follows: studies that receive 6–7 points are given a methodological quality that is high, those with 4–5 points a moderate methodological quality, and 0–3 points have a limited methodological quality [15]. 2.7. Management of the Identified Literature The bibliographical references that appear in this review have been managed using Mendeley software. 3. Results This section provides the results found in the selected RCTs. 3.1. Study Selection The searches resulted in 96,751 articles being found in the 5 databases as follows: PubMed, Scopus, PEDro, ProQuest, and Web of Science. Articles that did not meet the inclusion criteria set out in the “inclusion criteria” section were discarded. The titles and summaries of the found articles were read and the information was summarized to highlight the most relevant aspects, both positive and negative, of this therapy. The end result of the search and the methodological quality study of the preselected articles was 11 RCTs that met the admission criteria. The RCT selection process is shown in Figure 1by means of a flowchart in accordance with the guidelines and criteria established in the PRISMA 2009 declaration [13]. Healthcare 2023,11, 938 6 of 19 Healthcare 2023, 11, x FOR PEER REVIEW 6 of 20 Figure 1. Flow diagram following PRISMA system. Selection and exclusion process for the studies. 3.2. Methodological Quality Evaluation Once the articles had been selected, an evaluation of methodological quality was carried out following the aforementioned scales. The results are offered in Tables 2–4. 3.3. Study Characteristics Table 4 shows the main characteristics of the analyzed studies with the most important information being narrowed down to clarify the hypotheses proposed by this study. The type of study, the sample size, the intervention performed, the variables analyzed, and the results obtained, with their respective numerical values, are among the properties found. Figure 1. Flow diagram following PRISMA system. Selection and exclusion process for the studies. 3.2. Methodological Quality Evaluation Once the articles had been selected, an evaluation of methodological quality was carried out following the aforementioned scales. The results are offered in Tables 2–4. 3.3. Study Characteristics Table 4shows the main characteristics of the analyzed studies with the most important information being narrowed down to clarify the hypotheses proposed by this study. The type of study, the sample size, the intervention performed, the variables analyzed, and the results obtained, with their respective numerical values, are among the properties found. Healthcare 2023,11, 938 7 of 19 Table 2. Study of the methodological quality of the RCTs with the PEDro scale. Author, Year 1 * 2 3 4 5 6 7 8 9 10 11 Total Eduardo C. et al., 2020 [16] 1 1 1 1 1 1 0 1 1 1 1 9/10 Excellent Luciana GL. et al., 2018 [17] 1 1 1 1 1 1 1 1 1 1 1 10/10 Excellent Fernanda R. et al., 2018 [18] 1 1 0 1 1 0 0 0 0 1 1 6/10 Good Leyla K. et al., 2020 [19] 1 1 1 1 1 0 0 0 0 1 1 6/10 Good Mariana M. et al., 2018 [20] 1 1 1 1 1 1 1 1 1 1 1 10/10 Excellent De Souza R. et al., 2018 [21] 1 1 0 0 0 0 1 1 1 1 1 6/10 Good Shaiane S. et al., 2021 [22] 1 1 1 1 1 1 1 0 1 1 1 9/10 Excellent Chong R. et al., 2020 [23] 1 1 1 1 1 1 1 1 1 1 1 10/10 Excellent Taradaj J. et al., 2019 [24] 1 1 1 1 1 0 1 1 1 1 1 9/10 Excellent Fang-Yin L. et al., 2020 [25] 1 1 1 1 1 0 1 1 0 1 1 8/10 Good 1. The selection criteria were specified. 2. Subjects were randomly assigned to groups. 3. Allocation was concealed. 4. Groups were similar at baseline regarding the most important prognostic indicators. 