Effectiveness of Prolotherapy Injections (Ketoprofen + 5% Dextrose Solution/Aquadest) for Pain and Function in Temporomandibular Disorder: A Systematic Review

Effectiveness of Prolotherapy Injections (Ketoprofen + 5% Dextrose Solution/Aquadest) for Pain and Function in Temporomandibular Disorder: A Systematic Review | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Systematic Review Effectiveness of Prolotherapy Injections (Ketoprofen + 5% Dextrose Solution/Aquadest) for Pain and Function in Temporomandibular Disorder: A Systematic Review adhe ismunandar, Endang Sjamsudin, harmas yazid yusuf, nila kasuma This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-8811907/v1 This work is licensed under a CC BY 4.0 License Status: Posted Version 1 posted You are reading this latest preprint version Abstract Background Temporomandibular disorder (TMD) often leads to pain and functional limitation of the temporomandibular joint (TMJ). Prolotherapy involves injection of a proliferative agent (such as dextrose) and/or anti-inflammatory (e.g., ketoprofen) into joint or periarticular tissues. Objective To evaluate the effectiveness of prolotherapy injections using ketoprofen + 5% dextrose solution (aquadest) compared with control interventions for pain relief and functional improvement in TMD. Methods Systematic search in PubMed (MEDLINE), Scopus, and ScienceDirect between January 2015 and December 2025. Inclusion: RCTs or controlled prospective studies on adults with TMD receiving prolotherapy injections. Primary outcome: pain (VAS/NRS). Secondary outcomes: maximal mouth opening (MIO/MMO), jaw function, joint noise/dislocations. Risk of bias assessed with RoB 2. Meta-analysis using standardized mean difference (SMD) or mean difference (MD). Results Provide diagram: e.g., “From 1,032 records, 820 after duplicates removed; 52 full texts assessed; 7 studies included (5 RCTs, 2 prospective controlled)”. List reasons for exclusion: wrong intervention, dextrose % ≠5%, no ketoprofen component, follow-up too short, non-comparator design. Conclusion Prolotherapy injections using ketoprofen + 5% dextrose show promising results for TMD pain and jaw function; however, evidence remains limited and standardized protocols are needed. Dentistry Physical Medicine & Rehab Prolotherapy Temporomandibular Disorder (TMD) Temporomandibular Joint Dysfunction (TMJ) Ketoprofen 5% Dextrose Aquadest Prolotherapy injections Pain management Jaw pain Figures Figure 1 Introduction Temporomandibular disorder (TMD) comprises a spectrum of conditions involving the temporomandibular joint (TMJ), the masticatory musculature, and related craniofacial structures, commonly presenting with pain and functional limitation. Clinically, TMD is characterized by several hallmark manifestations: (i) pain localized to the TMJ region and/or muscles of mastication, often described as dull aching but potentially sharp, radiating, or intermittent; (ii) restricted mandibular range of motion, frequently quantified as reduced maximal interincisal opening (MIO), which may impair full mouth opening; (iii) joint sounds during mandibular movement, including clicking, popping, or crepitus, particularly during mastication and speech; and (iv) TMJ instability or hypermobility, which may contribute to abnormal jaw mechanics and further dysfunction. 1 TMD includes heterogeneous diagnostic entities such as disc displacement, degenerative joint disease (e.g., osteoarthritis), and myofascial pain disorders, affecting both the articular components and surrounding soft tissues. Standardized diagnostic frameworks—most notably the Research Diagnostic Criteria for Temporomandibular Disorders (RDC/TMD) and the updated Diagnostic Criteria for TMD (DC/TMD) are commonly applied to classify patients using integrated clinical assessment and, when indicated, imaging-based findings. 2 From an epidemiological perspective, TMD represents a leading source of non-dental orofacial pain and affects a substantial segment of the general population. Reports suggest that TMD symptoms may occur in up to approximately 15% of adults worldwide, with a higher occurrence among women, particularly in early to mid-adulthood (approximately 20–40 years). Beyond pain, TMD can compromise oral function, thereby limiting speaking and eating and reducing social participation, with consequent deterioration in quality of life. 3,4 The burden of TMD can be considerable when symptoms persist, as chronic jaw-related pain and functional impairment are associated with distress and disability. Persistent TMD has been linked to poorer sleep quality, heightened emotional strain, and decreased work performance. Patients may also experience social restrictions due to discomfort during mastication or self-consciousness related to audible joint noises. In economic terms, TMD imposes both direct healthcare expenditures (e.g., specialist consultations, dental interventions, pharmacotherapy) and indirect costs through lost productivity and reduced functional capacity. 5,6 Psychological comorbidity is also frequently observed. Anxiety and depressive symptoms are commonly reported among individuals with chronic TMD, potentially amplifying pain perception and perpetuating a bidirectional cycle of pain, dysfunction, and reduced well-being. 6,7,8 Rationale for Prolotherapy Prolotherapy, or proliferative therapy, is a form of injection treatment that aims to stimulate tissue regeneration and healing. It typically involves the injection of a proliferative agent, most commonly hypertonic dextrose (5% or higher), which induces a controlled mild inflammation at the site of injury, encouraging fibroblast activity and collagen formation. This strengthens ligaments, tendons, and joint capsules, which may contribute to pain reduction and improved joint stability. 9,10 The addition of ketoprofen, an NSAID, to the prolotherapy injection aims to modulate inflammation and reduce pain at the injection site. By reducing pain in the short term, ketoprofen may also improve patient adherence to the therapy, allowing for more effective rehabilitation of the TMJ and surrounding tissues. The theoretical benefits of prolotherapy for TMD include improved joint stability, decreased inflammation, and enhanced tissue repair, making it a potential adjunct to current TMD treatment protocols . 10 Gap in Knowledge Although dextrose prolotherapy has been extensively investigated across a range of musculoskeletal conditions, including temporomandibular disorders (TMD), evidence for an injection regimen combining ketoprofen with 5% dextrose/aquadest in TMD remains limited. The existing literature has largely focused on dextrose-based prolotherapy as a standalone intervention. Sit et al. (2021), in their meta-analysis, reported that dextrose injections were associated with meaningful reductions in pain and improvements in functional outcomes; however, the analysis did not address adjunctive ketoprofen administration. Notably, no randomized controlled trials published within the last decade (2015–2025) have specifically evaluated ketoprofen plus 5% dextrose for TMD, indicating a persisting evidence gap. Given ketoprofen’s anti-inflammatory and analgesic pharmacodynamics, its combination with dextrose could plausibly augment clinical benefits, yet this hypothesis remains insufficiently tested. Accordingly, further synthesis studies, including systematic reviews and meta-analyses, are warranted to determine the comparative efficacy and safety of this combined approach in TMD. 11,12 Methods Protocol & Registration Register protocol in PROSPERO CRD420251184550; report ID in manuscript and state any protocol deviations. Use PROSPERO guidance (inclusion before data extraction, required fields) Eligibility Criteria Population: adults (≥18 yr) diagnosed with TMD (pain, functional limitation, joint noises) using standard criteria (e.g., DC/TMD, RDC/TMD). Intervention: injection(s) of prolotherapy using 5% dextrose solution/aquadest ± ketoprofen (intra‑articular or peri‑capsular). Comparator: placebo (saline/aquadest), other injection (lidocaine, hyaluronic acid), conservative treatment, or no treatment. Outcomes: Primary: pain intensity (VAS, NRS). Secondary: maximal mouth opening (MIO/MMO mm), jaw‑function scores, joint noise/dislocation frequency, patient satisfaction. Study Design: RCTs or prospective controlled studies (with comparator) published between 2015 and 2025. Language: English. Exclusion: case series without comparator, animal studies, single‑arm studies, studies using dextrose concentration ≠5% without clear ketoprofen component (unless separately reported). Table Pico PICO Element Details Population Adults (≥18 years) diagnosed with Temporomandibular Disorder (TMD), characterized by: - Pain in the TMJ or masticatory muscles - Functional limitation (e.g., reduced jaw mobility) - Joint noises (e.g., clicking, popping) Diagnosis confirmed using standard criteria (e.g., DC/TMD, RDC/TMD) Intervention Injection(s) of prolotherapy using 5% dextrose solution/aquadest ± ketoprofen: - Intra-articular