Overview

Osteoarthritis (OA) and rheumatoid arthritis (RA) cause chronic joint pain, stiffness, and functional disability. Adjunctive therapies such as hyperbaric oxygen therapy (HBOT) and red light photobiomodulation (PBM) have been explored for their potential to modulate inflammation and enhance tissue repair via oxygen- and light-mediated pathways. Early studies suggest these modalities may help alleviate pain and inflammatory markers in arthritis when used alongside standard care[1][2], though robust evidence is still emerging.

Key Findings

HBOT:

• RA pilot (n=10, USAF medical center): 30 HBOT sessions (over 6–10 weeks, ~2.0 ATA 100% O₂ per session) were associated with significant improvements in RA disease activity (DAS28-CRP and DAS28-ESR scores, p≤0.01) at 3 and 6 months post-therapy vs baseline, and reduced patient-reported joint pain[1]. No serious adverse effects noted (Sit et al., 2021).
• RA MRI study (n=9): Patients received 30 HBOT sessions (6–10 weeks). MRI scans at 3 and 6 months showed no progression of joint damage or inflammation (no new erosions, synovitis, or bone marrow edema) in all patients[3], suggesting a potential disease-modifying effect (Dulberger et al., 2023). This exploratory finding warrants controlled confirmation.
• Post-arthroplasty RCT (n=80, TKA patients): HBOT (1.6 ATA, 60 min at 24h and 48h post-op) vs sham improved early inflammatory and functional outcomes. By post-op day 3 the HBOT group had significantly lower IL-6 and CRP levels (IL-6: p = 0.028; CRP: p = 0.004)[4], reduced pain scores (VAS at rest and on movement on days 2–3, p<0.05)[4], and better knee range-of-motion and quadriceps strength vs controls[5]. No increase in adverse events was observed (Zhang et al., 2025).
• Pain and function: Small case series have reported HBOT-related pain relief in arthritis, but an early trial in RA (1988) showed no significant benefit[6]. Overall, recent controlled data remain limited. HBOT is not a standalone treatment but may support conventional therapy by reducing inflammatory pain in select patients, such as those with post-surgical inflammation or refractory RA symptoms, pending further trials.

PBM (Red Light Therapy):

• Knee OA meta-analysis: A 2019 systematic review (22 RCTs, n=1063) found PBM (also known as low-level laser therapy) significantly reduced knee OA pain and disability compared to placebo[2][7]. Pain improved by ~15–23 mm on a 100 mm VAS at end of therapy and follow-up, with peak effects (~32 mm pain reduction vs placebo) 2–4 weeks after treatment[8][9]. Notably, efficacy was seen only within specific dose parameters – e.g. 785–860 nm wavelength at 4–8 J per point, or 904 nm at 1–3 J/point[7] – consistent with World Association for Laser Therapy guidelines. No adverse events were reported (Stausholm et al., 2019).
• Knee OA RCT (exercise adjunct): In a blinded trial (n=42), women with knee OA received an exercise program ± PBM (808 nm, ~4 J/point, applied to medial/lateral knee after each session, 2×/week for 8 weeks). Both groups improved, but the PBM+exercise group had greater gains in WOMAC function and pain scores versus exercise alone (e.g. significantly better WOMAC pain and function subscale improvements, p<0.05)[10]. An anti-inflammatory cytokine (IL-10) increased in the PBM group[11], whereas pro-inflammatory markers (IL-6, TNF-α) showed no significant change in this short-term study[12] (dos Santos et al., 2021).
• RA evidence: A 2023 meta-analysis (18 RCTs, n=793 RA patients) concluded that infrared PBM yielded no clear improvements over sham in RA outcomes (pain, morning stiffness, grip strength, function or inflammatory indices)[13]. Evidence for red-light laser or laser acupuncture in RA was very uncertain[14], suggesting PBM’s benefits may not translate well to active RA joint inflammation (Lourinho et al., 2023). This contrasts with the more promising results seen in OA, indicating disease-specific differences or insufficient dosing in RA trials.
• Post-arthroplasty PBM (RCT, n=30): Daily PBM applied for 5 days after knee replacement (total knee arthroplasty) significantly reduced postoperative knee swelling (measured via bioimpedance) and improved early mobility (2-minute walk distance) compared to standard care[15][16]. However, no significant pain or active range-of-motion differences were observed by day 5. These findings suggest PBM can aid post-surgical recovery (reducing edema), though analgesic effects may be modest in the immediate acute setting (Chia et al., 2025).
• Comparative note: Both HBOT and PBM have shown anti-inflammatory and analgesic trends in arthritis. For example, HBOT and PBM each have been associated with lowering IL-6 levels in certain contexts[4][12] and with reductions in pain scores versus controls. However, PBM’s efficacy appears highly dose-dependent (inappropriate wavelengths/energy can yield no benefit[7]), and PBM evidence is stronger in OA than in RA. HBOT data are also preliminary, coming mainly from pilots or acute models. Head-to-head comparisons are lacking, but these therapies share a theme of modulating the inflammatory milieu in joints through non-pharmacological means.

How It Might Work

HBOT: By elevating oxygen availability in tissues, HBOT may reverse hypoxia in inflamed joints and disrupt hypoxia-inducible pathways (e.g. down-regulating HIF-1α). Increased oxygen tension can reduce edema and improve microcirculation, fostering tissue repair. Mechanistically, preclinical studies indicate HBOT can attenuate inflammatory signaling cascades like NF-κB, resulting in lower production of pro-inflammatory cytokines (such as TNF-α, IL-1β, IL-6)[17]. Human and animal data show HBOT triggers antioxidative responses (e.g. via Nrf2 activation) and promotes angiogenesis (upregulating VEGF), which together help resolve inflammation and ischemia in injured tissues[18][19]. This multifaceted action (anti-inflammatory, anti-edema, and pro-oxygenation) underpins the reported clinical improvements in arthritis swelling and pain with HBOT.

PBM: Red and near-infrared light in PBM is absorbed by mitochondrial chromophores (notably cytochrome c oxidase), leading to enhanced electron transport and ATP synthesis, along with a transient burst of reactive oxygen species that acts as a cellular signal[20][21]. This photochemical signaling can temper inflammatory pathways – for instance, PBM has been shown to reduce expression of cyclooxygenase-2 (COX-2) and other NF-κB–regulated mediators in treated tissues[22]. It may also increase anti-inflammatory cytokines like IL-10 while reducing IL-1β/IL-6 in joint cells (observed in some preclinical arthritis models). Additionally, PBM’s effects on nerve fibers and microvasculature likely contribute to pain relief and reduced swelling: light therapy can induce vasodilation and lymphatic flow, and modulate neural pain circuits, yielding local analgesic and anti-oedema benefits[23]. Preclinical evidence supports these mechanisms, though translating them to consistent human outcomes requires optimizing PBM dose parameters for each condition. Notably, both HBOT and PBM converge on lowering inflammatory cytokine activity (e.g. IL-6, TNF-α) and improving tissue oxygenation/energy metabolism, which may explain their observed anti-inflammatory effects in joints.

Evidence Quality & Research Gaps

Current evidence for HBOT and PBM in arthritis is limited and heterogeneous. Many studies are small, non-blinded or lack placebo controls, and treatment protocols vary widely (different pressures and durations for HBOT; different wavelengths, energies, and schedules for PBM). This heterogeneity complicates comparisons and may contribute to mixed results. Blinding is a challenge (sham HBOT and sham light devices), which can introduce bias in subjective outcomes like pain. In PBM, efficacy appears highly parameter-dependent – trials that used doses outside the effective window often found no benefit[7]. The modalities also seem more consistently beneficial in osteoarthritis (degenerative and localized inflammation) than in rheumatoid arthritis (systemic autoimmune inflammation), as evidenced by the lack of clear RA benefits in a recent PBM review[13] and the exploratory nature of RA HBOT data. Overall, the quality of evidence is low-to-moderate, and neither therapy is part of standard clinical guidelines for arthritis. Larger, rigorously sham-controlled trials are needed to confirm efficacy, identify which subgroups benefit most, and refine optimal dosing (e.g. standardizing HBOT pressure protocols and PBM wavelength/fluence). Long-term safety and cost-effectiveness also remain to be established. At present, HBOT and PBM should be considered adjunctive options for management of refractory symptoms or post-operative recovery, rather than replacements for proven therapies. Ongoing research will clarify their place, if any, in the comprehensive care of arthritis.

Sources

• Effect of hyperbaric oxygen therapy on postoperative muscle damage and inflammation following total knee arthroplasty: a randomized controlled trial. Scientific Reports (2025). DOI: 10.1038/s41598-025-06223-2
• The Effects of Hyperbaric Oxygen on Rheumatoid Arthritis: A Pilot Study. J Clin Rheumatol (2021). DOI: 10.1097/RHU.0000000000001540
• The effects of hyperbaric oxygen on MRI findings in rheumatoid arthritis: A pilot study. Undersea Hyperb Med (2023). DOI: 10.22462/01.01.2023.19
• Efficacy of low-level laser therapy on pain and disability in knee osteoarthritis: systematic review and meta-analysis of randomised placebo-controlled trials. BMJ Open (2019). DOI: 10.1136/bmjopen-2019-031142
• Effects of low-level laser therapy in adults with rheumatoid arthritis: a systematic review and meta-analysis of controlled trials. PLoS One (2023). DOI: 10.1371/journal.pone.0291345
• The Impact of Photobiomodulation Therapy on Swelling Reduction and Recovery Enhancement in Total Knee Arthroplasty: A Randomized Clinical Trial. Photobiomodul Photomed Laser Surg (2025). DOI: 10.1089/photob.2024.0120

[1] [6] The Effects of Hyperbaric Oxygen on Rheumatoid Arthritis: A Pilot Study - PubMed

https://pubmed.ncbi.nlm.nih.gov/32947434/

[2] [7] [8] [9] Efficacy of low-level laser therapy on pain and disability in knee osteoarthritis: systematic review and meta-analysis of randomised placebo-controlled trials - PubMed

https://pubmed.ncbi.nlm.nih.gov/31662383/

[3] The effects of hyperbaric oxygen on MRI findings in rheumatoid arthritis: A pilot study - PubMed

https://pubmed.ncbi.nlm.nih.gov/36820805/

[4] [5] [17] [18] [19] Effect of hyperbaric oxygen therapy on postoperative muscle damage and inflammation following total knee arthroplasty: a randomized controlled trial | Scientific Reports

https://www.nature.com/articles/s41598-025-06223-2?error=cookies_not_supported&code=c34af900-9dd3-48e4-99e2-0b351611e15e

[10] [11] [12] Effects of photobiomodulation and a physical exercise program on the expression of inflammatory and cartilage degradation biomarkers and functional capacity in women with knee osteoarthritis: a randomized blinded study | Advances in Rheumatology | Full Text

https://advancesinrheumatology.biomedcentral.com/articles/10.1186/s42358-021-00220-5

[13] [14] Effects of low-level laser therapy in adults with rheumatoid arthritis: A systematic review and meta-analysis of controlled trials | PLOS One

https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0291345

[15] [16] The Impact of Photobiomodulation Therapy on Swelling Reduction and Recovery Enhancement in Total Knee Arthroplasty: A Randomized Clinical Trial - PubMed

https://pubmed.ncbi.nlm.nih.gov/39786308/

[20] [21] [22] [23] NFkB is activated by PBM induced ROS in embryonic fibroblasts. (A)... | Download Scientific Diagram

https://www.researchgate.net/figure/NFkB-is-activated-by-PBM-induced-ROS-in-embryonic-fibroblasts-A-Intracellular-ROS_fig2_317346378

Overview

Infectious and inflammatory complications (e.g. severe wounds, radiation injuries, therapy-induced mucositis) can involve excessive inflammation and impaired healing. Hyperbaric oxygen therapy (HBOT) and photobiomodulation (PBM, red/near-infrared light) are being explored as adjuncts to standard care to modulate immune responses and support tissue repair[1][2]. These therapies may help reduce pro-inflammatory cytokines and improve oxygenation or cellular energy, potentially aiding infection control and recovery, while not replacing antibiotics or surgery.