5. All subjects were blinded. 6. All therapists who administered the therapy were blinded. 7. All assessors who measured at least one key outcome were blinded. 8. Measures of at least one of the key outcomes were obtained from more than 85% of the subjects initially assigned to the groups. 9. Results were presented for all subjects who received treatment or were allocated to the control group, or where this could not be, data for at least one key outcome was analyzed by “intention to treat”. 10. The results of statistical comparisons between groups were reported for at least one key outcome. 11. The study provides point and variability measures for at least one key outcome. * Non-summation criterion for the PEDro scale [15]. Table 3. Internal validity of the selected RCTs. Author, Year 2 3 5 6 7 8 9 IVS Eduardo C. et al., 2020 [16] 1 1 1 1 0 1 1 6/7 High Luciana GL. et al., 2018 [17] 1 1 1 1 1 1 1 7/7 High Fernanda R. et al., 2018 [18] 1 0 1 1 0 0 0 3/7 Limited LeylaK. Et al., 2020 [19] 1 1 1 0 0 0 0 3/7 Limited Mariana M. et al., 2018 [20] 1 1 1 1 1 1 1 7/7 High De Souza R. et al., 2018 [21] 1 0 0 0 1 1 1 4/7 Limited Shaiane S. et al., 2021 [22] 1 1 1 1 1 0 1 6/7 High Chong R. et al., 2020 [23] 1 1 1 1 1 1 1 7/7 High Taradaj J. et al., 2019 [24] 1 1 1 0 1 1 1 6/7 High Fang-Yin L. et al., 2020 [25] 1 1 1 0 1 1 0 5/7 High Fernanda T. et al., 2018 [26] 1 0 0 0 1 1 1 4/7 Limited IVS: Internal Validity Score [15]. Healthcare 2023,11, 938 8 of 19 Table 4. Development of the general characteristics for the selected studies. Author, Year Type of Study Experimental Group Control Group Interventions Variables Results Nunes EC. et al., 2020 [16]Randomized Clinical Trial 35 people with post endodontic surgery pain. Men: 16 Women: 19 Age range: 20.8–37.2 Chronic illness: No Post operative pain: 1.3–2.9 Treatment time: 39.2–54.2 35 people with post endodontic surgery pain. Men: 15 Women: 20 Age range:18.4–42.2 Chronic illness: No Post operative pain: 1.4–3.2 Treatment time: 49.9–39.3 EG: Received PBMT at 4 points (attached to mucosa) after endodontic treatment. CG: Received endodontic treatment and prescribed ibuprofen 600 mg, to be taken every 12 h daily. Received sham PBMT. Verbal rating scale (VPRS) with ibuprofen. Verbal rating scale (VPRS) with PBMT. Numerical rating scale (NPRS) with ibuprofen. Numerical rating scale (NPRS) with PBMT. There is a significant decrease in pain in the first 24 h with PBMT compared to the administration of ibuprofen 600mg (p< 0.001). Gonçalves Langella L. et al., 2018 [17] Randomized Clinical Trial 9 people in the post-surgical period of knee arthroplasty. 9 people in the post-surgical period of knee arthroplasty. EG: PBMT applied at 5 points along the scar of the operation. CG: Sham PBMT applied at 5 points along the scar of the operation. Changes in color. Changes in IL-6. Changes in IL-8. Changes in TNF-α. There was a significant change in the group treated with PBMT, with reduced pain and serum levels of proinflammatory cytokines (p< 0.05) (IL-6, IL-8, TNF-α). Fernanda R. et al., 2018 [18]Randomized Clinical Trial Group US + LLLT: 14 Caucasian women with knee osteoarthritis. Age range: 77–67 Group US + ET + LLLT: 14 Caucasian women with knee osteoarthritis. Age range: 71–61 14 Caucasian women with knee osteoarthritis. Age range: 69–61. EG1 US + LLLT: US and LLLT applied to 5 specific points on the knee. EG2 US + ET + LLLT: US and LLLT applied to 5 specific points on the knee. In addition, performance of guided therapeutic exercise. CG: sham US and LLLT applied to 5 specific points on the knee. Subjects were blinded. Changes in pain pressure