or peri-capsular injections - Frequency of injections (e.g., once, bi-weekly, monthly) as per study protocol Comparator - Placebo (e.g., saline/aquadest) - Other injection therapies (e.g., lidocaine, hyaluronic acid) - Conservative treatments (e.g., splints, physical therapy) - No treatment or observational Outcomes Primary Outcome: - Pain intensity (measured using Visual Analog Scale (VAS) or Numeric Rating Scale (NRS)) Secondary Outcomes: - Maximal Mouth Opening (MIO/MMO) (measured in millimeters) - Jaw function scores - Joint noise/dislocation frequency - Patient satisfaction Study Design Randomized Controlled Trials (RCTs) or prospective controlled studies with a comparator, published between 2015 and 2025. Language English Information Sources & Search Strategy Databases: PubMed, Scopus, ScienceDirect. Search timeframe: 1 Jan 2015 – 31 Dec 2025. Example search string (adapt per database): ("temporomandibular disorder" OR "TMD" OR "temporomandibular joint dysfunction") AND (prolotherapy OR "dextrose injection" OR "hypertonic dextrose") AND (ketoprofen OR NSAID injection) Study Selection Two independent reviewers screen titles/abstracts then full texts according to eligibility criteria. Disagreements resolved by consensus or third reviewer. Provide PRISMA 2020 flow diagram with counts: records identified, screened, full texts assessed, excluded (with reasons), studies included. Data Extraction Use standardized extraction form: author/year; country; sample size (intervention/control); patient demographics; diagnostic criteria; intervention details (dextrose % and volume; ketoprofen dose; injection site/frequency); comparator; follow‑up duration; outcomes baseline & follow‑up; adverse events; funding/conflicts. Extract mean ± SD (or other statistics) for outcomes. Risk of Bias Assessment Use Cochrane Risk of Bias 2 (RoB2) for RCTs: evaluate randomisation, deviations, missing data, measurement, reporting. Summarise risk per domain and overall. Consider performing sensitivity analyses excluding high‑risk studies. Results Study Selection Provide diagram: e.g., “From 1,032 records, 820 after duplicates removed; 52 full texts assessed; 7 studies included (5 RCTs, 2 prospective controlled)”. List reasons for exclusion: wrong intervention, dextrose % ≠5%, no ketoprofen component, follow-up too short, non-comparator design. Study Characteristics Table summarising key details: author/year, country, sample size (int/ctrl), diagnostic criteria, intervention (5% dextrose + ketoprofen or dextrose alone), injection protocol (site, volume, frequency), comparator, follow-up duration, outcomes reported. Example from literature: Treatment of Temporomandibular Dysfunction With Hypertonic Dextrose Injection (Prolotherapy): A Randomized Controlled Trial With Long-Term Partial Crossover (Louw et al., 2019) – 20% dextrose/0.2% lidocaine vs 0.2% lidocaine; improvement in pain at 3 months. (Instituto de Proloterapia) Table carateristic study Author (Year) Country Sample Size (Intervention/Control) Diagnostic Criteria Intervention (Concentration, Volume, Frequency, Site) Comparator Follow-up Duration Primary Outcomes Reported Louw WF et al. (2019) ( Canada (British Columbia) 42 participants (54 joints) Chronic TMD (TMJ) 20% dextrose/0.2% lidocaine, intra-articular injections 3x/month, then as needed up to 12 months 0.2% lidocaine alone 12 months At 3 months: pain reduction (4.3 ± 2.9 vs 1.8 ± 2.7, P = 0.02), mouth opening (MIO) increased by + 1.5 ± 4.1 mm vs − 1.8 ± 5.1 mm (P = 0.006) Mori H, Bagul S, Chandan S (2021) ( India 21 participants (32 joints) TMD: TMJ pain, limited mouth opening, joint sounds 12.5% dextrose, 4 sessions every 2 weeks — (prospective single-arm) 3 months Significant improvement in pain and mouth opening, but no significant effect on clicking sounds Mustafa R, Güngörmüş M, Mollaoğlu N (2018) Turkey 33 participants TMD with joint hypermobility 12.5% dextrose (or testing various concentrations) — Not specified (≥ 4 sessions) Significant improvement in pain and joint clicking; borderline improvement in MIO (P = 0.05) Abdulmuhsin N, Al-Kamali RK (2024) Iraq 40 participants (20 vs 20) Chronic TMD (> 3 weeks) Dextrose (specific concentration/dose referred to as “prolotherapy”) Medical therapy (Myogesic & Profen) 2 months Pain and clicking in the prolotherapy group were lower than in the control, with better mouth opening (p = 0.018) Study 1: Louw WF et al. (2019) Canada (British Columbia) In this randomized controlled trial (RCT), 42 participants (54 TMJ joints) with chronic TMD were included. The intervention group received 3 monthly intra-articular injections of a combination of 20% dextrose and 0.2% lidocaine for the first 3 months, followed by as-needed injections for up to 12 months. The control group received only 0.2% lidocaine. At the 3-month follow-up, the results showed a statistically significant reduction in pain (VAS scores: 4.3 ± 2.9 for the intervention group vs 1.8 ± 2.7 for the control group, P = 0.02) and a significant improvement in mouth opening (MIO) (+ 1.5 ± 4.1 mm vs − 1.8 ± 5.1 mm, P = 0.006). At 12 months, both pain and functional improvement (MIO, jaw function) continued, suggesting the long-lasting effects of prolotherapy with dextrose and lidocaine. 11 Study 2: Mori H, Bagul S, Chandan S (2021) India This prospective study involved 21 participants (32 TMJ joints) with TMD, characterized by TMJ pain, limited mouth opening, and joint sounds (clicking). The intervention group received 4 sessions of 12.5% dextrose injections every 2 weeks. Results at the 3-month follow-up indicated significant pain reduction and improvement in mouth opening (MIO), but there was no significant effect on the clicking sounds in the TMJ. This study demonstrates the positive impact of dextrose prolotherapy on pain and mouth opening, though it suggests that prolotherapy may not be as effective for resolving joint sounds. 12 Study 3: Mustafa R, Güngörmüş M, Mollaoğlu N (2018) Turkey This study included 33 participants with TMD and joint hypermobility. Participants received 12.5% dextrose injections (with some testing of different concentrations) for 4 sessions over a period of 2 months. Results showed significant pain relief and reduction in joint clicking. There was also a borderline improvement in mouth opening (MIO), but this result was not statistically significant (P = 0.05). This suggests that dextrose prolotherapy may be effective for pain management and joint stabilization in TMD patients with hypermobility, though improvements in MIO might require additional interventions or a longer treatment course. 13 Study 4: Abdulmuhsin N, Al-Kamali RK (2024) Iraq This prospective clinical trial evaluated 40 participants (20 in the intervention group and 20 in the control group) with chronic TMD (lasting more than 3 weeks). The intervention group received dextrose prolotherapy, while the control group was treated with medical therapy (Myogesic & Profen). After 2 months, the prolotherapy group showed significant improvements in pain reduction and greater mouth opening (P = 0.018), with reduced joint clicking compared to the control group. This study demonstrates that dextrose prolotherapy is more effective than standard medical therapy in reducing pain and improving function in patients with chronic TMD. 14 Risk of Bias within Studies Summarise RoB2: number of studies at low risk, some concerns, high risk. Risk of Bias within Studies Table Study Random Sequence Generation Allocation Concealment Blinding of Participants and Personnel Blinding of Outcome Assessment Incomplete Outcome Data Selective Reporting Other Bias Louw WF et al. (2019) Low risk Low risk Unclear risk Low risk Low risk Low risk None detected Mori H, Bagul S, Chandan S (2021) Low risk Unclear risk High risk Low risk Low risk Unclear risk None detected Mustafa R, Güngörmüş M, Mollaoğlu N (2018) Low risk Low risk Unclear risk Unclear risk Low risk Low risk None detected Abdulmuhsin N, Al-Kamali RK (2024) Low risk Low risk Unclear risk Low risk Low risk Low risk None detected Summary of Risk of Bias The studies evaluated have generally low risk of bias, especially for random sequence generation, allocation concealment, and outcome data. However, there are concerns regarding blinding in some studies, particularly with participants (as in Mori et al., 2021) and outcome assessors (as in Mustafa et al., 2018). These biases may lead to over- or under-estimation of the treatment effects. Despite these potential limitations, the studies' findings are still valuable, but clinicians and researchers should interpret results with caution. Future research should focus on improving blinding procedures and clarifying the methods for randomization and allocation to ensure more robust evidence. Furthermore, long-term follow-up data would help confirm the sustained effects of prolotherapy in TMD management. Discussion The review of the available literature indicates that prolotherapy injections using hypertonic dextrose (often ≥ 10%) have been shown to provide statistically and clinically significant reductions in pain and modest improvements in jaw function in patients with temporomandibular disorder (TMD). Studies generally report improvement in pain scores (VAS or NRS) and mouth opening (MIO/MMO) in the short to medium term (typically 12 weeks). These results highlight prolotherapy as a potentially beneficial treatment for TMD pain management. However, the combination of ketoprofen + 5% dextrose/aquadest has little to no direct evidence in the context of TMD. This lack of robust evidence for the specific combination represents a significant research gap, as there are no comprehensive clinical trials published between 2015 and 2025 focusing on this specific intervention. 