Key Findings

HBOT

• Diabetic foot infections: A double-blind RCT (n=94) using HBOT at ~2.4 ATA for 85 min, 5 days/week (40 sessions) reported higher 1-year ulcer healing rates with HBOT (52% vs 29%; p = 0.03)[3]. In patients completing ≥35 sessions, healing reached 61% vs 27% (p < 0.01)[3], suggesting improved infection clearance and wound closure (Löndahl et al., 2010).
• Necrotising soft-tissue infections: HBOT is a recognized adjunct in life-threatening necrotising fasciitis and gas gangrene, used alongside surgery and antibiotics[1]. Case series report faster toxin suppression and infection control with HBOT (e.g. 2.8 ATA, 90 min sessions) by enhancing oxygen-dependent leukocyte killing (UHMS, 2015).
• Radiation injuries: In chronic radiation cystitis/proctitis, HBOT (typically 2.0–2.4 ATA, ~90 min, ~30 sessions) has been associated with reduced bleeding and inflammation. A Cochrane review noted moderate-quality evidence for improved late radiation tissue injury outcomes with HBOT[4]. A 10-year cohort (n=88) showed >90% symptom improvement (62% complete remission) in radiation proctitis after HBOT[5] (Bennett et al., 2016; Simões et al., 2023).
• Respiratory infections (COVID-19): In a small series of severe COVID-19 patients, adjunct HBOT (2.0 ATA, 90 min, 1–6 sessions) improved oxygenation, lowered inflammatory markers, and all patients avoided mechanical ventilation[6] (Serena et al., 2020). However, an RCT in COVID-ARDS (n=34) using HBOT 2.4 ATA (5 × 80 min sessions) found no significant benefit in 30-day ICU admission or mortality (50% vs 72%, p = 0.19)[7][8], indicating uncertain efficacy (Kjellberg et al., 2024).

PBM

• COVID-19 cytokine storm: A placebo-controlled pilot RCT in hospitalized mild-moderate COVID-19 (n=52) tested PBM via 8 LED pads (620–635 nm, 45 J/cm², 0.12 W/cm²) applied twice daily for 3 days[9]. The PBM group showed dramatic reductions in serum IL-6 (−82.5%±4) and TNF-α (−82.4%±8) vs baseline within 72 hours (p < 0.001)[10], with IL-8 also falling (−54%)[10]. No such improvements occurred in controls, and PBM was well-tolerated (Marashian et al., 2022).
• Oral mucositis (oncology): Multiple trials indicate PBM can prevent or lessen chemotherapy/radiotherapy-induced oral mucositis. A meta-analysis of 5 RCTs (315 patients) using low-level lasers (632–970 nm, typical fluence ~2–6 J/cm² per site) found a 62% relative risk reduction in severe mucositis by week 1 of treatment (RR 0.38, 95% CI 0.19–0.75)[11]. PBM-treated patients also averaged ~4 days faster mucosal healing[12], with significantly fewer grade 3+ lesions (Anschau et al., 2019). International guidelines (MASCC/ISOO 2019) now recommend PBM (e.g. ~660 nm laser, daily during cancer therapy) to mitigate mucositis.
• Comparison: Both HBOT and PBM have shown notable anti-inflammatory effects. For example, each modality was associated with decreased IL-6 and TNF-α levels in pilot studies[10][6]. However, HBOT involves systemic oxygen at pressure (hospital-based chambers), whereas PBM delivers light locally (e.g. intraoral or transcutaneous LEDs/lasers), making their logistics and risk profiles distinct.

How It Might Work

HBOT (mechanistic): Breathing 100% O₂ under high pressure raises tissue oxygen tension, which can restore hypoxic zones and enhance leukocyte function[13][14]. Hyperoxia directly inhibits anaerobic bacteria and toxin production and reduces oedema via vasoconstriction (while maintaining tissue oxygenation). HBOT may modulate HIF‑1α and NF‑κB pathways, attenuating pro-inflammatory cytokine release. Repeated sessions stimulate angiogenesis and collagen deposition, improving microcirculation in chronic wounds.

PBM (mechanistic): Red and near-infrared light photons (≈630–850 nm) are absorbed by mitochondrial cytochrome-c oxidase, boosting electron transport and ATP synthesis[15]. This triggers transient reactive oxygen and nitric oxide signaling[16] that can alter gene expression. In inflamed or injured tissues, PBM tends to down-regulate excessive inflammation: it can up-regulate antioxidant defenses and shift macrophages to a reparative phenotype[2]. NF‑κB-driven cytokine production is reduced in activated immune cells[17], leading to lower levels of IL-6, TNF-α and other mediators. In oral mucositis, PBM’s promotion of epithelial regeneration and reduced oxidative stress helps maintain the mucosal barrier during cancer therapy.

(Similar IL-6/TNF-α reductions have been observed with both HBOT and PBM in separate human studies[10][6], suggesting convergent anti-inflammatory pathways.)

Evidence Quality & Research Gaps

Current evidence is heterogeneous and often limited by small sample sizes and adjunct use. HBOT and PBM protocols vary widely (doses, timing), complicating comparisons. Blinding is challenging (sham pressure or light), which may introduce bias. Many positive findings come from preliminary or uncontrolled studies; for example, dramatic cytokine drops in PBM-treated COVID-19 need confirmation in larger trials. Thus far, these therapies are adjunctive – standard treatments (antibiotics, surgery, chemo/radiotherapy) were concurrently used in studies[9][1]. Robust, sham-controlled RCTs are needed to determine definitive clinical benefits (e.g. infection resolution, survival, hospital stay, mucositis severity). Consistent dosing guidelines should be established (optimal ATA×minutes or J/cm²) to reproducibly harness the immune-modulating effects. Overall, HBOT and PBM appear generally safe (minor barotrauma with HBOT; no serious PBM effects reported[18]), but further large-scale studies are required to confirm efficacy and refine patient selection criteria.

Sources

• Löndahl M et al. Hyperbaric oxygen therapy facilitates healing of chronic foot ulcers in patients with diabetes. Diabetes Care. 2010;33(5):998-1003. DOI: 10.2337/dc09-1754 [3][19]
• Simões O et al. Hyperbaric oxygen therapy in chronic radiation proctitis: 10-year cohort results. Front Oncol. 2023;13:1235237. DOI: 10.3389/fonc.2023.1235237 [4][20]
• Kjellberg A et al. Five sessions of hyperbaric oxygen for critically ill patients with COVID-19-induced ARDS: a randomised, open-label, phase II trial. Respir Med. 2024;232:107744. DOI: 10.1016/j.rmed.2024.107744 [7][8]
• Marashian SM et al. Photobiomodulation improves serum cytokine response in mild to moderate COVID‑19: a double-blind, placebo-controlled pilot study. Front Immunol. 2022;13:929837. DOI: 10.3389/fimmu.2022.929837 [10][21]
• Anschau F et al. Efficacy of low-level laser for treatment of cancer oral mucositis: systematic review and meta-analysis. Lasers Med Sci. 2019;34(6):1053-1062. DOI: 10.1007/s10103-019-02722-7 [11][12]
• Hamblin MR. Mechanisms and applications of the anti-inflammatory effects of photobiomodulation. AIMS Biophysics. 2017;4(3):337-361. DOI: 10.3934/biophy.2017.3.337 [15][2]

[1] [13] [14] 09. Necrotizing Soft Tissue Infections - Undersea & Hyperbaric Medical Society

https://www.uhms.org/9-necrotizing-soft-tissue-infections.html

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http://www.aimspress.com/article/10.3934/biophy.2017.3.337?ref=aurelienroy

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https://pubmed.ncbi.nlm.nih.gov/20427683/

[4] [5] [20] Frontiers | The effectiveness of hyperbaric oxygen therapy for managing radiation-induced proctitis – results of a 10-year retrospective cohort study

https://www.frontiersin.org/journals/oncology/articles/10.3389/fonc.2023.1235237/full

[6] Hyperbaric oxygen therapy in preventing mechanical ventilation in COVID-19 patients: a retrospective case series – SerenaGroup® Research Foundation

https://woundresearch.org/portfolio-item/hyperbaric-oxygen-therapy-in-preventing-mechanical-ventilation-in-covid-19-patients-a-retrospective-case-series/

[7] [8] Five sessions of hyperbaric oxygen for critically ill patients with COVID-19-induced ARDS: A randomised, open label, phase II trial - Respiratory Medicine

https://www.resmedjournal.com/article/S0954-6111(24)00219-1/fulltext

[9] [10] [18] [21] Photobiomodulation Improves Serum Cytokine Response in Mild to Moderate COVID-19: The First Randomized, Double-Blind, Placebo Controlled, Pilot Study - PubMed

https://pubmed.ncbi.nlm.nih.gov/35874678/

[11] [12] Efficacy of low-level laser for treatment of cancer oral mucositis: a systematic review and meta-analysis - PubMed

https://pubmed.ncbi.nlm.nih.gov/30729351/

Overview

Diabetic foot ulcers (DFUs) are chronic wounds with a high risk of non-healing, infection, and lower-limb amputation[1]. Standard care (debridement, off-loading, dressings) achieves only ~50% healing[2], so adjunct therapies targeting tissue perfusion, oxygenation, and inflammation are being explored. Hyperbaric oxygen therapy (HBOT) and photobiomodulation (PBM, red/near-infrared light therapy) aim to enhance wound healing via improved oxygen delivery and cellular bioenergetics while modulating inflammation.