threshold. Changes in the number of squats Radiological Evaluation (K-L Scale) There was a significant increase in the pain pressure threshold (p< 0.01). The number of squats was higher in the experimental groups after treatment when compared to the CG (p< 0.0001). There were no radiological findings that differed between any of the groups. (p> 0.05). Leyla K. et al., 2020 [19]Randomized Clinical Trial 20 people with nonspecific chronic low back pain. Men: 7 Women: 13 Age range: 25–65 Average age: 47 20 people with nonspecific chronic low back pain. Men: 5 Women: 15 Age range: 28–69 Average age: 51 EG: LLLT applied to the joint spaces of the spine (3 points per disc, 30 s each), adjacent paravertebral points, radiating pain zones, and tender and acupuncture points. CG: The same intervention as the experimental group but in the form of sham treatments. Changes in pain intensity (VAS). Changes in the range of motion of the lumbar spine. Functional status of the patients (according to RMQ). Spinal tenderness. Significant changes in pain, functional status (p< 0.001) and range of motion of the lumbar spine, with these benefits persisting during the 3-month treatment period (p< 0.001), unlike in the control group where there were only improvements during the first month. There were no significant differences between groups regarding spinal tenderness. Healthcare 2023,11, 938 9 of 19 Table 4. Cont. Author, Year Type of Study Experimental Group Control Group Interventions Variables Results Mariana M. et al., 2017 [20]Randomized Clinical Trial PBMT group: Formed of 2 groups, each containing 20 people with FM. ET group: Formed of 2 groups, each containing 20 people with FM. PBMT + ET group: Formed of 2 groups, each containing 20 people with FM. Set 1: Investigates the immediate effect of a single PBMT/ET session on chronic pain condition Age: 32–38 BMI (Kg/m2): 21–31 Set 2: Investigates the long-term effect (10 weeks) on the chronic pain condition and other FM symptoms Age: 38–42 BMI(Kg/m2): 23–31 Divided into 2 groups, each containing 20 people with FM. Set 1: Investigates the immediate effect of a single PBMT/ET session on chronic pain condition Age: 32–38 BMI (Kg/m2): 21–31 Set 2: Investigates the long-term effect (10 weeks) on the chronic pain condition and other FM symptoms Age: 38–42 BMI (Kg/m2): 23–31 EG1 (Set 1): Only one PBMT session was performed. These patients were evaluated at baseline and after 24 h. EG2 (Set 2): PBMT was applied 30 min before each exercise session. Outcome parameters were assessed at baseline (before group draw) and 48 h after the last day of intervention. PBMT: Applied for 300 s at each of 10 sensitive pain points. ET: Consisted of aerobic exercises and stretching 2 times/week for 10 weeks. They also performed TMJ exercises. PBMT + ET: They performed a combination of both protocols. Changes in pain threshold. Changes in pain intensity (VAS). FIQ score. Sleep score. Mouth opening. Pain threshold did not significantly improve after an exercise session; however, differences were noticeable with a PBMT session. Set 2 of the PBMT group showed similar results to Set 1. In Set 1, no additional benefits of the PBMT + ET combination were detected. The PBMT and PBMT + ET groups showed significant pain reduction versus the ET group and CG (Set 2). Furthermore, both combined therapies reduced the number of tender points. PBMT + ET had a beneficial role in anxiety, depression, and fatigue. De Souza R. et al., 2018 [21]Randomized Clinical Trial 66 people with FM. Age Range: 57.05–35.23 Average age: 46.14 (62 women and 4 men) Group A: 33 volunteers with FM and chronic pain. Group B: 33 volunteers with FM and chronic pain. None. 2 sessions/week for 6 weeks: Group A: GaAIAs diode laser irradiation for 40 s at each selected point. 