Chronic knee pain is a leading complaint in orthopedic and pain management clinics, especially among older and overweight adults. With growing demand for non-surgical relief, more clinics are turning to regenerative strategies that focus on preserving joint health. This article explores common causes of knee pain, current treatment limitations, and how regenerative medicine may support longer-term outcomes.
Chronic knee pain is persistent discomfort in the knee joint lasting more than six weeks. It may present as localized or diffuse pain caused by mechanical stress, structural degeneration, or low-grade inflammation. Accurate diagnosis is essential for non-surgical treatment planning, particularly in regenerative care settings.
These are some of the most frequently observed conditions associated with chronic knee pain:
These conditions frequently overlap in presentation, requiring detailed clinical evaluation to determine the dominant pain source and appropriate treatment path.
A clinical reference article by Hsu and Siwiec (2023) outlines a systematic approach to evaluating chronic knee pain. It begins with a detailed physical examination and is supported by imaging studies to identify underlying structural or biomechanical abnormalities.
This structured workup enables providers to distinguish among potential causes of chronic knee pain and supports individualized, non-surgical treatment planning.
Knee osteoarthritis is the most common cause of chronic knee pain in older adults, so many diagnostic criteria for non-traumatic cases follow its evaluation framework. The 2021 guideline by Kolasinski et al. presents the American College of Rheumatology’s symptom-based approach, which emphasizes physical findings and discourages routine imaging.
These criteria provide a practical foundation for identifying likely structural causes and selecting appropriate non-surgical interventions.
In the narrative review by Shtroblia et al. (2025), recent treatment advances for chronic knee pain are outlined across pharmacologic, non-pharmacologic, and biologic categories, each offering varying symptom relief and functional improvement levels.
Topical NSAIDs help reduce pain and inflammation directly at the joint, offering similar results to oral NSAIDs with fewer side effects. They are widely recommended as a first option because they are safer for long-term use, especially in older adults. Capsaicin cream also relieves joint pain by calming nerve pain signals, though it may cause a mild burning feeling that usually fades with continued use.
Acetaminophen is widely used but provides limited pain relief in chronic knee pain and poses risks like liver toxicity at higher or prolonged doses. NSAIDs are more effective for symptom control and are recommended by major guidelines, though they require caution due to gastrointestinal, renal, and cardiovascular risks. Opioids are reserved for cases where other treatments fail, as side effects and long-term safety concerns outweigh their modest benefits.
Corticosteroid injections may ease symptoms in the short term, but recent data show limited long-term benefit compared to physical therapy. Hyaluronic acid injections offer slight improvements in pain and function, especially with high-molecular-weight products, and have fewer side effects than oral NSAIDs. Other options like platelet-rich plasma, stem cells, and botulinum toxin show mixed results and remain experimental due to inconsistent outcomes and a lack of cartilage repair.
Some medications originally used for other conditions show added benefits for chronic knee pain. Metformin, statins, and RAAS inhibitors (ACE inhibitors and ARBs) may reduce inflammation, support cartilage preservation, and improve joint function in patients with chronic degenerative changes. These drugs offer a potential dual-purpose treatment for patients with metabolic or cardiovascular conditions, making them useful adjuncts in multimorbid care plans.
Certain supplements, such as curcumin, Boswellia serrata, and glucosamine-chondroitin, are marketed for chronic knee pain due to their potential anti-inflammatory or joint-supportive effects. However, clinical trials and meta-analyses show inconsistent or modest results, often limited by small sample sizes, unclear bias, or placebo effects. While some supplements may offer minor relief or slow symptom progression, their overall benefits remain uncertain and should not replace guideline-recommended treatments.
Physical modalities such as TENS, acupuncture, heat therapy, and cold therapy are often adjunct treatments for chronic knee pain. While some patients report relief, evidence from clinical trials is mixed, with many studies showing no clinically meaningful differences compared to placebo or sham treatments. These approaches may provide short-term comfort but should be considered supportive rather than primary interventions.
Due to their modulating inflammation, biologic agents like NGF, IL-1, and TNF-α inhibitors have been explored for chronic joint pain. NGF blockers such as tanezumab and Fulranumab show some pain and function improvements but carry risks like joint damage and inconsistent safety. IL-1 and TNF-α inhibitors have shown minimal or no clinical benefit in trials, limiting their relevance in standard care.
Regenerative treatments are often studied in knee osteoarthritis, a common cause of chronic knee pain in older adults. In a systematic review by Ip et al. (2020), the authors evaluated the effects of platelet-rich plasma and mesenchymal stem cells to guide biologic strategies to reduce symptoms and support joint function.
Current data support the use of PRP and MSCs as promising adjuncts for managing chronic knee pain caused by degenerative joint changes, especially in mild to moderate cases.
Chronic knee pain involves overlapping causes such as joint degeneration, inflammation, and altered mechanics that affect long-term mobility. Effective care depends on accurate diagnosis and multimodal treatment that balances symptom relief with functional goals. Regenerative therapies and pleiotropic agents may support non-surgical outcomes, but more research is needed to define their long-term role in chronic pain care.
Hsu, H., & Siwiec, R. M. (2023, June 26). Knee osteoarthritis. In StatPearls. StatPearls Publishing. https://www.ncbi.nlm.nih.gov/books/NBK507884/
Kolasinski, S. L., Neogi, T., Hochberg, M. C., Oatis, C., Guyatt, G., Block, J., Callahan, L., Copenhaver, C., Dodge, C., Felson, D., Gellar, K., Harvey, W. F., Hawker, G., Herzig, E., Kwoh, C. K., Nelson, A. E., Samuels, J., Scanzello, C., White, D., … Reston, J. (2020). 2019 American College of Rheumatology/Arthritis Foundation guideline for managing hand, hip, and knee osteoarthritis. Arthritis Care & Research, 72(2), 149–162. https://doi.org/10.1002/acr.24131
Shtroblia, V., Petakh, P., Kamyshna, I., Halabitska, I., & Kamyshnyi, O. (2025). Recent advances in the management of knee osteoarthritis: A narrative review. Frontiers in Medicine, 12, 1523027. https://doi.org/10.3389/fmed.2025.1523027
Ip, H. L., Nath, D. K., Sawleh, S. H., Kabir, M. H., & Jahan, N. (2020). Regenerative medicine for knee osteoarthritis – The efficacy and safety of intra-articular platelet-rich plasma and mesenchymal stem cells injections: A literature review. Cureus, 12(9), e10575. https://doi.org/10.7759/cureus.10575