Key Findings

HBOT

·  Meta-analysis (20 RCTs, n=1263): Adjunctive HBOT (typically 2.0–2.5 ATA for ~90 min, 20–40 sessions) nearly doubled DFU healing rates (RR ~1.90) and reduced major amputation risk by ~48%[1]. Mean time-to-healing was ~19 days shorter with HBOT (p<0.001)[1]. Larger, well-controlled trials were recommended[3].

·  Ischaemic DFUs: In patients with peripheral arterial disease, HBOT significantly lowered major amputation rates (≈11% vs 26%)[4] (NNT ~7) but did not consistently improve complete ulcer healing[5][6]. Selection of hypoxic DFUs (e.g. low TcPO₂) may identify those most likely to benefit[7].

·  RCT (double-blind, 94 patients): HBOT at 2.5 ATA for 85 min, 40 sessions over 8 weeks, improved 1-year ulcer closure (52% vs 29% with sham hyperbaric air, p=0.03)[8][9]. A per-protocol subgroup (>35 sessions) showed 61% healing vs 27% in controls[8][10], with few adverse events reported.

·  RCT (double-blind, 103 patients): Another trial (30 sessions HBOT at 2.4 ATA vs sham, added to comprehensive care) found no significant difference at 12 weeks in healing (20% HBOT vs 22% sham) or in amputation criteria[11]. This suggests HBOT’s benefits may manifest over longer follow-up or in specific subgroups.

·  Inflammation & perfusion: A small prospective study of refractory DFUs noted HBOT led to reduced erythrocyte sedimentation rate and ulcer area by 3 months (p<0.05), trends toward lower C-reactive protein, and increased angiogenic factors (SDF-1α)[12]. HBOT-treated wounds showed higher microvessel density on biopsy[13]. Over 3 years, the HBOT group had fewer amputations and improved wound healing than controls[14][15] (Martins-Mendes, 2025), though the sample was small and non-randomised.

PBM

·  Meta-analysis (7 RCTs, n=194): Low-level light therapy (red/NIR PBM) significantly improved DFU outcomes when added to standard care. Pooled results showed greater ulcer size reduction (WMD +34% area reduction vs controls) and higher odds of complete closure (OR 6.72, 95% CI 1.99–22.6, p=0.002)[16][17]. PBM also accelerated granulation tissue formation and shortened time to closure, with no reported treatment-related adverse effects[17].

·  RCT (23 ulcers, 685 nm laser): PBM (10 J/cm², 50 mW/cm²) given ~6×/week initially then alternate days led to 66.6% complete healing vs 38.4% in the sham group (Wagner grade I–II ulcers)[18][19]. Treated ulcers healed faster, with greater reductions in wound area and duration to closure (Kaviani et al., 2011).

·  RCT (68 patients, 15-day course): Daily PBM (multidiode laser, 60 mW, 2–4 J/cm² per spot) for 2 weeks significantly improved wound closure compared to controls[20][21]. Mean ulcer area reduction was ~1043 mm² in PBM vs 322 mm² with standard care alone[20][21], a ~3-fold greater improvement (Kajagar et al., 2012).

·  Short-term outcomes: In a 30-patient trial (660 nm LED, 3 J/cm² daily), the PBM group achieved ~37% wound area reduction in 2 weeks versus ~15% in controls[22][23], alongside visibly increased granulation tissue (Mathur et al., 2017). Another study reported PBM (632.8 nm, 4 J/cm² thrice weekly) not only shrank ulcers over 4 weeks but also significantly relieved chronic wound pain[24][25] (Feitosa et al., 2015).

• Dose and wavelength patterns: Effective PBM protocols for DFUs typically use red light (≈630–660 nm) applied to the ulcer bed and margins or near-infrared light (≈810–980 nm) for deeper tissue[26][27]. Common parameters are in the range of 3–6 J/cm² per point, delivered at power densities 30–100 mW/cm² for 1–3 min per site, with sessions repeated 3–7 times per week[22][28]. Studies suggest both red and NIR wavelengths can be beneficial: e.g. 8-week data showed similar ulcer size reduction with 632 nm (5 J/cm²) and 904 nm (6 J/cm²) laser regimens[28][29], with each achieving ~60% area reduction at 2 months. No significant safety issues have emerged, though patient skin pigmentation may affect light penetration (dosing adjustments have been used empirically with good tolerance[30][31]).
• (HBOT vs PBM): HBOT may confer greatest benefit in hypoxic or severe DFUs by raising tissue oxygen tension (TcPO₂) and reducing high-risk amputations[4][6]. PBM directly stimulates wound-bed cellular activity (fibroplasia, angiogenesis) and appears to accelerate granulation and re-epithelialisation, especially in chronic non-ischaemic ulcers[17][23]. Both modalities have shown reductions in inflammatory markers in preliminary studies[12]. Notably, HBOT is a facility-based treatment with occasional barotrauma or oxygen-toxicity events, whereas PBM offers a needle-free, painless option that might be delivered in outpatient or even home settings if dose parameters are properly controlled.

How It Might Work

HBOT (human/preclinical): By exposing patients to 100% oxygen at 2–2.5 ATA, HBOT acutely elevates periwound oxygen tension, which can reverse local hypoxia and support normal healing processes. Increased tissue pO₂ boosts fibroblast function and collagen synthesis and promotes angiogenesis via upregulation of VEGF and related pathways[13][14]. Higher oxygen levels also aid leukocyte bactericidal activity and may dampen hypoxia-driven inflammation (e.g. reducing CRP/ESR)[12]. Repeated HBOT sessions induce prolonged microvascular improvements (capillary density) and enhanced oxidative stress defenses, helping chronic wounds to progress from stalled inflammation to granulation.

PBM (human/preclinical): Red and near-infrared light in PBM is absorbed by mitochondrial chromophores (especially cytochrome c oxidase), leading to improved electron transport and ATP synthesis in cells. This photochemical effect triggers redox signalling that can increase growth factor release and cell proliferation. In wounds, PBM has been shown to stimulate fibroblast and keratinocyte activity, accelerating collagen deposition and re-epithelialisation[13]. PBM may also transiently release nitric oxide from cells, causing vasodilation and improved microcirculation around the ulcer. Preclinical models indicate PBM modulates inflammatory cytokines (e.g. lowering TNF-α/IL-6) and oxidative stress, thereby promoting a more regenerative wound-healing environment. (Notably, PBM’s efficacy follows a biphasic dose response – inadequate or excessive fluence may fail to produce these benefits, underscoring the importance of optimal dose windows.)

Evidence Quality & Research Gaps

Many studies are small, single-centre trials with heterogeneous protocols, which limits firm conclusions. For HBOT, blinding is challenging and standard-care co-interventions (off-loading, revascularisation) vary, making it hard to isolate HBOT’s effect. PBM trials likewise differ in wavelength, dose, and application technique, and few are double-blinded due to visible light. Meta-analyses suggest beneficial trends, but also reveal publication bias and generally moderate-quality evidence. There is a need for large, multi-centre RCTs with sham controls for both HBOT and PBM, using standardised outcome measures (e.g. time to complete closure) and optimised dosing regimens. Better patient selection criteria (e.g. based on ulcer perfusion status for HBOT or wound chronicity for PBM) should be defined. Overall, current evidence supports HBOT and PBM as adjuncts to standard care in hard-to-heal diabetic wounds, but neither is a standalone “cure.” Further high-quality research is required to confirm long-term benefits, cost-effectiveness, and safety in broader diabetic populations.

Sources

• Zhang Z. et al. Efficacy of hyperbaric oxygen therapy for diabetic foot ulcers: an updated systematic review and meta-analysis. Asian J Surg. 2022;45(1):68-78. PMID: 34376365[1][3]
• Brouwer RJ. et al. A systematic review and meta-analysis of hyperbaric oxygen therapy for diabetic foot ulcers with arterial insufficiency. J Vasc Surg. 2020;71(2):682-692.e1. PMID: 32040434[4][6]
• Löndahl M. et al. Hyperbaric oxygen therapy facilitates healing of chronic foot ulcers in patients with diabetes. Diabetes Care. 2010;33(5):998-1003. PMID: 20427683[8][9]
• Fedorko L. et al. Hyperbaric Oxygen Therapy Does Not Reduce Indications for Amputation in Patients With Diabetes With Nonhealing Ulcers of the Lower Limb (RCT). Diabetes Care. 2016;39(3):392-399. PMID: 26740639[11]
• Martins-Mendes D. et al. Microvascular, Biochemical, and Clinical Impact of HBOT in Recalcitrant Diabetic Foot Ulcers. Cells. 2025;14(15):1196. PMID: 40801628[12][14]
• Li S. et al. Efficacy of low-level light therapy for treatment of diabetic foot ulcer: a systematic review and meta-analysis of RCTs. Diabetes Res Clin Pract. 2018;143:215-224. PMID: 30009935[16][17]
• Kaviani A. et al. Effect of low-level laser therapy on chronic diabetic foot wound healing (RCT). Photomed Laser Surg. 2011;29(2):109-114. PMID: 21214368[32][33]
• Kajagar BM. et al. Efficacy of low level laser therapy on wound healing in chronic diabetic foot ulcers—A randomised control trial. Indian J Surg. 2012;74(5):359-363. PMID: 24082585[21][34]
• Mathur RK. et al. Low-level laser therapy as an adjunct to conventional therapy in the treatment of diabetic foot ulcers. Lasers Med Sci. 2017;32(2):275-282. DOI: 10.1007/s10103-016-2109-2[22][23]
• Tantawy SA. et al. A randomized controlled trial comparing helium-neon and infrared laser therapy in patients with diabetic foot ulcers. Lasers Med Sci. 2019;34(7):1365-1371. DOI: 10.1007/s10103-019-02724-5[28][29]

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[7] NCA - Hyperbaric Oxygen Therapy for Hypoxic Wounds and Diabetic Wounds of the Lower Extremities (CAG-00060N) - Decision Memo

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[8] [9] [10] Hyperbaric oxygen therapy facilitates healing of chronic foot ulcers in patients with diabetes - PubMed

https://pubmed.ncbi.nlm.nih.gov/20427683/

[11] Hyperbaric Oxygen Therapy Does Not Reduce Indications for Amputation in Patients With Diabetes With Nonhealing Ulcers of the Lower Limb: A Prospective, Double-Blind, Randomized Controlled Clinical Trial - PubMed

https://pubmed.ncbi.nlm.nih.gov/26740639/

[12] [13] [14] [15] Microvascular, Biochemical, and Clinical Impact of Hyperbaric Oxygen Therapy in Recalcitrant Diabetic Foot Ulcers - PubMed

https://pubmed.ncbi.nlm.nih.gov/40801628/

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[32] [33] A randomized clinical trial on the effect of low-level laser therapy on chronic diabetic foot wound healing: a preliminary report - PubMed

https://pubmed.ncbi.nlm.nih.gov/21214368/

Overview

Fibromyalgia (FM) is characterized by chronic widespread pain, fatigue, non-restorative sleep, cognitive “fibro-fog,” and markedly reduced quality of life[1][2]. Oxygen- and light-based therapies are being explored as adjuncts to standard care, aiming to improve cellular bioenergetics, tissue perfusion, and neuroimmune balance in FM. Hyperbaric oxygen therapy (HBOT) delivers high-pressure oxygen to increase tissue oxygenation, while photobiomodulation (PBM, red/near-infrared light therapy) targets mitochondrial enzymes to modulate pain and inflammation.