780 nm wavelength. Power: 50 mW. Energy: 2 J. Point-skin distance: 1 cm. 1 session/week for 4 weeks: Group B: Anesthetic injection of 2% lidocaine without vasoconstrictor. Volume: 0.5 mL at each tender point. Stretching after infiltrations. Intensity of orofacial pain (VAS). Tenderness in the facial muscles. Perception of efficacy and well-being of both treatments. Significant decrease in pain (p= 0.0001), although without any noticeable difference between groups. There was a decrease in pain intensity in tender points with both treatments. All the muscles analyzed had a response except for the temporal post (p< 0.05). The perception of the patients and their well-being improved in both groups with a slight difference in favor of Group A. Healthcare 2023,11, 938 16 of 19 in pain threshold. Both combined therapies reduced the number of tender points and had a beneficial role in patients’ anxiety, depression, and fatigue [20]. The second study, unlike the previous one, did not have a CG, but instead had two EGs each comprised of 33 people suffering from FM and with an average age of 46 years. One group received PBM and the other an aesthetic infiltration of lidocaine. The group that received PBM showed a significant decrease in the intensity of orofacial pain, in the same way as the group that received the infiltration. In both groups, all the analyzed study variables improved significantly, although the patients’ perception of well-being was better for the group that received laser irradiation [21]. Current research shows promising short-term results of whole-body PBM on fibromyalgia sufferers, however, the long-term results are still to be explored [6,7]. 4.3. Temporomandibular Pain and Dysfunction This disorder is a very common condition experienced mainly by young middle-aged women. The etiology is unknown but the following risk factors seem to be associated with it: bruxism, depression, multiple pain conditions, gender, trauma, and hypermobility [ 36 ]. In this study, we incorporated an RCT that verifies the efficacy of photobiomodulation in this condition. It was verified by applying PBM three times a week for a month. The study had no CG but had three EGs receiving, TFBM, TM, or a combination of both. The study had 41 subjects, only 2 of them men. All groups experienced a significant reduction in pain and anxiety. PBM promoted improvements in five conditions, TM in two, and combined therapies in one [17]. 4.4. Oral Pain and Inflammation Two selected RCTs tried to report on the impact of PBM on patients with periodontal and endodontic pain and inflammation. The first applied laser therapy to a group of 35 people ranging from 20–37 years old with similar male/female ratios. This article highlights the significant improvement that the therapy produced during the first 24 h when compared to the placebo group [25]. The other group had an EG of 27 people who, after receiving the interventions, were evaluated for subjective pain and the FGC biomarkers associated with pain. The group that received the PBM obtained improvements1 h and 24 h after treatment. Additionally, subjective pain was also significantly better than in the CG at an interval of 3 days post-application [ 24 ]. 