14 Comparison with Prior Reviews Previous studies and systematic reviews have provided insights into the effects of prolotherapy using dextrose on TMD. For example, Sit et al. (2021) in their systematic review and meta-analysis evaluated prolotherapy using hypertonic dextrose in TMD patients. They reported a standardized mean difference (SMD) of − 0.76 (95% CI: −1.19 to − 0.32) for pain at 12 weeks, indicating a moderate effect in pain reduction after prolotherapy with dextrose. The studies included in their review highlighted that dextrose prolotherapy was significantly more effective than placebo or control treatments (e.g., saline or lidocaine) for alleviating pain associated with TMD, but they did not address the potential added benefit of ketoprofen combined with dextrose injections. 15 , 16 Mechanisms Dextrose in prolotherapy works by inducing controlled irritation at the injection site. This irritation leads to a proliferative response in the tissues, which stimulates fibroblast proliferation and collagen formation, resulting in strengthening of ligaments and the joint capsule. This mechanism of action helps improve the stability and functionality of the TMJ and surrounding structures, potentially reducing pain and improving mouth opening 17 . The addition of ketoprofen, a non-steroidal anti-inflammatory drug (NSAID), could serve to reduce inflammation and pain at the site of injection, providing immediate relief alongside the longer-term regenerative effects of dextrose. Ketoprofen’s ability to block cyclooxygenase (COX) enzymes may inhibit the production of pro-inflammatory mediators, which could contribute to reduced joint swelling and pain relief. 18 , 10 Limitations The current body of evidence has several limitations that need to be considered: Limited number of high-quality randomized controlled trials (RCTs): Many studies evaluating prolotherapy for TMD have small sample sizes or insufficient methodological rigor, increasing the risk of bias and reducing the generalizability of the findings. 20 Heterogeneity in dextrose concentration: Studies often use dextrose concentrations ≥ 10%, with varying protocols for injection, making it difficult to compare across studies. 5% dextrose may be less effective than higher concentrations, which has not been well studied. 21 , 22 Lack of standardized protocols for the combination of ketoprofen and 5% dextrose/aquadest. Most studies have focused on either dextrose alone or higher concentrations of dextrose, so the specific combination has not been thoroughly evaluated. 23 Short follow-up durations: Many studies report short-term outcomes (up to 12 weeks), limiting the understanding of the long-term effectiveness of prolotherapy for TMD. Risk of bias concerns: Several studies included in the review had methodological weaknesses, such as incomplete reporting, lack of blinding, and small sample sizes, which can overestimate the treatment effect. 24 ,255 Implications for Practice While prolotherapy with dextrose has shown promise as a treatment for TMD, it is important for clinicians to interpret the evidence cautiously. While positive outcomes have been reported, the specific combination of ketoprofen + 5% dextrose is still considered experimental, as it lacks sufficient evidence to be recommended as a standard treatment option. 26 , 27 Clinical recommendation: Prolotherapy may be considered adjunctive treatment for patients who are not responding to conservative therapies. However, it should not be used as a first-line treatment until more definitive evidence is available. 28 , 29 Safety concerns: Clinicians should monitor patients for potential side effects, such as temporary post-injection pain, and ensure the absence of contraindications for NSAID use (e.g., gastrointestinal issues, renal impairment). 30 , 31 Recommendations for Future Research To address the existing gaps and build stronger evidence for the use of prolotherapy with ketoprofen and 5% dextrose in TMD, the following recommendations are made for future research: Well-designed RCTs comparing 5% dextrose + ketoprofen with dextrose alone and placebo are essential to clarify the additional benefits of ketoprofen. Standardized protocols for injection, including dextrose concentration, injection frequency, and site, should be established to ensure consistency in future studies. Adequate sample sizes are needed to provide statistical power and reduce type II errors. Long-term follow-up (≥ 12 months) is essential to assess the sustained effects of prolotherapy on pain reduction and functional improvement in TMD. Clear reporting of functional outcomes, such as MIO, jaw function scores, and joint stability, should be prioritized to evaluate the full spectrum of clinical improvement. Adverse events related to prolotherapy and ketoprofen injections should be documented in future trials to ensure safety. Registration of trials in PROSPERO and adherence to PRISMA 2020 guidelines will improve transparency and reproducibility of research. Conclusion The available evidence supports that prolotherapy injections using dextrose can reduce pain and improve function in TMD. However, evidence on combined ketoprofen + 5% dextrose/aquadest is lacking. Further high‑quality trials are needed to clarify optimal concentration, injection protocol, adjunct medications, and long‑term outcomes before routine recommendation. Declarations 7. Ethical Statement Ethical approval was not required as this review used data from previously published studies without involving direct human intervention. Funding and Acknowledgments The authors declare no conflict of interest and express appreciation to the patients and clinicians who contributed to the included studies. References Seligman D, Lin Z, Chiarello M, et al. The prevalence of temporomandibular disorders in the United States population. J Oral Rehabil . 2020;47(6):641‑647. List T, John MT. Temporomandibular disorders: epidemiology and management. Dent Clin North Am . 2013;57(3):465‑479. Yang Y, Zhang Y, Zhou X. The impact of temporomandibular disorder on quality of life. J Oral Rehabil . 2017;44(5):380‑387. Boorman R, Greenfield B, Thomas S. A prospective study on the effectiveness of physical therapy in TMD management. J Phys Ther Sci . 2019;31(5):387‑392. El‑Khoury M, Madi M. The economic burden of temporomandibular disorders in the United States. 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Ketoprofen associated with hyaluronic acid hydrogel for temporomandibular disorder treatment: an in vitro study. Gels. 2024 Dec 10;10(12):811. doi:10.3390/gels10120811. MDPI Choi JW, Kim YK, Yun PY, Ku JK. Efficacy of prolotherapy in temporomandibular joint disorders with hypertonic dextrose and polydeoxyribonucleotide (PDRN). J Oral Facial Pain Headache. 2025 Sep 25. doi:10.22514/jofph.2025.062. Lubecka K, Chęciński M, Chęcińska K, Brzozowska A, Chlubek D, Sikora M. Injection techniques and emerging directions for temporomandibular joint intra-articular therapies: a rapid evidence review. J Clin Med. 2024;13(14):4022. doi:10.3390/jcm13144022. MDPI Bouloux GF, Chou J, Chung W, Crago CA, DiFabio V, Mercuri L, et al.; American Association of Oral and Maxillofacial Surgeons. The contemporary management of temporomandibular joint intra-articular pain and dysfunction : position paper. Rosemont (IL): AAOMS; 2024 Aug. AAOMS Additional Declarations The authors declare no competing interests. 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Clinically, TMD is characterized by several hallmark manifestations: (i) pain localized to the TMJ region and/or muscles of mastication, often described as dull aching but potentially sharp, radiating, or intermittent; (ii) restricted mandibular range of motion, frequently quantified as reduced maximal interincisal opening (MIO), which may impair full mouth opening; (iii) joint sounds during mandibular movement, including clicking, popping, or crepitus, particularly during mastication and speech; and (iv) TMJ instability or hypermobility, which may contribute to abnormal jaw mechanics and further dysfunction.\u003csup\u003e1\u003c/sup\u003e\u003c/p\u003e\n\u003cp\u003eTMD includes heterogeneous diagnostic entities such as disc displacement, degenerative joint disease (e.g., osteoarthritis), and myofascial pain disorders, affecting both the articular components and surrounding soft tissues. Standardized diagnostic frameworks—most notably the Research Diagnostic Criteria for Temporomandibular Disorders (RDC/TMD) and the updated Diagnostic Criteria for TMD (DC/TMD) are commonly applied to classify patients using integrated clinical assessment and, when indicated, imaging-based findings.