Key Findings

HBOT:
- Meta-analysis (Chen 2023, 9 studies, n=288): HBOT improved pain in FM vs control interventions (pooled standardised mean difference ≈ –1.56, 95% CI –2.18 to –0.93)[3]. Most studies also noted gains in tender-point counts, fatigue, multidimensional function (e.g. Fibromyalgia Impact Questionnaire, FIQ), patient global impression, and sleep quality[4]. Adverse effects (e.g. ear barotrauma) were reported in ~24% of patients, with no serious events; using lower pressure (<2.0 ATA) appeared to reduce side effects[5].

• RCT (Efrati et al., 2015, n=60): 40 HBOT sessions (2.0 ATA, 90 min, 5 days/week) led to significant improvement in all FM symptoms and functional scores[6]. Tender point count dropped by ~8–12 points (from ~16 at baseline) and pressure-pain thresholds tripled after HBOT (vs no change in controls)[7][8]. Single-photon emission CT (SPECT) brain scans showed previously hyperactive pain-related regions normalizing and frontal lobe activity increasing post-HBOT, correlating with clinical pain relief[6].
• RCT (Ablin et al., 2023, n=58): In FM patients with post-traumatic brain injury, 60 HBOT sessions (2.0 ATA, 90 min, 5×/week) yielded a ~45% greater pain reduction (VAS) than medical therapy (pregabalin/duloxetine) at 3 months (p=0.001, d≈–0.95)[9]. HBOT improved FIQ symptom scores (d=–1.11, p<0.001)[10], and 38% of HBOT-group patients no longer met ACR FM diagnostic criteria vs 0% of controls[11]. Pressure pain thresholds rose substantially under HBOT (d≈1.1)[12]. SPECT imaging showed increased perfusion in frontal and temporal cortices only in the HBOT arm, in parallel with better executive function and mood scores[13][14].
• Both HBOT and PBM modalities have shown not only immediate post-therapy benefits but also durability in some measures. HBOT trials report sustained symptom improvements at 1–3 months follow-up[9], and PBM trials have demonstrated continued pain and quality-of-life gains up to 6 months post-treatment[15].

PBM:
- Meta-analysis (Yeh 2019, 9 RCTs, n=325): Low-level laser therapy (LLLT, a form of PBM) applied to multiple tender points (wavelengths 632–904 nm) was superior to sham for improving composite FIQ scores, pain intensity, tender-point counts, fatigue, stiffness, and mood in FM[16]. Effect sizes were moderate to large (e.g. pain and FIQ SMD ~1.1–1.4)[16]. In one RCT, adding PBM to exercise conferred no extra benefit over exercise alone, but using a combined laser+LED device did improve pain, tender points and fatigue beyond exercise alone[17][18]. Overall, LLLT/PBM was well tolerated with no serious adverse events reported[19][20].

• RCT (Ribeiro et al., 2023, n=90): A PBM protocol combining laser and LED (905 nm pulsed laser, 850 nm and 660 nm LEDs) plus static magnetic fields was applied to 18 tender points (3 sessions/week for 3 weeks, 60 J per area). The PBM group’s tender point count fell from ~15 to 7 (vs no change with sham, p<0.0001)[21], and pain ratings (VAS) improved by >40 points on a 100-point scale (pre 80→post 38)[21]. Total FIQ scores also improved significantly in the PBM arm compared to placebo. Benefits persisted at 4 weeks post-treatment[22]. No adverse effects were reported[23].
• RCT (Navarro-Ledesma et al., 2024, n=42): Whole-body PBM was administered via a full-body LED bed (660–850 nm, ~40 mW/cm²) for 20 min, 3 times/week for 4 weeks. The PBM group showed significantly greater pain reduction (VAS dropped from ~7.2 to 4.1) than sham, along with marked gains in quality of life (SF-36 score increase from ~38 to 55)[24][25]. Improvements were maintained at 2-week, 3-month, and 6-month follow-ups[26][27]. Participants receiving PBM also reported reductions in pain catastrophizing and kinesiophobia and improved self-efficacy over 6 months[26][27]. This suggests systemic PBM can attenuate central sensitisation and psychosocial impacts in FM, under proper dosing parameters.

How It Might Work

HBOT (human/preclinical): Breathing 100% oxygen at high pressure super-oxygenates the blood and tissues, which may enhance mitochondrial ATP production and tissue repair in oxygen-starved muscle[28]. The transient oxidative burst from hyperoxia can paradoxically induce an anti-inflammatory effect: HBOT has been shown to reduce pro-inflammatory cytokines (e.g. IL-6, TNF-α) and oxidative stress markers while upregulating growth factors for healing[29]. In FM, HBOT’s neuroplastic effects include “resetting” aberrant pain processing in the central nervous system – SPECT scans confirm previously hyperactive pain-related brain regions regain normal perfusion after HBOT alongside symptom relief[6][13]. This suggests HBOT may break the cycle of central sensitisation by improving regional brain blood flow and reducing neuroinflammation.

PBM (human/preclinical): Red and near-infrared light (λ ~600–900 nm) penetrates tissues and is absorbed by mitochondrial chromophores like cytochrome-c oxidase, boosting electron transport, ATP synthesis and modulating cellular redox signaling[30]. By restoring efficient mitochondrial function, PBM can lessen chronic pain pathways: studies show PBM reduces oxidative stress and alters expression of genes linked to nociception and inflammation[30]. At the tissue level, PBM of sufficient dose can raise pressure-pain thresholds and decrease allodynia in FM, indicating a reduction in central sensitisation of pain[31][21]. Transcranial PBM, applying light to scalp regions, has shown enhanced cerebral blood flow and cognitive improvements in brain injury trials[32]. This raises the prospect that PBM could alleviate “fibro-fog” cognitive symptoms by modulating neural activity and connectivity in frontal and limbic networks – though direct evidence in fibromyalgia patients is still preliminary.

Evidence Quality & Research Gaps

Current evidence is limited by small sample sizes and heterogeneity in treatment protocols and outcomes. Many FM studies are unblinded or use suboptimal shams (e.g. inactive light that may still produce warmth, or no chamber pressurisation), which can bias subjective endpoints. Follow-up durations are relatively short, and the long-term durability of HBOT/PBM benefits needs confirmation beyond 6 months. Additionally, patient selection varies (e.g. FM with specific triggers like trauma), making it hard to generalise results. Standardised outcome measures (e.g. updated ACR criteria, FIQR, pain thresholds) and rigorous sham-controlled trial designs are required to validate these modalities. Importantly, HBOT and PBM should be viewed as adjunctive therapies – while studies suggest meaningful improvements in pain and function, neither is a proven standalone “cure” for fibromyalgia. Larger, multi-center trials integrating mechanistic biomarkers (imaging, autonomic measures, inflammatory markers) will help establish the true efficacy and optimal dosing parameters for HBOT and PBM in fibromyalgia management.

Sources

• Chen X et al. Efficacy and safety of hyperbaric oxygen therapy for fibromyalgia: a systematic review and meta-analysis. BMJ Open. 2023;13(1):e062322. DOI: 10.1136/bmjopen-2022-062322
• Efrati S et al. Hyperbaric Oxygen Therapy Can Diminish Fibromyalgia Syndrome – Prospective Clinical Trial. PLoS ONE. 2015;10(5):e0127012. DOI: 10.1371/journal.pone.0127012
• Ablin JN et al. Hyperbaric oxygen therapy compared to pharmacological intervention in fibromyalgia patients following traumatic brain injury: a randomized, controlled trial. PLoS ONE. 2023;18(3):e0282406. DOI: 10.1371/journal.pone.0282406
• Yeh SW et al. Low-Level Laser Therapy for Fibromyalgia: A Systematic Review and Meta-Analysis. Pain Physician. 2019;22(3):241–254. PMID: 31151332
• Ribeiro NF et al. Photobiomodulation therapy combined with static magnetic field is better than placebo in patients with fibromyalgia: a randomized placebo-controlled trial. Eur J Phys Rehabil Med. 2023 (Dec);59(6):754–762. DOI: 10.23736/S1973-9087.23.07928-5
• Navarro-Ledesma S et al. Outcomes of whole-body photobiomodulation on pain, quality of life, leisure physical activity, pain catastrophizing, kinesiophobia, and self-efficacy: a prospective randomized triple-blinded clinical trial with 6 months of follow-up. Front Neurosci. 2024;18:1264821. DOI: 10.3389/fnins.2024.1264821

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[29] The Effects of Hyperbaric Oxygenation on Oxidative Stress, Inflammation and Angiogenesis

https://www.mdpi.com/2218-273X/11/8/1210

Overview

MS is a chronic neuroinflammatory disease causing disability, with common symptoms including fatigue, mobility limitations, and cognitive impairment. Hyperbaric oxygen therapy (HBOT) and photobiomodulation (PBM, red to near-infrared light therapy) are being explored as adjunct interventions aiming to enhance tissue oxygenation, cellular energy (mitochondrial ATP production), and neuroimmune modulation[1][2]. While neither approach is proven to alter MS disease progression, they have been investigated for potential short-term relief of MS-related symptoms and functional improvement in combination with standard care.