4.5. Post-Surgery Pain and Swelling Inflammation is known to be the body’s response to an injury to our system. Inflammatory mediators induce pain through the direct activation of nociceptors, hence the two are closely related concepts [37]. One article reviewed the influence of PBM on acute pain and swelling after knee arthroplasty. To accomplish this, nine patients in the EG had an application of PBM. The results revealed a positive and significant improvement in both pain and inflammation post-therapy on five points along the surgical scar [22]. 4.6. Strengths and Weaknesses of the Study The present review shows the following strengths: Good methodological quality and therefore the results are assured by the use of the PEDro scale. The wide variety of medical conditions presented by the subjects of the selected studies. The study highlights the lack of studies on this subject and hence the proposal for a novel therapy that can non-invasively address chronic musculoskeletal pain and inflammation. As weak points there are certain limitations: Limited RCTs showing the influence of PBM on subjects with inflammation. A lack of studies that describe the ideal standard parameters according to the type of condition. Since only English studies were included, the extent of the study is reduced. Healthcare 2023,11, 938 17 of 19 Heterogeneity of the study subjects, due to the fact that chronic musculoskeletal pain conditions come from different etiologies. Therefore, biomarkers and pain-generating mechanisms may differ. 4.7. Prospective After observing and analyzing the results, it can be seen that the scientific evidence on PBM in relation to chronic pain and inflammation is scarce. Therefore, different lines of research are proposed as follows: Implementation of RCTs on the efficacy of PBM application strategies in subjects with different kinds of inflammation. Conduct RCTs on the efficacy of PBM application strategies in subjects with chronic musculoskeletal pain. Perform RCTs that try to discern standard parameters according to the type of pain or inflammation, in order to move towards a consensus and be able to research the influence of laser therapy under standardized conditions. Although new evidence analyzing the effects of PBM on sports performance has been carried out [ 38 ], studies that show the effects of PBM on elite athletes suffering from pain are still needed. Finally, studies in subjects below 18 years of age who suffer from acute or chronic pain are necessary. 5. Conclusions The quality of the studies collected on the application of PBM in the treatment of inflammation and chronic pain is generally high, so they have excellent quality in terms of methodology. The symptoms of pain and chronic pain are influenced by laser irradiation. However, there is a lack of studies to clarify this ability to reduce pain, especially in the long term. There is not enough evidence on the effects and benefits of PBM on inflammation. Although the studies confirm the positive effects that this therapy has on proinflammatory biomarkers, there are only a few RCTs that verify this, and more research is needed. Author Contributions: Study conception (S.N.-L. and A.G.-M.), design (S.N.-L. and A.G.-M.), acquisition of data (A.G.-M.), analysis and interpretation of data (S.N.-L., A.G.-M., M.C.-C., M.A.-G., D.H.-H., J.J.P.-M. and D.A.-N.) drafting of manuscript (S.N.-L., A.G.-M., M.C.-C., M.A.-G., L.P., D.H.-H., J.J.P.-M. and D.A.-N.) and critical revision (S.N.-L., A.G.-M., M.C.-C., M.A.-G., D.H.-H., J.J.P.-M., L.P. and D.A.