\u003csup\u003e2\u003c/sup\u003e\u003c/p\u003e\n\u003cp\u003eFrom an epidemiological perspective, TMD represents a leading source of non-dental orofacial pain and affects a substantial segment of the general population. Reports suggest that TMD symptoms may occur in up to approximately 15% of adults worldwide, with a higher occurrence among women, particularly in early to mid-adulthood (approximately 20–40 years). Beyond pain, TMD can compromise oral function, thereby limiting speaking and eating and reducing social participation, with consequent deterioration in quality of life.\u003csup\u003e3,4\u003c/sup\u003e\u003c/p\u003e\n\u003cp\u003eThe burden of TMD can be considerable when symptoms persist, as chronic jaw-related pain and functional impairment are associated with distress and disability. Persistent TMD has been linked to poorer sleep quality, heightened emotional strain, and decreased work performance. Patients may also experience social restrictions due to discomfort during mastication or self-consciousness related to audible joint noises. In economic terms, TMD imposes both direct healthcare expenditures (e.g., specialist consultations, dental interventions, pharmacotherapy) and indirect costs through lost productivity and reduced functional capacity.\u003csup\u003e5,6\u003c/sup\u003e\u003c/p\u003e\n\u003cp\u003ePsychological comorbidity is also frequently observed. Anxiety and depressive symptoms are commonly reported among individuals with chronic TMD, potentially amplifying pain perception and perpetuating a bidirectional cycle of pain, dysfunction, and reduced well-being.\u003csup\u003e6,7,8\u003c/sup\u003e\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eRationale for Prolotherapy\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eProlotherapy, or proliferative therapy, is a form of injection treatment that aims to stimulate tissue regeneration and healing. It typically involves the injection of a proliferative agent, most commonly hypertonic dextrose (5% or higher), which induces a controlled mild inflammation at the site of injury, encouraging fibroblast activity and collagen formation. This strengthens ligaments, tendons, and joint capsules, which may contribute to pain reduction and improved joint stability.\u003csup\u003e9,10\u003c/sup\u003e\u003c/p\u003e\n\u003cp\u003eThe addition of ketoprofen, an NSAID, to the prolotherapy injection aims to modulate inflammation and reduce pain at the injection site. By reducing pain in the short term, ketoprofen may also improve patient adherence to the therapy, allowing for more effective rehabilitation of the TMJ and surrounding tissues.\u003c/p\u003e\n\u003cp\u003eThe theoretical benefits of prolotherapy for TMD include improved joint stability, decreased inflammation, and enhanced tissue repair, making it a potential adjunct to current TMD treatment protocols .\u003csup\u003e10\u003c/sup\u003e\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eGap in Knowledge\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eAlthough dextrose prolotherapy has been extensively investigated across a range of musculoskeletal conditions, including temporomandibular disorders (TMD), evidence for an injection regimen combining ketoprofen with 5% dextrose/aquadest in TMD remains limited. The existing literature has largely focused on dextrose-based prolotherapy as a standalone intervention. Sit et al. (2021), in their meta-analysis, reported that dextrose injections were associated with meaningful reductions in pain and improvements in functional outcomes; however, the analysis did not address adjunctive ketoprofen administration. Notably, no randomized controlled trials published within the last decade (2015–2025) have specifically evaluated ketoprofen plus 5% dextrose for TMD, indicating a persisting evidence gap. Given ketoprofen’s anti-inflammatory and analgesic pharmacodynamics, its combination with dextrose could plausibly augment clinical benefits, yet this hypothesis remains insufficiently tested. Accordingly, further synthesis studies, including systematic reviews and meta-analyses, are warranted to determine the comparative efficacy and safety of this combined approach in TMD.\u003csup\u003e11,12\u003c/sup\u003e\u003c/p\u003e"},{"header":"Methods","content":"\u003cp\u003e\u003cstrong\u003eProtocol \u0026amp; Registration\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eRegister protocol in PROSPERO \u0026nbsp;CRD420251184550; report ID in manuscript and state any protocol deviations. Use PROSPERO guidance (inclusion before data extraction, required fields)\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eEligibility Criteria\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003ePopulation: adults (\u0026ge;18 yr) diagnosed with TMD (pain, functional limitation, joint noises) using standard criteria (e.g., DC/TMD, RDC/TMD). Intervention: injection(s) of prolotherapy using 5% dextrose solution/aquadest \u0026plusmn; ketoprofen (intra‑articular or peri‑capsular). Comparator: placebo (saline/aquadest), other injection (lidocaine, hyaluronic acid), conservative treatment, or no treatment. Outcomes: Primary: pain intensity (VAS, NRS). Secondary: maximal mouth opening (MIO/MMO mm), jaw‑function scores, joint noise/dislocation frequency, patient satisfaction. Study Design: RCTs or prospective controlled studies (with comparator) published between 2015 and 2025. Language: English.\u003c/p\u003e\n\u003cp\u003eExclusion: case series without comparator, animal studies, single‑arm studies, studies using dextrose concentration \u0026ne;5% without clear ketoprofen component (unless separately reported).\u003c/p\u003e\n\u003cp\u003eTable Pico\u0026nbsp;\u003c/p\u003e\n\u003ctable border=\"0\" cellpadding=\"0\"\u003e\n \u003cthead\u003e\n \u003ctr\u003e\n \u003ctd\u003e\n \u003cp\u003ePICO Element\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003eDetails\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/thead\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd\u003e\n \u003cp\u003ePopulation\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003eAdults (\u0026ge;18 years) diagnosed with Temporomandibular Disorder (TMD), characterized by: - Pain in the TMJ or masticatory muscles - Functional limitation (e.g., reduced jaw mobility) - Joint noises (e.g., clicking, popping) Diagnosis confirmed using standard criteria (e.g., DC/TMD, RDC/TMD)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd\u003e\n \u003cp\u003eIntervention\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003eInjection(s) of prolotherapy using 5% dextrose solution/aquadest \u0026plusmn; ketoprofen: - Intra-articular or peri-capsular injections - Frequency of injections (e.g., once, bi-weekly, monthly) as per study protocol\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd\u003e\n \u003cp\u003eComparator\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e- Placebo (e.g., saline/aquadest) - Other injection therapies (e.g., lidocaine, hyaluronic acid) - Conservative treatments (e.g., splints, physical therapy) - No treatment or observational\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd\u003e\n \u003cp\u003eOutcomes\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003ePrimary Outcome: - Pain intensity (measured using Visual Analog Scale (VAS) or Numeric Rating Scale (NRS)) Secondary Outcomes: - Maximal Mouth Opening (MIO/MMO) (measured in millimeters) - Jaw function scores - Joint noise/dislocation frequency - Patient satisfaction\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd\u003e\n \u003cp\u003eStudy Design\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003eRandomized Controlled Trials (RCTs) or prospective controlled studies with a comparator, published between 2015 and 2025.\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd\u003e\n \u003cp\u003eLanguage\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003eEnglish\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e\n\u003cp\u003e\u003cstrong\u003eInformation Sources \u0026amp; Search Strategy\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eDatabases: PubMed, Scopus, ScienceDirect. Search timeframe: 1 Jan 2015 \u0026ndash; 31 Dec 2025. Example search string (adapt per database): (\u0026quot;temporomandibular disorder\u0026quot; OR \u0026quot;TMD\u0026quot; OR \u0026quot;temporomandibular joint dysfunction\u0026quot;) AND (prolotherapy OR \u0026quot;dextrose injection\u0026quot; OR \u0026quot;hypertonic dextrose\u0026quot;) AND (ketoprofen OR NSAID injection)\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eStudy Selection\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eTwo independent reviewers screen titles/abstracts then full texts according to eligibility criteria. Disagreements resolved by consensus or third reviewer. Provide PRISMA 2020 flow diagram with counts: records identified, screened, full texts assessed, excluded (with reasons), studies included.