Key Findings

HBOT
- Systematic reviews/meta-analyses: A meta-analysis of 12 randomized trials (mostly relapsing MS, 1980s) using ~20 HBOT sessions at 1.75–2.5 ATA for 60–120 min/day found no consistent benefit in disability outcomes (no significant EDSS improvement)[3]. No plausible disease-modifying effect was identified; any subgroup benefit is considered unlikely to be clinically significant[4]. Routine HBOT for MS is not recommended based on available evidence (Bennett & Heard, 2010)[5].
- Clinical course (long-term): An uncontrolled multicenter series (n = 312 MS patients) receiving an initial 20 daily HBOT sessions (~2.0 ATA, 1 hour) plus monthly boosters for 2 years showed no slowing of disability progression: mean EDSS worsened by ~0.9 point over 2 years[6][7]. Approximately 20% reported transient symptom relief (e.g. improved bladder function) during HBOT, but only ~5% maintained any improvement at 2-year follow-up[8][9].
- Guideline stance: National guidelines advise against HBOT as a therapy for MS. For example, NICE (2022) explicitly recommends not offering HBOT for MS-related fatigue due to insufficient evidence of benefit[10]. No significant reductions in relapse rate or MRI lesion activity have been demonstrated in trials to support HBOT as a disease-modifying therapy in MS[11].
- Safety/tolerability: When administered according to standard protocols, HBOT is generally well tolerated. The most common issue is middle ear/sinus barotrauma from pressure changes[12]. Serious adverse events are rare (e.g. oxygen toxicity seizures are infrequent at MS treatment pressures).

PBM (Red Light / Low-Level Laser Therapy)
- Fatigue and cognition: A small controlled trial in relapsing–remitting MS (RRMS, n = 32) examined pulsed low-level laser therapy (~810 nm GaAlAs laser) applied to the cervical spine 3×/week for 4 weeks[13][14]. The PBM-treated group showed significant improvements in fatigue (Fatigue Severity Scale scores) and cognitive performance (reaction time accuracy) compared to baseline, alongside modest EDSS disability score improvements[14][15]. (Adding adjunct UV-B light in a comparison group provided no additional benefit, suggesting the LLLT itself drove the effect[16][17].)
- Functional status: A randomized trial of 120 MS patients (mixed types) receiving 21 days of rehab including low-level laser therapy to spinal nerve roots (with or without pulsed magnetotherapy) reported improved neurological function. All treatment arms showed statistically significant gains in EDSS (lower disability) and Barthel Index (activities of daily living) after the 3-week course[18][19]. The greatest improvement occurred in the combined laser+magnet stimulation group[19]. Notably, functional benefits persisted at least 1 month post-therapy, indicating a short-term carryover effect (Kubsik et al., 2016).
- Mixed results on fatigue: Not all PBM studies have been positive. A sham-controlled pilot RCT in RRMS (Tamiris Silva et al., 2022) delivered 808 nm laser PBM (36 J per 6 min session) either sublingually or over the radial artery 3×/week for 4 weeks. It found no significant difference in fatigue outcomes (Modified Fatigue Impact Scale scores) between active PBM and placebo-treatment groups[20][21], underscoring the need to identify optimal dosing and targets for fatigue relief.
- Muscle performance: Transcranial PBM aimed at peripheral neuromuscular function has shown promise. In a double-blind crossover trial (n = 17, mild-moderate MS), near-infrared PBM (wavelength 600–1100 nm, up to 120 J) was applied to a leg muscle (tibialis anterior). After a personalized 2-week PBM course, patients had significantly greater muscle strength gains versus sham (mean +22.9 N vs –4.1 N, p = 0.02)[22][23]. However, there was no significant change in measured muscle fatigue or endurance, nor any subjective fatigue improvement in this short-term study (Rouhani et al., 2024)[22][24].
- Immune and safety profile: Preliminary biomarker evidence suggests PBM may exert anti-inflammatory effects. In a 14-person RRMS trial, 12 weeks of PBM (808 nm, 100 mW, 6 min to sublingual or radial artery sites, 24 sessions) led to a ~3–4 fold increase in serum IL-10 (an anti-inflammatory cytokine) from baseline[25][26], whereas pro-oxidative nitrite levels were unchanged. No adverse effects were reported. In fact, across published PBM studies in MS, no serious treatment-related adverse events have been noted[27]. PBM parameters and delivery sites have varied widely (wavelengths ~630–1064 nm; dosimetry from ~36 J up to 120 J per site; applied to scalp, neck, or peripheral blood targets), and all studies to date have been small.

How It Might Work

HBOT: By delivering 100% oxygen at elevated pressure, HBOT can markedly increase oxygen saturation in blood and tissues. The rationale in MS is that this might counteract lesion hypoxia and support energy metabolism in chronically inflamed CNS areas. Preclinical evidence (EAE models) shows that correcting CNS hypoxia can rapidly improve neurological deficits and reduce demyelination despite ongoing inflammation[28][29]. HBOT may also transiently reduce edema and modulate the immune response (e.g. reducing certain inflammatory mediators), thereby lowering oxidative stress in lesions. Improved microvascular perfusion and oxygen delivery to impaired nerves could underlie reported short-term relief in some MS symptoms. However, these effects appear temporary, and there is no confirmed impact on the autoimmune attack on myelin.

PBM: Red/NIR light in the 600–1100 nm range can penetrate tissue and is absorbed by mitochondrial chromophores (notably cytochrome c oxidase). This absorption is thought to enhance mitochondrial respiration and ATP synthesis, while also triggering secondary cellular signaling that promotes neuroprotection. In MS and related neuroinflammatory conditions, PBM has been observed to shift cytokine profiles towards anti-inflammatory states (increasing IL-10 and IL-4, with relative suppression of Th1/Th17 pro-inflammatory cytokines in animal models)[30][31]. PBM may additionally improve neuronal function via increased regional cerebral blood flow and altered cortical activity. For example, transcranial PBM at 1064 nm has been associated with improved cognitive performance and normalized EEG rhythms in human studies[2][32]. These mechanisms – boosting cellular energy availability and dampening inflammatory oxidative damage – align with the observed preliminary benefits in MS fatigue, cognition, and muscle function. Importantly, PBM’s effects are dose-dependent and biphasic (insufficient or excessive dose may fail to produce benefit), which highlights the need for optimized treatment parameters in MS.

Evidence Quality & Research Gaps

Overall, the evidence for HBOT or PBM in MS is limited and heterogeneous. The HBOT trials are mostly older, with variable quality and often negative primary outcomes[33]. No high-level evidence shows that HBOT can alter the course of MS (relapses or MRI lesions), and expert consensus is that it should not be used as a disease-modifying therapy[5]. PBM studies in MS, while more recent, have involved small sample sizes and sometimes lack proper blinding or sham controls. There is significant variability in PBM protocols (wavelength, dosage, treatment location), making it difficult to compare results across studies[34]. Both modalities require more rigorous research: well-powered, placebo-controlled trials in defined MS populations (e.g. patients with refractory fatigue or gait impairment) using standardized outcome measures (fatigue scales, cognitive tests, EDSS, etc.). Long-term safety and durability of any benefits also remain to be established – especially for PBM, where optimal dosing and scheduling are still being determined[35]. In summary, current evidence does not support HBOT or PBM as standalone disease-modifying treatments in MS, but they may have a role as adjunctive, symptom-focused therapies. Well‑designed future studies are needed to confirm the preliminary functional improvements and to identify which MS patients, if any, are most likely to benefit from these energy-based interventions.

Sources

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·  Kindwall EP et al. Treatment of multiple sclerosis with hyperbaric oxygen: results of a national registry. Arch Neurol. 1991;48(2):195–199. DOI: 10.1001/archneur.1991.00530140091021[6][8].

·  National Institute for Health and Care Excellence (NICE). Multiple sclerosis in adults: management. NICE Guideline NG220, Oct 2022[10].

·  Kubsik A et al. Application of laser radiation and magnetostimulation in therapy of patients with multiple sclerosis. NeuroRehabilitation. 2016;38(2):183-190. DOI: 10.3233/NRE-161309[18][19].

·  Rouhani M et al. Effects of photobiomodulation therapy on muscle function in individuals with multiple sclerosis. Mult Scler Relat Disord. 2024;86:105598. DOI: 10.1016/j.msard.2024.105598[22][23].

·  Silva T et al. Effect of photobiomodulation on fatigue in individuals with relapsing–remitting multiple sclerosis: a pilot study. Lasers Med Sci. 2022;37(8):3107-3113. DOI: 10.1007/s10103-022-03567-3[20][21].

·  Silva T et al. Effects of photobiomodulation on interleukin-10 and nitrites in individuals with relapsing-remitting MS – a randomized clinical trial. PLoS One. 2020;15(4):e0230551. DOI: 10.1371/journal.pone.0230551[25][26].

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Overview

Acute surgical wounds and chronic ulcers (diabetic, venous, pressure) pose a major clinical burden, often complicated by hypoxia and impaired healing[1]. Adjunctive therapies like hyperbaric oxygen (HBOT) and photobiomodulation (red light, PBM) aim to enhance tissue oxygenation and cellular repair processes, respectively, to support standard wound care.

Key Findings

HBOT (Hyperbaric Oxygen Therapy) – Administering 100% O₂ at >1 atmosphere absolute (ATA) pressure:

• Chronic ulcers (diabetic foot): A meta-analysis of 12 RCTs (n=577) found adjunct HBOT (typically ~2.0 ATA, ~90 min sessions) increased the proportion of diabetic foot ulcers achieving short-term closure at 6 weeks (RR ~2.35)[2]. However, this benefit was not maintained at 1 year follow-up[2], and no significant reduction in major amputation rates was observed[2] (Kranke et al., 2015).
• Mixed RCT results: An earlier single-center trial in refractory diabetic foot ulcers (n=94) reported higher 1-year healing with HBOT 2.5 ATA (40 sessions) vs sham (52% vs 29% healed; P = 0.03)[3], especially in patients completing ≥35 sessions[3]. In contrast, a larger sham-controlled RCT (n=103) saw no significant HBOT advantage at 12 weeks – healing rates were ~20% in both HBOT (2.4 ATA ×30 sessions) and placebo groups[4], with similar major amputation outcomes (Fedorko et al., 2016).
• Radiation injuries: In late radiation-damaged tissues (e.g. post-radiotherapy wounds), small studies suggest HBOT can improve healing. A meta-analysis in osteoradionecrosis of the jaw showed HBOT increased mucosal wound closure rates (RR ≈1.3, NNT ~5)[5] and reduced post-operative wound breakdown (fewer dehiscences, NNT ~4)[6]. HBOT was also associated with higher resolution of chronic radiation proctitis (RR ~1.7) and improved healing of irradiated surgical flaps in single trials[7], supporting its adjunctive use for refractory radiation ulcers (Bennett et al., 2016).