-N.). All authors have read and agreed to the published version of the manuscript. Funding: This study has been partially funded by the University Chair in Clinical Psychoneuroimmunology (University of Granada and PNI Europe). Institutional Review Board Statement: Not applicable. Informed Consent Statement: Not applicable. Data Availability Statement: All data associated with this study are present in the paper. All requests for other materials will be reviewed by the corresponding author to verify whether the request is subject to any intellectual property or confidentiality obligations. Conflicts of Interest: The authors declare no conflict of interest. References 1. Salehpour, F.; Mahmoudi, J.; Kamari, F.; Sadigh-Eteghad, S.; Rasta, S.H.; Hamblin, M.R. Brain Photobiomodulation Therapy: A Narrative Review. Mol. Neurobiol. 2018,55, 6601–6636. [CrossRef] 2. Karu, T.I.; Pyatibrat, L.V.; Kolyakov, S.F.; Afanasyeva, N.I. Absorption measurements of a cell monolayer relevant to phototherapy: Reduction of cytochrome c oxidase under near IR radiation. J. Photochem. Photobiol. B Biol. 2005,81, 98–106. [CrossRef] 3. Yeh, S.W.; Hong, C.H.; Shih, M.C.; Tam, K.W.; Huang, Y.H.; Kuan, Y.C. Low-level laser therapy for fibromyalgia: A systematic review and meta-analysis. Pain Physician 2019,22, 241–254. [PubMed] 4. Gur, A.; Karakoc, M.; Cevik, R.; Nas, K.; Sarac, A.J.; Karakoc, M. Efficacy of low power laser therapy and exercise on pain and functions in chronic low back pain. Lasers Surg. Med. 2003,32, 233–238. [CrossRef] [PubMed] Healthcare 2023,11, 938 18 of 19 5. Honda, Y.; Sakamoto, J.; Hamaue, Y.; Kataoka, H.; Kondo, Y.; Sasabe, R.; Goto, K.; Fukushima, T.; Oga, S.; Sasaki, R.; et al. Effects of Physical-Agent Pain Relief Modalities for Fibromyalgia Patients: A Systematic Review and Meta-Analysis of Randomized Controlled Trials. Pain Res. Manag. 2018,2018, 1–9. [CrossRef] [PubMed] 6. Navarro-Ledesma, S.; Carroll, J.; Burton, P.; Ana, G.-M. Short-Term Effects of Whole-Body Photobiomodulation on Pain, Quality of Life and Psychological Factors in a Population Suffering from Fibromyalgia: A Triple-Blinded Randomised Clinical Trial. Pain Ther. 2022,12, 225–239. [CrossRef] 7. Navarro-Ledesma, S.; Carroll, J.; González-Muñoz, A.; Pruimboom, L.; Burton, P. Changes in Circadian Variations in Blood Pressure, Pain Pressure Threshold and the Elasticity of Tissue after a Whole-Body Photobiomodulation Treatment in Patients with Fibromyalgia: A Tripled-Blinded Randomized Clinical Trial. Biomedicines 2022,10, 2678. [CrossRef] 8. Wickenheisser, V.A.; Zywot, E.M.; Rabjohns, E.M.; Lee, H.H.; Lawrence, D.S.; Tarrant, T.K. Laser Light Therapy in Inflammatory, Musculoskeletal, and Autoimmune Disease. Curr. Allergy Asthma Rep. 2019,19, 37. [CrossRef] [PubMed] 9. Schwan, J.; Sclafani, J.; Tawfik, V.L. Chronic Pain Management in the Elderly. Anesthesiol. Clin. 2019 ,37, 547–560. [CrossRef] [PubMed] 10. Mills, S.E.E.; Nicolson, K.P.; Smith, B.H. Chronic pain: A review of its epidemiology and associated factors in population-based studies. Br. J. Anaesth. 2019,123, e273–e283. [CrossRef] 11. Domenichiello, A.F.; Ramsden, C.E. The silent epidemic of chronic pain in older adults. Prog. Neuro-Psychopharmacol. Biol. Psychiatry 2019,93, 284–290. [CrossRef] 12. Kaushik, A.S.; Strath, L.J.; Sorge, R.E. Dietary Interventions for Treatment of Chronic Pain: Oxidative Stress and Inflammation. Pain Ther. 2020,9, 487–498. [CrossRef] [PubMed] 13. Bosch-Capblanch, X.; Lavis, J.N.; Lewin, S.; Atun, R.; Røttingen, J.