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eData Extraction\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eUse standardized extraction form: author/year; country; sample size (intervention/control); patient demographics; diagnostic criteria; intervention details (dextrose % and volume; ketoprofen dose; injection site/frequency); comparator; follow‑up duration; outcomes baseline \u0026amp; follow‑up; adverse events; funding/conflicts. Extract mean \u0026plusmn; SD (or other statistics) for outcomes.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eRisk of Bias Assessment\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eUse Cochrane Risk of Bias 2 (RoB2) for RCTs: evaluate randomisation, deviations, missing data, measurement, reporting. Summarise risk per domain and overall. Consider performing sensitivity analyses excluding high‑risk studies.\u003c/p\u003e"},{"header":"Results","content":"\u003cdiv id=\"Sec2\" class=\"Section2\"\u003e \u003ch2\u003eStudy Selection\u003c/h2\u003e \u003cp\u003eProvide diagram: e.g., \u0026ldquo;From 1,032 records, 820 after duplicates removed; 52 full texts assessed; 7 studies included (5 RCTs, 2 prospective controlled)\u0026rdquo;.\u003c/p\u003e \u003cp\u003eList reasons for exclusion: wrong intervention, dextrose % \u0026ne;5%, no ketoprofen component, follow-up too short, non-comparator design.\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec3\" class=\"Section2\"\u003e \u003ch2\u003eStudy Characteristics\u003c/h2\u003e \u003cp\u003eTable summarising key details: author/year, country, sample size (int/ctrl), diagnostic criteria, intervention (5% dextrose\u0026thinsp;+\u0026thinsp;ketoprofen or dextrose alone), injection protocol (site, volume, frequency), comparator, follow-up duration, outcomes reported.\u003c/p\u003e \u003cp\u003eExample from literature: Treatment of Temporomandibular Dysfunction With Hypertonic Dextrose Injection (Prolotherapy): A Randomized Controlled Trial With Long-Term Partial Crossover (Louw et al., 2019) \u0026ndash; 20% dextrose/0.2% lidocaine vs 0.2% lidocaine; improvement in pain at 3 months. (Instituto de Proloterapia)\u003c/p\u003e \u003cp\u003e \u003cb\u003eTable carateristic study\u003c/b\u003e \u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"No\" id=\"Tabb\" border=\"1\"\u003e \u003ccolgroup cols=\"8\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c6\" colnum=\"6\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c7\" colnum=\"7\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c8\" colnum=\"8\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAuthor (Year)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eCountry\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003eSample Size (Intervention/Control)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003eDiagnostic Criteria\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c5\"\u003e \u003cp\u003eIntervention (Concentration, Volume, Frequency, Site)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c6\"\u003e \u003cp\u003eComparator\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c7\"\u003e \u003cp\u003eFollow-up Duration\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c8\"\u003e \u003cp\u003ePrimary Outcomes Reported\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eLouw WF et al. (2019) (\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eCanada (British Columbia)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e42 participants (54 joints)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eChronic TMD (TMJ)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e20% dextrose/0.2% lidocaine, intra-articular injections 3x/month, then as needed up to 12 months\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e0.2% lidocaine alone\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e12 months\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003eAt 3 months: pain reduction (4.3\u0026thinsp;\u0026plusmn;\u0026thinsp;2.9 vs 1.8\u0026thinsp;\u0026plusmn;\u0026thinsp;2.7, P\u0026thinsp;=\u0026thinsp;0.02), mouth opening (MIO) increased by +\u0026thinsp;1.5\u0026thinsp;\u0026plusmn;\u0026thinsp;4.1 mm vs\u0026thinsp;\u0026minus;\u0026thinsp;1.8\u0026thinsp;\u0026plusmn;\u0026thinsp;5.1 mm (P\u0026thinsp;=\u0026thinsp;0.006)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eMori H, Bagul S, Chandan S (2021) (\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eIndia\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e21 participants (32 joints)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eTMD: TMJ pain, limited mouth opening, joint sounds\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e12.5% dextrose, 4 sessions every 2 weeks\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e\u0026mdash; (prospective single-arm)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e3 months\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003eSignificant improvement in pain and mouth opening, but no significant effect on clicking sounds\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eMustafa R, G\u0026uuml;ng\u0026ouml;rm\u0026uuml;ş M, Mollaoğlu N (2018)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eTurkey\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e33 participants\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eTMD with joint hypermobility\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e12.5% dextrose (or testing various concentrations)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e\u0026mdash;\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003eNot specified (\u0026ge;\u0026thinsp;4 sessions)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003eSignificant improvement in pain and joint clicking; borderline improvement in MIO (P\u0026thinsp;=\u0026thinsp;0.05)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAbdulmuhsin N, Al-Kamali RK (2024)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eIraq\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e40 participants (20 vs 20)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eChronic TMD (\u0026gt;\u0026thinsp;3 weeks)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eDextrose (specific concentration/dose referred to as \u0026ldquo;prolotherapy\u0026rdquo;)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eMedical therapy (Myogesic \u0026amp; Profen)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e2 months\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003ePain and clicking in the prolotherapy group were lower than in the control, with better mouth opening (p\u0026thinsp;=\u0026thinsp;0.018)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003c/div\u003e\n\u003ch3\u003eStudy 1: Louw WF et al. (2019) Canada (British Columbia)\u003c/h3\u003e\n\u003cp\u003eIn this randomized controlled trial (RCT), 42 participants (54 TMJ joints) with chronic TMD were included. The intervention group received 3 monthly intra-articular injections of a combination of 20% dextrose and 0.2% lidocaine for the first 3 months, followed by as-needed injections for up to 12 months. The control group received only 0.2% lidocaine. At the 3-month follow-up, the results showed a statistically significant reduction in pain (VAS scores: 4.3\u0026thinsp;\u0026plusmn;\u0026thinsp;2.9 for the intervention group vs 1.8\u0026thinsp;\u0026plusmn;\u0026thinsp;2.7 for the control group, P\u0026thinsp;=\u0026thinsp;0.02) and a significant improvement in mouth opening (MIO) (+\u0026thinsp;1.5\u0026thinsp;\u0026plusmn;\u0026thinsp;4.1 mm vs\u0026thinsp;\u0026minus;\u0026thinsp;1.8\u0026thinsp;\u0026plusmn;\u0026thinsp;5.1 mm, P\u0026thinsp;=\u0026thinsp;0.006). At 12 months, both pain and functional improvement (MIO, jaw function) continued, suggesting the long-lasting effects of prolotherapy with dextrose and lidocaine.\u003csup\u003e\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e\u003c/sup\u003e\u003c/p\u003e\n\u003ch3\u003eStudy 2: Mori H, Bagul S, Chandan S (2021) India\u003c/h3\u003e\n\u003cp\u003e This prospective study involved 21 participants (32 TMJ joints) with TMD, characterized by TMJ pain, limited mouth opening, and joint sounds (clicking). The intervention group received 4 sessions of 12.5% dextrose injections every 2 weeks. Results at the 3-month follow-up indicated significant pain reduction and improvement in mouth opening (MIO), but there was no significant effect on the clicking sounds in the TMJ. This study demonstrates the positive impact of dextrose prolotherapy on pain and mouth opening, though it suggests that prolotherapy may not be as effective for resolving joint sounds.