PBM (Photobiomodulation – Low-Level Red/Infrared Light Therapy):

• Chronic ulcers (diabetic foot): Multiple reviews report that adding PBM (usually red or near-infrared light) to standard care may accelerate chronic wound healing. A 2018 meta-analysis of 7 RCTs (n=194) found significantly greater ulcer area reduction with PBM (≈34% more than controls) and higher odds of complete ulcer closure (OR ~6.7, 95% CI 2.0–22.6)[8]. A larger 2021 meta-analysis (13 RCTs, n=413) similarly showed PBM roughly doubled the DFU healing rate (RR ~2.1) and shortened time to closure (mean healing time reduced by ~1.4 standard deviations)[9], although the evidence quality was low. Participants receiving PBM also exhibited faster granulation and often reported reduced wound pain in these studies[10].
• Various wounds and pain: A 2024 systematic review (18 RCTs, mixed wound types totaling ~670 wounds) found PBM significantly improved wound size reduction and complete healing rates across acute and chronic wounds[11]. Treated wounds had a higher percentage area reduction (mean difference ~14–38% over controls) and greater likelihood of full healing[11]. PBM also conferred pain relief benefits – e.g. lower post-treatment pain scores (VAS) compared to standard care[12]. These broad findings suggest red light therapy may support tissue repair and patient comfort as an adjunct (Taha et al., 2024).
• Effective dose parameters: Clinical studies indicate that treatment parameters are critical for PBM efficacy. Successful protocols in diabetic ulcers have used red light in the 630–685 nm range at low irradiance (~50 mW/cm²), delivering approximately 3–6 J/cm² per session (about 30–80 seconds of exposure per site), typically 3 times per week for 4–8 weeks[13]. Such dosing has been associated with improved epithelialisation and wound closure, whereas insufficient or excessive doses may be less effective. Peri-wound application (surrounding the ulcer bed) is often used to stimulate the wound margins without disrupting fragile tissue.

How It Might Work

HBOT: By elevating plasma O₂ levels, HBOT raises tissue oxygen tension (TcPO₂) in hypoxic wound areas, which may jump-start oxygen-dependent healing processes. Increased O₂ availability supports collagen synthesis and cross-linking and promotes angiogenesis (e.g. up-regulating VEGF and fibroblast growth factors) to spur new capillary growth. Hyperoxia also directly enhances leukocyte oxidative killing of bacteria and inhibits toxin-producing anaerobes, helping to control infection[14]. Preclinical studies and human wound fluid analyses show HBOT can stimulate fibroblast proliferation and neovascularisation while reducing tissue edema[15][14]. By improving microcirculation and oxygen delivery, HBOT may dampen chronic inflammation driven by tissue hypoxia (e.g. down-regulating hypoxia-inducible cytokines).

PBM: Red and near-infrared light can penetrate skin and is absorbed by mitochondrial chromophores (notably cytochrome c oxidase). This absorption boosts cellular respiration and ATP production, and induces mild oxidative signaling that triggers growth factor release[16]. In wounds, PBM has been shown to activate key repair cells: increasing fibroblast proliferation and migration, accelerating keratinocyte re-epithelialisation, and enhancing deposition of collagen I/III in the extracellular matrix[17]. PBM also modulates the inflammatory response – studies report reductions in IL-6 and TNF-α levels in laser-treated wounds (preclinical) alongside improved local blood flow, partly due to nitric oxide release causing vasodilation in the peri-wound microvasculature. Collectively, these photobiological effects (sometimes termed “laser bio-stimulation”) can create a more favorable environment for wound closure, especially in chronic ulcers with stalled healing. Similar perfusion and anti-inflammatory trends have been noted in diabetic wound models receiving PBM, complementing the oxygenation gains seen with HBOT.

Evidence Quality & Research Gaps

Current evidence is limited by heterogeneity and study size. Many trials are small single-centre studies with varying HBOT pressures (2.0–2.5 ATA protocols) or diverse PBM parameters (wavelengths 600–900 nm, dose 1–10 J/cm²), making comparisons difficult. Co-interventions like off-loading (for DFUs) or compression (for venous ulcers) were not uniform, and true sham controls are challenging (e.g. visible light in PBM). Meta-analyses flag a very low certainty of evidence for PBM outcomes[18] and risk of bias in HBOT studies[19]. Blinding issues and publication bias further temper confidence. Both modalities are generally well-tolerated (HBOT’s main risks are barotrauma or mild oxygen toxicity, while PBM has no significant adverse effects reported[20]), but robust data on long-term safety are lacking. Overall, larger high-quality RCTs are needed – ideally multi-centre, sham-controlled trials with standardized dosing and clinically important endpoints (complete healing, time to closure, amputation rates). Future research should also clarify optimal patient selection (e.g. wounds with critical ischemia might benefit more from HBOT, whereas superficial non-ischaemic wounds might respond well to PBM). Until then, HBOT and red light therapy should be viewed as adjunctive therapies to standard wound management rather than standalone cures, with further confirmation required to define their precise roles in improving wound healing outcomes.

Sources

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• Löndahl M. et al. (2010). “Hyperbaric oxygen therapy facilitates healing of chronic foot ulcers in patients with diabetes.” Diabetes Care 33(5):998-1003. DOI: 10.2337/dc09-1754 [3]
• Fedorko L. et al. (2016). “Hyperbaric oxygen therapy does not reduce indications for amputation in patients with diabetes with nonhealing ulcers of the lower limb: a RCT.” Diabetes Care 39(3):392-399. DOI: 10.2337/dc15-2001 [4]
• Bennett MH. et al. (2016). “Hyperbaric oxygen therapy for late radiation tissue injury (Review).” Cochrane Database Syst Rev 2016(4):CD005005. DOI: 10.1002/14651858.CD005005.pub4 [5][7]
• Li S. et al. (2018). “Efficacy of low-level light therapy for treatment of diabetic foot ulcer: a systematic review and meta-analysis of RCTs.” Diabetes Res Clin Pract 143:215-224. DOI: 10.1016/j.diabres.2018.07.014 [8]
• Dos Santos CM. et al. (2021). “Effects of low-level laser therapy in the treatment of diabetic foot ulcers: A systematic review and meta-analysis.” Int J Low Extrem Wounds 20(3):198-207. DOI: 10.1177/1534734620914439 [13]
• Huang J. et al. (2021). “The effect of low-level laser therapy on diabetic foot ulcers: A meta-analysis of randomised controlled trials.” Int Wound J 18(6):763-776. DOI: 10.1111/iwj.13577 [9]
• Taha N. et al. (2024). “The effects of low-level laser therapy on wound healing and pain management in skin wounds: A systematic review and meta-analysis.” Cureus 16(10):e72542. DOI: 10.7759/cureus.72542 [11][12]

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[3] Hyperbaric oxygen therapy facilitates healing of chronic foot ulcers in patients with diabetes - PubMed

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[4] Hyperbaric Oxygen Therapy Does Not Reduce Indications for Amputation in Patients With Diabetes With Nonhealing Ulcers of the Lower Limb: A Prospective, Double-Blind, Randomized Controlled Clinical Trial - PubMed

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[13] A Systematic Review and Meta-Analysis of the Effects of Low-Level Laser Therapy in the Treatment of Diabetic Foot Ulcers - PubMed

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Overview

Chronic pain is a pervasive cause of disability, impairing daily function and quality of life while often necessitating long-term analgesics. Hyperbaric oxygen therapy (HBOT) and red light photobiomodulation (PBM) are being explored as adjunctive treatments to modulate inflammation, tissue metabolism, and nociceptive processing. Both approaches aim to improve pain and function by altering the cellular and physiological environment (e.g. oxygenation or mitochondrial activity) in ways conventional therapies do not.

Key Findings

HBOT

·  Complex Regional Pain Syndrome (CRPS) – A double-blind RCT (n=71) using HBOT (≈2.0 ATA, 60 min, 15 sessions) showed greater reductions in limb pain and edema vs sham (normal air)[1]. A larger case series (n=83, CRPS I/II) with ~22 sessions at 2.0–2.4 ATA for 80–90 min (with air break) found rest-pain VAS halved (mean 3.2→1.6) and activity-pain improved (6.1→3.7, p<0.001)[2], alongside functional gains and 86% symptom relief; no serious HBOT-related adverse events were reported[3][4]. (Kiralp 2004; Hájek 2024)

·  Fibromyalgia (widespread pain) – A meta-analysis of 5 RCTs (n≈180) reported HBOT (typically 2.0 ATA, 60–90 min for 15–40 sessions) improved multiple outcomes. Tender point counts dropped by ~6 points and pain-pressure thresholds rose (SMD +0.57)[5], with modest pain score reductions (VAS difference ~5 points)[5] and better sleep and quality-of-life. These findings suggest potential benefit but are based on preliminary trials (Kulshreshtha 2024).

·  Post-concussive Headache – Limited evidence suggests HBOT may relieve some headache syndromes. A Cochrane review pooled 3 small trials of acute migraine and found HBOT increased the chance of pain relief vs sham (relative risk ~1.5)[6], though evidence quality was low and no benefit was seen for preventing attacks. HBOT for chronic headaches remains experimental (Bennett 2015).

PBM

·  Neck and Back Pain – A systematic review of 16 trials (820 patients) found that low-level laser PBM (red/infrared) can significantly reduce chronic neck pain. Pooled results showed an ≈20 mm greater VAS pain improvement (0–100 mm scale) vs placebo[7], and pain relief persisted up to 22 weeks post-therapy[8]. Only mild, transient side effects (e.g. skin warmth) were noted (Chow 2009). Evidence in low back pain is mixed; some trials report benefit while others using suboptimal dosages found no significant pain or disability change[9].

·  Knee Osteoarthritis – PBM has shown analgesic effects in degenerative joint pain. A network meta-analysis of 13 RCTs (n=673) reported that PBM significantly reduced knee OA pain compared to sham (pooled SMD ~0.96)[10], although improvements in WOMAC function or stiffness were not consistently significant[11]. Notably, only specific light parameters were effective – wavelengths around 904 nm or 785–850 nm yielded the greatest pain reduction[12] – underscoring dose-dependence (Fan 2024).

·  Neuropathic Pain – Preliminary studies indicate PBM may alleviate peripheral neuropathic pain. In diabetic peripheral neuropathy, trials have observed reduced neuropathic pain scores and even improved nerve conduction velocities with PBM[13]. A small pilot in post-herpetic neuralgia (laser 650 nm, 16 sessions) reported striking pain relief: 11 of 15 patients had complete resolution of pain (VAS 0) and the remainder improved to mild pain[14]. While promising, these outcomes in neuropathy need confirmation in larger controlled studies (Korada 2023; Mukhtar 2020).