-A.; Dröschel, D.; Beck, L.; Abalos, E.; El-Jardali, F.; Gilson, L.; et al. Policy Forum Guidance for Evidence-Informed Policies about Health Systems: Rationale for and Challenges of Guidance Development. PLoS Med. 2012,9, e1001185. [CrossRef] [PubMed] 14. Clijsen, R.; Brunner, A.; Barbero, M.; Clarys, P.; Taeymans, J. Effects of low-level laser therapy on pain in patients with musculoskeletal disorders: A systematic review and meta-analysis. Eur. J. Phys. Rehabil. Med. 2017 ,53, 603–610. [CrossRef] [PubMed] 15. Maher, C.G.; Sherrington, C.; Herbert, R.D.; Moseley, A.M.; Elkins, M. Reliability of the PEDro Scale for Rating Quality of Randomized Controlled Trials. Phys. Ther. 2003,83, 713–721. [CrossRef] 16. Nunes, E.C.; Herkrath, F.J.; Suzuki, E.H.; Júnior, E.C.G.; Marques, A.A.F.; Júnior, E.C.S. Comparison of the effect of photobiomodulation therapy and Ibuprofen on postoperative pain after endodontic treatment: Randomized, controlled, clinical study. Lasers Med Sci. 2019,35, 971–978. [CrossRef] [PubMed] 17. Langella, L.G.; Casalechi, H.L.; Tomazoni, S.S.; Johnson, D.S.; Albertini, R.; Pallotta, R.C.; Marcos, R.L.; Carvalho, P.D.T.C.D.; Leal-Junior, E.C.P. Photobiomodulation therapy (PBMT) on acute pain and inflammation in patients who underwent total hip arthroplasty-a randomized, triple-blind, placebo-controlled clinical trial. Lasers Med Sci. 2018,33, 1933–1940. [CrossRef] 18. Paolillo, F.R.; Paolillo, A.R.; João, J.P.; Frascá, D.; Duchêne, M.; João, H.A.; Bagnato, V.S. Ultrasound plus low-level laser therapy for knee osteoarthritis rehabilitation: A randomized, placebo-controlled trial. Rheumatol. Int. 2018,38, 785–793. [CrossRef] 19. Kholoosy, L.; Elyaspour, D.; Akhgari, M.R.; Razzaghi, Z.; Khodamardi, Z.; Bayat, M. Evaluation of the therapeutic effect of low level laser in controlling low back pain: A randomized controlled trial. J. Lasers Med. Sci. 2020,11, 120–125. [CrossRef] 20. da Silva, M.M.; Albertini, R.; Carvalho, P.D.T.C.D.; Leal-Junior, E.C.P.; Bussadori, S.K.; Vieira, S.S.; Bocalini, D.S.; de Oliveira, L.V.F.; Grandinetti, V.; Silva, J.A.; et al. Randomized, blinded, controlled trial on effectiveness of photobiomodulation therapy and exercise training in the fibromyalgia treatment. Lasers Med Sci. 2017,33, 343–351. [CrossRef] 21. de Souza, R.-C.-V.; de Sousa, E.-T.; Oliveira Scudine, K.-G.; Meira, U.-M.; de Oliveira Silva, E.-D.; Gomes, A.-C.-A.; Limeira-Junior, F.-d.A. Low-level laser therapy and anesthetic infiltration for orofacial pain in patients with fibromyalgia: A randomized clinical trial. Med. Oral Patol. Oral Y Cir. Bucal 2018,23, e65–e71. [CrossRef] [PubMed] 22. Tomazoni, S.S.; Costa, L.O.P.; Joensen, J.; Stausholm, M.B.; Naterstad, I.F.; Ernberg, M.; Leal-Junior, E.C.P.; Bjordal, J.M. Photobiomodulation Therapy is Able to Modulate PGE 2 Levels in Patients with Chronic Non-Specific Low Back Pain: A Randomized Placebo-Controlled Trial. Lasers Surg. Med. 2020,53, 236–244. [CrossRef] [PubMed] 23. Ren, C.; McGrath, C.; Gu, M.; Jin, L.; Zhang, C.; Sum, F.H.K.M.H.; Wong, K.W.F.; Chau, A.C.M.; Yang, Y. Low-level laser-aided orthodontic treatment of periodontally compromised patients: A randomised controlled trial. Lasers Med Sci. 2019 ,35, 729–739. [CrossRef] [PubMed] 24. Taradaj, J.; Rajfur, K.; Rajfur, J.; Ptaszkowski, K.; Ptaszkowska, L.; Sopel, M.; Rosi´nczuk, J.; Dymarek, R. Effect of laser treatment on postural control parameters in patients with chronic nonspecific low back pain: A randomized placebo-controlled trial. Braz. J. Med. Biol. Res. 2019,52. [CrossRef] 25. Liao, F.-Y.; Lin, C.-L.; Lo, S.-F.; Chang, C.-C.; Liao, W.-Y.; Chou, L.-W. Efficacy of Acupoints Dual-Frequency Low-Level Laser Therapy on Knee Osteoarthritis. Evid.-Based Complement. Altern. Med. 2020,2020, 1–7. [CrossRef] 26. Brochado, F.T.; De Jesus, L.H.; Carrard, V.C.; Freddo, A.L.; Chaves, K.D.; Martins, M.D. Comparative effectiveness of photobiomodulation and manual therapy alone or combined in TMD patients: A randomized clinical trial. Braz. Oral Res. 2018 ,32, e50. [CrossRef] 27. Sung, Y.