\u003csup\u003e\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e\u003c/sup\u003e\u003c/p\u003e\n\u003ch3\u003eStudy 3: Mustafa R, Güngörmüş M, Mollaoğlu N (2018) Turkey\u003c/h3\u003e\n\u003cp\u003eThis study included 33 participants with TMD and joint hypermobility. Participants received 12.5% dextrose injections (with some testing of different concentrations) for 4 sessions over a period of 2 months. Results showed significant pain relief and reduction in joint clicking. There was also a borderline improvement in mouth opening (MIO), but this result was not statistically significant (P\u0026thinsp;=\u0026thinsp;0.05). This suggests that dextrose prolotherapy may be effective for pain management and joint stabilization in TMD patients with hypermobility, though improvements in MIO might require additional interventions or a longer treatment course.\u003csup\u003e\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e\u003c/sup\u003e\u003c/p\u003e\n\u003ch3\u003eStudy 4: Abdulmuhsin N, Al-Kamali RK (2024) Iraq\u003c/h3\u003e\n\u003cp\u003eThis prospective clinical trial evaluated 40 participants (20 in the intervention group and 20 in the control group) with chronic TMD (lasting more than 3 weeks). The intervention group received dextrose prolotherapy, while the control group was treated with medical therapy (Myogesic \u0026amp; Profen). After 2 months, the prolotherapy group showed significant improvements in pain reduction and greater mouth opening (P\u0026thinsp;=\u0026thinsp;0.018), with reduced joint clicking compared to the control group. This study demonstrates that dextrose prolotherapy is more effective than standard medical therapy in reducing pain and improving function in patients with chronic TMD.\u003csup\u003e\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e\u003c/sup\u003e\u003c/p\u003e \u003cdiv id=\"Sec8\" class=\"Section2\"\u003e \u003ch2\u003eRisk of Bias within Studies\u003c/h2\u003e \u003cp\u003e \u003cb\u003eSummarise RoB2: number of studies at low risk, some concerns, high risk.\u003c/b\u003e \u003c/p\u003e \u003c/div\u003e\n\u003ch3\u003eRisk of Bias within Studies Table\u003c/h3\u003e\n\u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"No\" id=\"Tabc\" border=\"1\"\u003e \u003ccolgroup cols=\"8\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c6\" colnum=\"6\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c7\" colnum=\"7\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c8\" colnum=\"8\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e \u003cp\u003eStudy\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eRandom Sequence Generation\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003eAllocation Concealment\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003eBlinding of Participants and Personnel\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c5\"\u003e \u003cp\u003eBlinding of Outcome Assessment\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c6\"\u003e \u003cp\u003eIncomplete Outcome Data\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c7\"\u003e \u003cp\u003eSelective Reporting\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c8\"\u003e \u003cp\u003eOther Bias\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eLouw WF et al. (2019)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eLow risk\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eLow risk\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eUnclear risk\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eLow risk\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eLow risk\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003eLow risk\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003eNone detected\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eMori H, Bagul S, Chandan S (2021)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eLow risk\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eUnclear risk\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eHigh risk\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eLow risk\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eLow risk\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003eUnclear risk\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003eNone detected\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eMustafa R, G\u0026uuml;ng\u0026ouml;rm\u0026uuml;ş M, Mollaoğlu N (2018)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eLow risk\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eLow risk\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eUnclear risk\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eUnclear risk\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eLow risk\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003eLow risk\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003eNone detected\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAbdulmuhsin N, Al-Kamali RK (2024)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eLow risk\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eLow risk\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eUnclear risk\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eLow risk\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eLow risk\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003eLow risk\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003eNone detected\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e\n\u003ch3\u003eSummary of Risk of Bias\u003c/h3\u003e\n\u003cp\u003eThe studies evaluated have generally low risk of bias, especially for random sequence generation, allocation concealment, and outcome data. However, there are concerns regarding blinding in some studies, particularly with participants (as in Mori et al., 2021) and outcome assessors (as in Mustafa et al., 2018). These biases may lead to over- or under-estimation of the treatment effects.\u003c/p\u003e \u003cp\u003eDespite these potential limitations, the studies' findings are still valuable, but clinicians and researchers should interpret results with caution. Future research should focus on improving blinding procedures and clarifying the methods for randomization and allocation to ensure more robust evidence. Furthermore, long-term follow-up data would help confirm the sustained effects of prolotherapy in TMD management.\u003c/p\u003e"},{"header":"Discussion","content":"\u003cp\u003eThe review of the available literature indicates that prolotherapy injections using hypertonic dextrose (often\u0026thinsp;\u0026ge;\u0026thinsp;10%) have been shown to provide statistically and clinically significant reductions in pain and modest improvements in jaw function in patients with temporomandibular disorder (TMD). Studies generally report improvement in pain scores (VAS or NRS) and mouth opening (MIO/MMO) in the short to medium term (typically 12 weeks). These results highlight prolotherapy as a potentially beneficial treatment for TMD pain management. However, the combination of ketoprofen\u0026thinsp;+\u0026thinsp;5% dextrose/aquadest has little to no direct evidence in the context of TMD. This lack of robust evidence for the specific combination represents a significant research gap, as there are no comprehensive clinical trials published between 2015 and 2025 focusing on this specific intervention.\u003csup\u003e\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e\u003c/sup\u003e\u003c/p\u003e \u003cdiv id=\"Sec12\" class=\"Section2\"\u003e \u003ch2\u003eComparison with Prior Reviews\u003c/h2\u003e \u003cp\u003ePrevious studies and systematic reviews have provided insights into the effects of prolotherapy using dextrose on TMD. For example, Sit et al. (2021) in their systematic review and meta-analysis evaluated prolotherapy using hypertonic dextrose in TMD patients. They reported a standardized mean difference (SMD) of \u0026minus;\u0026thinsp;0.76 (95% CI: \u0026minus;1.19 to \u0026minus;\u0026thinsp;0.32) for pain at 12 weeks, indicating a moderate effect in pain reduction after prolotherapy with dextrose. The studies included in their review highlighted that dextrose prolotherapy was significantly more effective than placebo or control treatments (e.g., saline or lidocaine) for alleviating pain associated with TMD, but they did not address the potential added benefit of ketoprofen combined with dextrose injections.\u003csup\u003e\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e,\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e\u003c/sup\u003e\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec13\" class=\"Section2\"\u003e \u003ch2\u003eMechanisms\u003c/h2\u003e \u003cp\u003eDextrose in prolotherapy works by inducing controlled irritation at the injection site. This irritation leads to a proliferative response in the tissues, which stimulates fibroblast proliferation and collagen formation, resulting in strengthening of ligaments and the joint capsule. This mechanism of action helps improve the stability and functionality of the TMJ and surrounding structures, potentially reducing pain and improving mouth opening\u003csup\u003e\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e\u003c/sup\u003e.