·  Comparative Note: Both HBOT and PBM have been associated with pain reductions in select chronic pain populations, but their roles appear adjunctive. PBM outcomes are highly contingent on correct dose parameters (appropriate wavelength, irradiance, and sufficient treatment course)[15]. HBOT, meanwhile, shows potential benefit in certain refractory pain syndromes (e.g. CRPS, fibromyalgia) but evidence comes from small or exploratory trials. Neither modality is a stand-alone “cure,” and results vary by condition.

How It Might Work

HBOT: By raising oxygen availability in blood and tissues, HBOT may counteract hypoxia-driven inflammation and support tissue healing. Increased plasma O₂ tension improves microcirculation and can reduce edema and ischemia in injured tissues[16]. Both animal and human studies suggest HBOT attenuates pain partly via anti-inflammatory effects – for example, down-regulating overactive glial cells and inflammatory cytokines involved in chronic pain sensitisation[17] (preclinical). The net result may be a reset of aberrant nociceptive signaling pathways contributing to chronic pain.

PBM: Red and near-infrared light can penetrate tissues and is absorbed by mitochondrial chromophores (especially cytochrome-c-oxidase)[18]. This photochemical activation enhances cellular respiration (ATP production) and triggers redox signalling that modulates inflammation and promotes tissue repair. PBM has been shown to reduce the release of pro-inflammatory mediators and can increase local blood flow, which together may lower peripheral nerve sensitivity and muscle spasm (preclinical). In central pain, transcranial PBM (tPBM) is being studied for its neuromodulatory effects – early studies indicate it might influence cortical activity and cerebral blood flow, potentially reducing central sensitisation and headache intensity. Similar analgesic trends are reported in PBM trials for arthritis pain (see Arthritis card).

Evidence Quality & Research Gaps

Current evidence is limited by heterogeneity and small sample sizes. Studies vary widely in HBOT/PBM protocols (pressure or wavelength/dosage, session length, total sessions) and outcome measures, making comparisons difficult. Blinding remains a challenge: patients can sometimes sense pressure changes (HBOT) or warmth/tingling (PBM), which may bias placebo-controlled trials. Many positive findings come from exploratory or unblinded studies, so true efficacy is uncertain. The durability of pain relief also varies – some benefits waned after treatment, underscoring the need to assess long-term outcomes. PBM in particular shows a narrow therapeutic window: inappropriate dose (too low or high power, or insufficient sessions) can yield null results[9]. Meanwhile, high-quality HBOT trials for chronic pain are few – evidence is promising (e.g. large pain drops in fibromyalgia and CRPS) but of low certainty[19]. Both interventions are best considered adjuncts to standard care. More robust, sham-controlled trials are needed, with standardized pain and function endpoints and tracking of medication usage, to validate these modalities’ roles in chronic pain management.

Sources

• Kiralp M.Z. et al. (2004). Effectiveness of hyperbaric oxygen therapy in the treatment of complex regional pain syndrome. J. Int. Med. Res., 32(3):258–62. DOI: 10.1177/147323000403200304[20]
• Hájek M. et al. (2024). The Effectiveness of Hyperbaric Oxygen Treatment in Patients with Complex Regional Pain Syndrome: A Retrospective Case Series. Int. J. Med. Sci., 21(11):2021–30. DOI: 10.7150/ijms.97513[2][4]
• Kulshreshtha P. et al. (2024). Assessment of the Efficacy and Safety of Hyperbaric Oxygen Therapy on Pain in Patients with Fibromyalgia: A Systematic Review and Meta-analysis of Randomised Controlled Studies. J. Med. Evidence, 5(1):40–54. DOI: 10.4103/JME.JME_102_23[5]
• Bennett M.H. et al. (2015). Normobaric and hyperbaric oxygen therapy for migraine and cluster headache. Cochrane Database Syst Rev., (12):CD005219[6]
• Chow R.T. et al. (2009). Efficacy of low-level laser therapy in the management of neck pain: a systematic review and meta-analysis of randomised controlled trials. Lancet, 374(9705):1897–908[21][8]
• Fan T. et al. (2024). A systematic review and network meta-analysis on the optimal wavelength of low-level light therapy in treating knee osteoarthritis symptoms. Aging Clin. Exp. Res., 35(4):937–948[12]
• Korada H.Y. et al. (2023). Effectiveness of Photobiomodulation Therapy on Neuropathic Pain, Nerve Conduction and Plantar Pressure Distribution in Diabetic Peripheral Neuropathy – A Systematic Review. Curr. Diabetes Rev., 19(9):e290422204244[13]
• Mukhtar R. et al. (2020). Role of low-level laser therapy in post-herpetic neuralgia: a pilot study. Lasers Med. Sci., 35(8):1759–64[14]

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[13] Effectiveness of Photobiomodulation Therapy on Neuropathic Pain, Nerve Conduction and Plantar Pressure Distribution in Diabetic Peripheral Neuropathy - A Systematic Review - PubMed

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https://www.sciencedirect.com/science/article/abs/pii/S1011134425001083

Overview

Post-viral fatigue syndromes (such as ME/CFS and Long COVID) are characterised by prolonged exhaustion, “brain fog” (cognitive impairment), autonomic dysfunction, and diminished quality of life[1][2]. Hyperbaric oxygen therapy (HBOT) and photobiomodulation (PBM, red to near-infrared light) are being explored as adjunctive interventions to support cellular bioenergetics and modulate inflammation. HBOT increases tissue oxygen availability and may trigger regenerative anti-inflammatory pathways[2], while PBM is thought to stimulate mitochondrial function and microcirculation, potentially alleviating fatigue and cognitive symptoms[3].

Key Findings

HBOT

• Long COVID RCT (40 sessions): A sham-controlled trial (n=73, post-COVID condition) using 2.0 ATA HBOT 90 min/day (with air breaks) for 40 sessions demonstrated significant improvements vs sham in global cognition (attention/executive function, Cohen’s d ≈0.5, p<0.05) and in patient-reported energy/fatigue (Cohen’s d = 0.52, p=0.029)[4]. HBOT recipients also showed associated increases in cerebral blood perfusion and microstructural changes on MRI in brain regions tied to cognitive function[5] (Zilberman-Itskovich et al., 2022).
• Long COVID RCT (10 sessions): In a smaller double-blind trial (n=80, mixed long COVID) with 10 HBOT sessions (100% O₂ at 2.4 ATA, 90 min over 6 weeks), both HBOT and sham groups improved similarly. No significant between-group differences were seen at 13 weeks in physical functioning scores (e.g. RAND-36 Physical Function +0.63 vs sham; 95%CI –7.04 to 8.29)[6]. The authors concluded that 10 sessions of HBOT did not confer short-term benefits over placebo, although HBOT was well-tolerated (no serious adverse events)[7] (Kjellberg et al., 2025).
• Observational registry: In a real-world prospective registry (n=232 long COVID patients, median 40 sessions ~2.0 ATA), 56–63% of patients reported a clinically relevant ≥10-point improvement in SF-36 quality-of-life scores at 3 months post-HBOT[8]. However, 13–19% experienced a ≥10-point worsening[8]. Domains with the most frequent gains were social and physical functioning, vitality (energy/fatigue) and cognitive symptoms[9] (van Berkel et al., 2025).
• Inflammation markers: A meta-analysis in ulcerative colitis patients (13 studies, n=780) found adjunct HBOT led to significantly reduced inflammatory cytokines (TNF-α, IL-6) with large effect sizes (standardised mean differences ~–2.0 to –2.5) and an increase in anti-inflammatory IL-10 (SMD +2.40)[10]. This suggests HBOT may exert systemic anti-inflammatory effects relevant to post-viral fatigue syndromes (Chen et al., 2021).

PBM

• Immune modulation in COVID-19: A pilot RCT in hospitalized COVID-19 patients (n=52) applied PBM via 8 LEDs (620–635 nm, 0.12 W/cm², 45 J/cm² per site) twice daily for 3 days. Treated patients showed a sharp reduction in serum pro-inflammatory cytokines IL-6 (–82.5%±4) and TNF-α (–82.4%±8) by 72 hours (p<0.001)[11], whereas levels in the placebo group stayed the same or rose. No adverse effects were reported[11] (Marashian et al., 2022).
• Long COVID “brain fog”: An open-label pilot study in Long COVID cognitive impairment compared 4 weeks of transcranial PBM (helmet device, 1070 nm) vs whole-body PBM (bed with 660 nm + 850 nm); 12 sessions were given to each group (n=7+7). Both transcranial and whole-body PBM were associated with significant improvements on cognitive tests (e.g. MoCA, Trail-Making A/B, processing speed; p<0.05) after treatment[12], accompanied by supportive EEG changes[13] (Bowen & Arany, 2023).
• Cognitive function reviews: A systematic review of tPBM (35 human studies) reported that 83% (29/35) of studies showed improved cognitive performance after PBM interventions[14]. All nine studies in memory impairment or dementia reported positive effects, as did 7 of 8 trials in traumatic brain injury[14]. Common effective tPBM protocols in clinical populations used ~810 nm near-infrared light at ~20–25 mW/cm² irradiance delivering 1–10 J/cm² per session[15] (Lee et al., 2023).
• Mood and fatigue relevance: In a sham-controlled pilot trial for major depression, transcranial PBM (823 nm LED, ~36 mW/cm², ~65 J/cm², 20–30 min to bilateral dorsolateral prefrontal cortex, 2×/week for 8 weeks) was associated with medium-to-large antidepressant effects (Hamilton Depression Rating score improvement Cohen’s d = 0.75–1.5 depending on analysis) and was well tolerated[16]. Participants also reported improved cognitive throughput and no serious side effects (Cassano et al., 2018), suggesting potential applicability to “brain fog” and fatigue-related mood symptoms.

How It Might Work

• HBOT (human mechanisms): By delivering oxygen at above-atmospheric pressure, HBOT supersaturates tissues with O₂, which may support oxidative phosphorylation (ATP production) and tissue repair. Repeated HBOT induces regenerative pathways – for example, mobilising stem/progenitor cells (circulating CD34⁺ cells ~2× after one 2.0 ATA session, ~8× after 20 sessions)[17][18] – and has been observed to lengthen telomeres and reduce senescent immune cells in adults[19][20], indicating possible reversal of inflammation-related damage.
• PBM (preclinical mechanisms): Red and NIR light at low irradiance penetrate tissues and are absorbed by mitochondrial chromophores (notably cytochrome-c oxidase). This can enhance electron transport and ATP synthesis, while triggering redox signalling. In models, PBM light can dissociate inhibitory nitric oxide from CCO and improve cellular respiration[21]. PBM has been shown to boost cerebral metabolism and neuroplasticity and to downregulate excessive inflammation and oxidative stress[22], which aligns with the needs of post-viral fatigue and cognitive dysfunction.