-T.; Wu, J.-S. The Visual Analogue Scale for Rating, Ranking and Paired-Comparison (VAS-RRP): A new technique for psychological measurement. Behav. Res. Methods 2018,50, 1694–1715. [CrossRef] Healthcare 2023,11, 938 19 of 19 28. Van Wilgen, C.P.; Vuijk, P.; Van Ittersum, M.W.; Nijs, J. Not throwing out the baby with the bathwater: Lessons from the Fibromyalgia Impact Questionnaire. Clin. Rheumatol. 2012,32, 333–339. [CrossRef] 29. Winocur, E.; Steinkeller-Dekel, M.; Reiter, S.; Eli, I. A retrospective analysis of temporomandibular findings among Israeli-born patients based on the RDC⁄TMD. J. Oral Rehabil. 2009,36, 11–17. [CrossRef] 30. Madan, J.; Khan, K.A.; Petrou, S.; Lamb, S.E. Can Mapping Algorithms Based on Raw Scores Overestimate QALYs Gained by Treatment? A Comparison of Mappings between the Roland-Morris Disability Questionnaire and the EQ-5D-3L Based on Raw and Differenced Score Data. Pharmacoeconomics 2017,35, 549–559. [CrossRef] 31. Primorac, D.; Molnar, V.; Rod, E.; Jeleˇc, Ž.; ˇ Cukelj, F.; Matiši´c, V.; Vrdoljak, T.; Hudetz, D.; Hajsok, H.; Bori´c, I. Knee Osteoarthritis: A Review of Pathogenesis and State-Of-The-Art Non-Operative Therapeutic Considerations. Genes 2020,11, 854. [CrossRef] 32. Oehlert, M.E.; Nelson, K.G.; King, N.; Reis, D.J.; Sumerall, S.; Neal, C.; Henry, P. Measurement-based care: Use of the beck anxiety inventory (BAI) in a veteran population. Psychol. Serv. 2020,17, 372–379. [CrossRef] [PubMed] 33. Oliveira, I.S.; Tomazoni, S.S.; Vanin, A.A.; Araujo, A.C.; De Medeiros, F.C.; Oshima, R.K.A.; Costa, L.O.P.; Costa, L.D.C.M. Management of Acute Low Back Pain in Emergency Departments in São Paulo, Brazil: A Descriptive, Cross-Sectional Analysis of Baseline Data from a Prospective Cohort Study. BMJ Open 2022,12. [CrossRef] 34. Thomsen, M.G.; Latifi, R.; Kallemose, T.; Barfod, K.W.; Husted, H.; Troelsen, A. Good validity and reliability of the forgotten joint score in evaluating the outcome of total knee arthroplasty. Acta Orthop. 2016,87, 280–285. [CrossRef] [PubMed] 35. Navarro-Ledesma, S.; Gonzalez-Muñoz, A.; Carroll, J.; Burton, P. Shortand Long-Term Effects of Whole-Body Photobiomodulation on Pain, Functionality, Tissue Quality, Central Sensitisation and Psychological Factors in a Population Suffering from Fibromyalgia: Protocol for a Triple-Blinded Randomised Clinical Trial. Ther. Adv. Chronic. Dis. 2022 ,13, 204062232210780. [CrossRef] 36. Mishra, R.; Drangsholt, M.T.; Leresche, L.; Kassebaum, N. Global Burden of Temporomandibular Disorder (Tmd): A Systematic Review of Tmd Prevalence and Incidence (1990–January 2019). 1990. Available online: https://digital.lib.washington.edu/ researchworks/bitstream/handle/1773/45167/Mishra_washington_0250O_20844.pdf?sequence=1&isAllowed=y (accessed on 15 March 2023). 37. Matsuda, M.; Huh, Y.; Ji, R.-R. Roles of inflammation, neurogenic inflammation, and neuroinflammation in pain. J. Anesth. 2018 , 33, 131–139. [CrossRef] 38. González-Muñoz, A.; Perez-Montilla, J.J.; Cuevas-Cervera, M.; Aguilar-García, M.; Aguilar-Nuñez, D.; Hamed-Hamed, D.; Pruimboom, L.; Navarro-Ledesma, S. Effects of Photobiomodulation in Sports Performance: A Literature Review. Appl. Sci. 2023 , 13, 3147. [CrossRef] Disclaimer/Publisher’s Note: The statements, opinions and data contained in all publications are solely those of the individual author(s) and contributor(s) and not of MDPI and/or the editor(s). MDPI and/or the editor(s) disclaim responsibility for any injury to people or property resulting from any ideas, methods, instructions or products referred to in the content.