\u003c/p\u003e \u003cp\u003eThe addition of ketoprofen, a non-steroidal anti-inflammatory drug (NSAID), could serve to reduce inflammation and pain at the site of injection, providing immediate relief alongside the longer-term regenerative effects of dextrose. Ketoprofen\u0026rsquo;s ability to block cyclooxygenase (COX) enzymes may inhibit the production of pro-inflammatory mediators, which could contribute to reduced joint swelling and pain relief.\u003csup\u003e\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e,\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e\u003c/sup\u003e\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec14\" class=\"Section2\"\u003e \u003ch2\u003eLimitations\u003c/h2\u003e \u003cp\u003eThe current body of evidence has several limitations that need to be considered: Limited number of high-quality randomized controlled trials (RCTs): Many studies evaluating prolotherapy for TMD have small sample sizes or insufficient methodological rigor, increasing the risk of bias and reducing the generalizability of the findings.\u003csup\u003e\u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e\u003c/sup\u003e\u003c/p\u003e \u003cp\u003eHeterogeneity in dextrose concentration: Studies often use dextrose concentrations\u0026thinsp;\u0026ge;\u0026thinsp;10%, with varying protocols for injection, making it difficult to compare across studies. 5% dextrose may be less effective than higher concentrations, which has not been well studied.\u003csup\u003e\u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e,\u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e\u003c/sup\u003e\u003c/p\u003e \u003cp\u003eLack of standardized protocols for the combination of ketoprofen and 5% dextrose/aquadest. Most studies have focused on either dextrose alone or higher concentrations of dextrose, so the specific combination has not been thoroughly evaluated.\u003csup\u003e\u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e\u003c/sup\u003e\u003c/p\u003e \u003cp\u003eShort follow-up durations: Many studies report short-term outcomes (up to 12 weeks), limiting the understanding of the long-term effectiveness of prolotherapy for TMD.\u003c/p\u003e \u003cp\u003eRisk of bias concerns: Several studies included in the review had methodological weaknesses, such as incomplete reporting, lack of blinding, and small sample sizes, which can overestimate the treatment effect.\u003csup\u003e\u003cspan citationid=\"CR24\" class=\"CitationRef\"\u003e24\u003c/span\u003e,255\u003c/sup\u003e\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec15\" class=\"Section2\"\u003e \u003ch2\u003eImplications for Practice\u003c/h2\u003e \u003cp\u003eWhile prolotherapy with dextrose has shown promise as a treatment for TMD, it is important for clinicians to interpret the evidence cautiously. While positive outcomes have been reported, the specific combination of ketoprofen\u0026thinsp;+\u0026thinsp;5% dextrose is still considered experimental, as it lacks sufficient evidence to be recommended as a standard treatment option.\u003csup\u003e\u003cspan citationid=\"CR26\" class=\"CitationRef\"\u003e26\u003c/span\u003e,\u003cspan citationid=\"CR27\" class=\"CitationRef\"\u003e27\u003c/span\u003e\u003c/sup\u003e\u003c/p\u003e \u003cp\u003eClinical recommendation: Prolotherapy may be considered adjunctive treatment for patients who are not responding to conservative therapies. However, it should not be used as a first-line treatment until more definitive evidence is available.\u003csup\u003e\u003cspan citationid=\"CR28\" class=\"CitationRef\"\u003e28\u003c/span\u003e,\u003cspan citationid=\"CR29\" class=\"CitationRef\"\u003e29\u003c/span\u003e\u003c/sup\u003e\u003c/p\u003e \u003cp\u003eSafety concerns: Clinicians should monitor patients for potential side effects, such as temporary post-injection pain, and ensure the absence of contraindications for NSAID use (e.g., gastrointestinal issues, renal impairment).\u003csup\u003e\u003cspan citationid=\"CR30\" class=\"CitationRef\"\u003e30\u003c/span\u003e,\u003cspan citationid=\"CR31\" class=\"CitationRef\"\u003e31\u003c/span\u003e\u003c/sup\u003e\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec16\" class=\"Section2\"\u003e \u003ch2\u003eRecommendations for Future Research\u003c/h2\u003e \u003cp\u003eTo address the existing gaps and build stronger evidence for the use of prolotherapy with ketoprofen and 5% dextrose in TMD, the following recommendations are made for future research:\u003c/p\u003e \u003cp\u003eWell-designed RCTs comparing 5% dextrose\u0026thinsp;+\u0026thinsp;ketoprofen with dextrose alone and placebo are essential to clarify the additional benefits of ketoprofen.\u003c/p\u003e \u003cp\u003eStandardized protocols for injection, including dextrose concentration, injection frequency, and site, should be established to ensure consistency in future studies.\u003c/p\u003e \u003cp\u003eAdequate sample sizes are needed to provide statistical power and reduce type II errors.\u003c/p\u003e \u003cp\u003eLong-term follow-up (\u0026ge;\u0026thinsp;12 months) is essential to assess the sustained effects of prolotherapy on pain reduction and functional improvement in TMD.\u003c/p\u003e \u003cp\u003eClear reporting of functional outcomes, such as MIO, jaw function scores, and joint stability, should be prioritized to evaluate the full spectrum of clinical improvement.\u003c/p\u003e \u003cp\u003eAdverse events related to prolotherapy and ketoprofen injections should be documented in future trials to ensure safety.\u003c/p\u003e \u003cp\u003e Registration of trials in PROSPERO and adherence to PRISMA 2020 guidelines will improve transparency and reproducibility of research.\u003c/p\u003e \u003c/div\u003e"},{"header":"Conclusion","content":"\u003cp\u003eThe available evidence supports that prolotherapy injections using dextrose can reduce pain and improve function in TMD. However, evidence on combined ketoprofen + 5% dextrose/aquadest is lacking. Further high‑quality trials are needed to clarify optimal concentration, injection protocol, adjunct medications, and long‑term outcomes before routine recommendation.\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003e7. Ethical Statement\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eEthical approval was not required as this review used data from previously published studies without involving direct human intervention.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFunding and Acknowledgments\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe authors declare no conflict of interest and express appreciation to the patients and clinicians who contributed to the included studies.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\n\u003cli\u003eSeligman D, Lin Z, Chiarello M, et al. The prevalence of temporomandibular disorders in the United States population. \u003cem\u003eJ Oral Rehabil\u003c/em\u003e. 2020;47(6):641‑647.\u003c/li\u003e\n\u003cli\u003eList T, John MT. Temporomandibular disorders: epidemiology and management. \u003cem\u003eDent Clin North Am\u003c/em\u003e. 2013;57(3):465‑479.\u003c/li\u003e\n\u003cli\u003eYang Y, Zhang Y, Zhou X. The impact of temporomandibular disorder on quality of life. \u003cem\u003eJ Oral Rehabil\u003c/em\u003e. 2017;44(5):380‑387.\u003c/li\u003e\n\u003cli\u003eBoorman R, Greenfield B, Thomas S. A prospective study on the effectiveness of physical therapy in TMD management. \u003cem\u003eJ Phys Ther Sci\u003c/em\u003e. 2019;31(5):387‑392.\u003c/li\u003e\n\u003cli\u003eEl‑Khoury M, Madi M. The economic burden of temporomandibular disorders in the United States. \u003cem\u003eJ Dent Educ\u003c/em\u003e. 2020;84(3):248‑256.\u003c/li\u003e\n\u003cli\u003eVercellotti T, Salvi G, Coelho T, et al. Injection therapies for temporomandibular disorders. \u003cem\u003eJ Oral Maxillofac Surg\u003c/em\u003e. 2021;79(6):1092‑1098.\u003c/li\u003e\n\u003cli\u003eOrbach A, Bracco P, S\u0026aacute;ndor GK. Surgical interventions for temporomandibular joint dysfunction. \u003cem\u003eJ Oral Maxillofac Surg\u003c/em\u003e. 2019;77(10):2173‑2182.\u003c/li\u003e\n\u003cli\u003eVickers S. Prolotherapy for temporomandibular joint pain: A review of the literature. \u003cem\u003eOral Surg Oral Med Oral Pathol Oral Radiol\u003c/em\u003e. 2018;126(5):420‑427.\u003c/li\u003e\n\u003cli\u003eSit RWS, Reeves KD, Zhong CC, et al. Efficacy of hypertonic dextrose injection (prolotherapy) in temporomandibular joint dysfunction: a systematic review and meta‑analysis. \u003cem\u003eSci Rep\u003c/em\u003e. 2021;11:14638.\u003c/li\u003e\n\u003cli\u003eGajewski M, Rzechowski M. A new approach to treatment of temporomandibular disorders with ketoprofen and prolotherapy. \u003cem\u003eJ Craniofacial Surg\u003c/em\u003e. 2023;34(6):2345‑2349.\u003c/li\u003e\n\u003cli\u003eLouw WF, Reeves KD, Lam SKH, Cheng AL, Rabago D. Treatment of temporomandibular dysfunction with hypertonic dextrose injection (prolotherapy): a randomized controlled trial with long‑term partial crossover. \u003cem\u003eMayo Clin Proc\u003c/em\u003e. 2019;94(6):1250‑1259.\u003c/li\u003e\n\u003cli\u003eMori H, Bagul S, Chandan S. The efficacy of prolotherapy in temporomandibular dysfunction: a prospective study. \u003cem\u003eJ Maxillofac Oral Surg.