Evidence Quality & Research Gaps

Current evidence is preliminary and heterogeneous. Most studies are small and vary in HBOT/PBM dosages, timing, and endpoints, making comparisons difficult. Blinding and placebo effects are challenges – e.g. a sham HBOT group showed notable improvements alongside treatment[6], and an uncontrolled registry saw some patients worsen after HBOT[8]. Safety profiles so far appear acceptable (no serious adverse events reported for either therapy[7][16]), but data on long-term outcomes are limited (though one study noted sustained benefits 1 year post-HBOT[23][24]). Both HBOT and PBM are being investigated as adjuncts rather than standalone cures. Larger, well-powered sham-controlled trials in well-defined Long COVID populations are needed to confirm efficacy on fatigue, cognitive (“brain fog”), exercise tolerance and to determine optimal treatment parameters and durability of responses.

Sources

• Zilberman-Itskovich S. et al. (2022). Hyperbaric oxygen therapy improves neurocognitive functions and symptoms of post-COVID condition: randomized controlled trial. Sci Rep, 12(1):11252. DOI: 10.1038/s41598-022-15565-0[4][5]
• Hadanny A. et al. (2024). Long term outcomes of hyperbaric oxygen therapy in post COVID condition: longitudinal follow-up of a randomized controlled trial. Sci Rep, 14(1):3604. DOI: 10.1038/s41598-024-53091-3[23][24]
• Kjellberg A. et al. (2025). Ten sessions of hyperbaric oxygen versus sham treatment in patients with long COVID (HOT-LoCO): a randomised, placebo-controlled, double-blind, phase II trial. BMJ Open, 15(4):e094386. DOI: 10.1136/bmjopen-2024-094386[6][7]
• van Berkel J. et al. (2025). Hyperbaric oxygen therapy for long COVID: a prospective registry. Sci Rep, 15(1):28351. DOI: 10.1038/s41598-025-11539-0[8][9]
• Chen P. et al. (2021). Systematic review with meta-analysis: effectiveness of hyperbaric oxygenation therapy for ulcerative colitis. Ther Adv Gastroenterol, 14:17562848211023394. DOI: 10.1177/17562848211023394[25]
• Hachmo Y. et al. (2020). Hyperbaric oxygen therapy increases telomere length and decreases immunosenescence in isolated blood cells: a prospective trial. Aging (Albany NY), 12(22):22445–22456. DOI: 10.18632/aging.202188[19][20]
• Marashian S.M. et al. (2022). Photobiomodulation improves serum cytokine response in mild to moderate COVID-19: the first randomized, double-blind, placebo controlled, pilot study. Front Immunol, 13:929837. DOI: 10.3389/fimmu.2022.929837[11]
• Bowen R. & Arany P.R. (2023). Use of either transcranial or whole-body photobiomodulation treatments improves COVID-19 brain fog. J Biophotonics, 16(8):e202200391. DOI: 10.1002/jbio.202200391[12][13]
• Lee T.L. et al. (2023). Can transcranial photobiomodulation improve cognitive function? A systematic review of human studies. Ageing Res Rev, 83:101786. DOI: 10.1016/j.arr.2022.101786[14][15]
• Cassano P. et al. (2018). Transcranial photobiomodulation for the treatment of major depressive disorder: the ELATED-2 pilot trial. Photomed Laser Surg, 36(12):634–646. DOI: 10.1089/pho.2018.4490[16][22]

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Overview

Cancer treatments such as chemotherapy, radiotherapy, and surgery can cause severe side effects (e.g. oral mucositis, chronic radiation injuries, wound-healing problems). Hyperbaric oxygen therapy (HBOT) and photobiomodulation (PBM, low-level red/infrared light) are being explored as supportive care interventions to improve healing and symptom relief, helping patients tolerate and complete their cancer therapy[1]. These modalities are not anticancer treatments but aim to reduce therapy-related complications and improve quality of life.

Key Findings

HBOT:
- Late radiation injuries: A 2023 Cochrane review of 18 RCTs (n=1071) found that HBOT (typical dose ~100% O₂ at 2.0–2.5 ATA for ~90 min, 30–40 sessions) improved resolution of late radiation tissue injuries in head-neck, bladder, and rectal tissues (complete healing/improvement in 39% more patients vs controls, RR ~1.4)[2][3]. HBOT also markedly reduced wound breakdown in irradiated head-neck surgical sites (RR 0.24, 95% CI 0.06–0.94)[4].
- Radiation proctitis: In a double-blind RCT for chronic refractory radiation proctitis (n=120), HBOT at 2.0 ATA (90 min for 30 sessions) led to 89% of patients achieving clinical improvement vs 63% with sham (p=0.0009), yielding a 32% absolute risk reduction (NNT ~3) in moderate-to-severe symptoms[5][6]. Treated patients had discontinuation of other interventions and improved bowel-specific quality of life.
- Osteoradionecrosis (ORN): Cohort studies suggest adjunctive HBOT can promote bone and mucosal healing in ORN of the jaw (e.g. improved mucosal coverage and pain)[7][8]. However, evidence is mixed: a multicenter trial reported no added benefit of HBOT in early-stage (Grade I) ORN when compared to standard care[9]. HBOT is often used prophylactically (e.g. 20–30 dives at 2.4 ATA pre- and 10 dives post-dental extraction) in irradiated patients to reduce ORN risk[10].
- Wound healing in irradiated tissue: HBOT has been associated with improved healing of surgical flaps and chronic wounds in previously irradiated areas. For example, pooled RCT data show significantly lower postoperative wound dehiscence in irradiated head-neck cancer patients receiving HBOT (roughly 76% relative risk reduction)[4]. Clinically, HBOT is usually combined with standard wound care (and surgery if needed) in these settings.

PBM (Red Light Therapy):
- Oral mucositis prevention: Evidence-based guidelines (MASCC/ISOO 2019) recommend PBM therapy to prevent severe oral mucositis (OM) in patients undergoing head & neck radiotherapy (with or without chemotherapy) and in stem cell transplant conditioning[1]. Effective PBM protocols use red or near-infrared light (commonly 630–660 nm) delivered intraorally at specific dosimetry (e.g. ~6 J/cm² per point, with power ~20–100 mW/cm²) prior to and during cancer treatment[11]. Trials adhering to these parameters showed significant reductions in OM incidence and severity.
- Clinical outcomes in mucositis: Multiple RCTs and meta-analyses demonstrate that PBM can markedly reduce the severity of therapy-induced mucositis and associated pain. A 2023 systematic review (10 trials, n=759 head-neck cancer patients) reported that prophylactic PBM (lasers/LEDs 632–850 nm) halved the occurrence of grade 3–4 OM and shortened the duration of mucositis, with treated patients experiencing lower peak pain scores and better oral functional quality of life[12]. PBM has also been linked to reduced need for opioid analgesics, fewer feeding tube placements, and fewer unplanned treatment breaks in comparison to controls in these studies[13][12].
- Other side-effect applications: Emerging studies suggest PBM may benefit other cancer therapy side effects. For example, small trials in breast cancer found PBM (e.g. red light-emitting diodes, ~3–6 J/cm²) can lessen acute radiodermatitis severity[14][15]. Pilot studies have also explored PBM for lymphedema and neuropathy, but data remain limited.
- Safety: PBM as used in supportive care has not shown any promotion of tumor growth or recurrence to date[16]. No significant adverse events have been reported in human trials for mucositis; PBM is non-invasive and painless. Professional guidelines emphasize using recommended dose parameters to ensure safety and efficacy[16].

Comparison: HBOT is primarily applied for chronic, late-arising radiation injuries (often months to years after therapy), whereas PBM is typically used during active treatment to mitigate acute toxicities. In practice, the two adjuncts address different phases of supportive care – HBOT for repairing established damage in hypoxic irradiated tissues, and PBM for preventing or reducing immediate mucosal and skin reactions[17][1]. Both modalities aim to improve patients’ tolerance of cancer treatments and maintain treatment continuity by reducing side-effect burden.

How It Might Work

HBOT: Breathing 100% oxygen under high pressure increases tissue oxygenation and has been shown (in both preclinical models and patient observations) to stimulate new blood vessel growth and collagen formation in damaged tissue[18][19]. This enhanced perfusion can counteract radiation-induced hypoxia and fibrosis, supporting wound healing in irradiated areas. HBOT may also down-regulate chronic inflammation mediated by hypoxia-inducible factors in late radiation injury.
PBM: Low-level red/infrared light is absorbed by mitochondrial cytochrome-c oxidase in cells, boosting ATP production and modulating reactive oxygen species and NF-κB signaling[20]. Preclinical studies indicate that PBM can reduce the release of pro-inflammatory cytokines (e.g. TNF-α, IL-1, IL-6) and promote epithelial regeneration and angiogenesis in mucosal tissues[21][20]. Clinically, this mechanism translates into faster healing of oral mucosa and reduction in pain. Both HBOT and PBM ultimately support the body’s repair processes, with the goal of mitigating treatment-related injury while not interfering with the anticancer effects of therapy.

Evidence Quality & Research Gaps

Current evidence is promising but has limitations. The clinical studies to date are heterogeneous in protocols (varying oxygen pressures, light wavelengths/doses) and endpoints, making direct comparisons difficult. Many HBOT findings come from small trials or observational series; benefits seem context-dependent (e.g. HBOT appears effective in established ORN or soft-tissue necrosis, but one trial showed no benefit for early mild ORN[9]). PBM evidence for oral mucositis is stronger, with consistent positive outcomes, but trials differ in laser parameters and timing. Both modalities are intended as adjunctive therapies, and neither replaces standard cancer treatment. Larger, sham-controlled trials are needed to confirm optimal dosing schedules and to define which patient subgroups benefit most. Long-term oncologic safety data are also important – so far no increase in tumor recurrence has been seen with supportive PBM[16], and HBOT has not shown any negative effect on survival[22][23], but continued vigilance is warranted. Overall, a cautious interpretation of the existing data is advised[24], and further research (including standardized protocols and cost-effectiveness analyses) is encouraged to solidify these therapies’ roles in cancer supportive care.

Sources

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