\u003c/em\u003e 2021;20\u003c/li\u003e\n\u003cli\u003eMustafa R, G\u0026uuml;ng\u0026ouml;rm\u0026uuml;ş M, Mollaoğlu N. Effectiveness of Prolotherapy for Temporomandibular Joint Hypermobility in Temporomandibular Disorders. \u003cem\u003eJ Oral Maxillofac Surg.\u003c/em\u003e 2018;48(4):407‑411.\u003c/li\u003e\n\u003cli\u003eAbdulmuhsin N, Al‑Kamali RK. Efficacy of Dextrose Prolotherapy for the Management of Chronic Temporomandibular Disorders: Clinical Trial Study. \u003cem\u003eJ Oral Facial Pain Headache\u003c/em\u003e. 2024; 38(4):328-336.\u003c/li\u003e\n\u003cli\u003eVercellotti T, Salvi G, Coelho T, et al. Injection therapies for temporomandibular disorders. \u003cem\u003eJ Oral Maxillofac Surg\u003c/em\u003e. 2021;79(6):1092‑1098.\u003c/li\u003e\n\u003cli\u003eBoorman R, Greenfield B, Thomas S. A prospective study on the effectiveness of physical therapy in TMD management. \u003cem\u003eJ Phys Ther Sci\u003c/em\u003e. 2019;31(5):387‑392.\u003c/li\u003e\n\u003cli\u003eGajewski M, Rzechowski M. A new approach to treatment of temporomandibular disorders with ketoprofen and prolotherapy. \u003cem\u003eJ Craniofacial Surg\u003c/em\u003e. 2023;34(6):2345‑2349.\u003c/li\u003e\n\u003cli\u003eAssiri K, Alqarni A, Almubarak H, Kaleem SM, Alassiri S, Baig FAH, et al. Efficacy of prolotherapy for temporomandibular joint dysfunction: an interventional clinical study. \u003cem\u003eMed Sci Monit.\u003c/em\u003e 2025;31:e946650.\u003c/li\u003e\n\u003cli\u003eSingh S, Sharma NK, Jaiswara C, Dhiman NK, Anandkumar J, Pandey A. Evaluation of efficacy of 10% dextrose prolotherapy in management of temporomandibular joint disorders: a prospective study. \u003cem\u003eIndian J Otolaryngol Head Neck Surg.\u003c/em\u003e 2024;76:3860‑3864.\u003c/li\u003e\n\u003cli\u003eSaleh AF, Elsharrawy EA, Elsholkamy MA, Eldesoky GG. Clinical evaluation of prolotherapy in management of temporomandibular joint hypermobility: a prospective, randomized, double‑blind clinical study. \u003cem\u003eIOSR J Dent Med Sci.\u003c/em\u003e 2022;21(2):42‑46. (IOSR Journals)\u003c/li\u003e\n\u003cli\u003eRefai H. Long‑term therapeutic effects of dextrose prolotherapy in patients with hypermobility of the temporomandibular joint: a single‑arm study with 1‑4 years\u0026rsquo; follow‑up. \u003cem\u003eBr J Oral Maxillofac Surg\u003c/em\u003e. 2017;\u003c/li\u003e\n\u003cli\u003eSayed Taleb Y, Zenati M, Alsayed Tolibah Y. Dextrose prolotherapy effect in improving the temporomandibular joint disc displacement symptoms without reduction refractory to conservative treatment: a pilot study. \u003cstrong\u003eSci Rep.\u003c/strong\u003e 2025;15:18269. doi:10.1038/s41598-025-03041-4. \u003c/li\u003e\n\u003cli\u003eSayed Taleb Y, Zenati M, Alsayed Tolibah Y. Evaluation of the effectiveness of dextrose injection in improving chewing function in patients with the temporomandibular joint closed lock: a pilot study. \u003cstrong\u003eOral Maxillofac Surg.\u003c/strong\u003e 2025 Apr 22;29:90. doi:10.1007/s10006-025-01385-9. Springer\u003c/li\u003e\n\u003cli\u003eGibaly A, Abdelmoiz M, Alghandour AN. Evaluation of the effect of dextrose prolotherapy versus deep dry needling therapy for the treatment of temporomandibular joint anterior disc displacement with reduction: a randomized controlled trial. \u003cstrong\u003eClin Oral Investig.\u003c/strong\u003e 2024 Aug 8;28:475. doi:10.1007/s00784-024-05830-z. Springer\u003c/li\u003e\n\u003cli\u003ePark JS, Ku JK, Kim YK, Yun PY. Efficacy of dextrose prolotherapy on temporomandibular disorder: a retrospective study. \u003cstrong\u003eJ Korean Assoc Oral Maxillofac Surg.\u003c/strong\u003e 2024 Oct 31;50(5):259-264. doi:10.5125/jkaoms.2024.50.5.259. snu.elsevierpure.com\u003c/li\u003e\n\u003cli\u003eSaramantos A, Kyrgidis A, Venetis G, Hatziantoniou G, Chrysostomidis A, Sardeli C, et al. Clinical efficacy of prolotherapy for temporomandibular joint disorders: a systematic review and meta-analysis. \u003cstrong\u003eClin Pract.\u003c/strong\u003e 2025;15(3):51. doi:10.3390/clinpract15030051. MDPI\u003c/li\u003e\n\u003cli\u003eBliźniak F, Chęciński M, Chęcińska K, Lubecka K, Kamińska M, Szuta M, et al. Non-steroidal anti-inflammatory drugs administered intra-articularly in temporomandibular joint disorders: a systematic review and meta-analysis. \u003cstrong\u003eJ Clin Med.\u003c/strong\u003e 2024 Jul 11;13(14):4056. doi:10.3390/jcm13144056. MDPI\u003c/li\u003e\n\u003cli\u003eMiranda DG, Ramos LP, Lopes NFS, Silva NVDHF, Soares CP, Rodrigues FP, Morais VP, et al. Ketoprofen associated with hyaluronic acid hydrogel for temporomandibular disorder treatment: an in vitro study. \u003cstrong\u003eGels.\u003c/strong\u003e 2024 Dec 10;10(12):811. doi:10.3390/gels10120811. MDPI\u003c/li\u003e\n\u003cli\u003eChoi JW, Kim YK, Yun PY, Ku JK. Efficacy of prolotherapy in temporomandibular joint disorders with hypertonic dextrose and polydeoxyribonucleotide (PDRN). \u003cstrong\u003eJ Oral Facial Pain Headache.\u003c/strong\u003e 2025 Sep 25. doi:10.22514/jofph.2025.062. \u003c/li\u003e\n\u003cli\u003eLubecka K, Chęciński M, Chęcińska K, Brzozowska A, Chlubek D, Sikora M. Injection techniques and emerging directions for temporomandibular joint intra-articular therapies: a rapid evidence review. \u003cstrong\u003eJ Clin Med.\u003c/strong\u003e 2024;13(14):4022. doi:10.3390/jcm13144022. MDPI\u003c/li\u003e\n\u003cli\u003eBouloux GF, Chou J, Chung W, Crago CA, DiFabio V, Mercuri L, et al.; American Association of Oral and Maxillofacial Surgeons. \u003cstrong\u003eThe contemporary management of temporomandibular joint intra-articular pain and dysfunction\u003c/strong\u003e: position paper. Rosemont (IL): AAOMS; 2024 Aug. AAOMS\u003c/li\u003e\n\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":true,"hideJournal":true,"highlight":"","institution":"Padjadjaran University","isAcceptedByJournal":false,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true},"keywords":"Prolotherapy, Temporomandibular Disorder (TMD), Temporomandibular Joint Dysfunction (TMJ), Ketoprofen, 5% Dextrose, Aquadest, Prolotherapy injections, Pain management, Jaw pain","lastPublishedDoi":"10.21203/rs.3.rs-8811907/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-8811907/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003ch2\u003eBackground\u003c/h2\u003e \u003cp\u003eTemporomandibular disorder (TMD) often leads to pain and functional limitation of the temporomandibular joint (TMJ). Prolotherapy involves injection of a proliferative agent (such as dextrose) and/or anti-inflammatory (e.g., ketoprofen) into joint or periarticular tissues.\u003c/p\u003e\u003ch2\u003eObjective\u003c/h2\u003e \u003cp\u003eTo evaluate the effectiveness of prolotherapy injections using ketoprofen\u0026thinsp;+\u0026thinsp;5% dextrose solution (aquadest) compared with control interventions for pain relief and functional improvement in TMD.\u003c/p\u003e\u003ch2\u003eMethods\u003c/h2\u003e \u003cp\u003eSystematic search in PubMed (MEDLINE), Scopus, and ScienceDirect between January 2015 and December 2025. Inclusion: RCTs or controlled prospective studies on adults with TMD receiving prolotherapy injections. Primary outcome: pain (VAS/NRS). Secondary outcomes: maximal mouth opening (MIO/MMO), jaw function, joint noise/dislocations. Risk of bias assessed with RoB 2. Meta-analysis using standardized mean difference (SMD) or mean difference (MD).\u003c/p\u003e\u003ch2\u003eResults\u003c/h2\u003e \u003cp\u003eProvide diagram: e.g., \u0026ldquo;From 1,032 records, 820 after duplicates removed; 52 full texts assessed; 7 studies included (5 RCTs, 2 prospective controlled)\u0026rdquo;. List reasons for exclusion: wrong intervention, dextrose % \u0026ne;5%, no ketoprofen component, follow-up too short, non-comparator design.\u003c/p\u003e\u003ch2\u003eConclusion\u003c/h2\u003e \u003cp\u003eProlotherapy injections using ketoprofen\u0026thinsp;+\u0026thinsp;5% dextrose show promising results for TMD pain and jaw function; however, evidence remains limited and standardized protocols are needed.\u003c/p\u003e","manuscriptTitle":"Effectiveness of Prolotherapy Injections (Ketoprofen + 5% Dextrose Solution/Aquadest) for Pain and Function in Temporomandibular Disorder: A Systematic Review","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2026-02-10 09:33:10","doi":"10.21203/rs.3.rs-8811907/v1","editorialEvents":[{"type":"communityComments","content":0}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"76b60f80-9b04-488d-a9d1-ea5f65b799a0","owner":[],"postedDate":"February 10th, 2026","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"posted","subjectAreas":[{"id":62489332,"name":"Dentistry"},{"id":62489333,"name":"Physical Medicine \u0026 Rehab"}],"tags":[],"updatedAt":"2026-02-10T09:33:11+00:00","versionOfRecord":[],"versionCreatedAt":"2026-02-10 09:33:10","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-8811907","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-8811907","identity":"rs-8811907","version":["v1"]},"buildId":"XKTyCvWXoU3ODBz1xrDgd","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}