BlueCross BlueShield of Tennessee Medical Policy Manual

Prolotherapy for Musculoskeletal Disorders


Prolotherapy describes a procedure intended for healing and strengthening ligaments and tendons by injecting an agent that induces inflammation and stimulates endogenous repair mechanisms. Prolotherapy may also be referred to as proliferant injection, prolo, joint sclerotherapy, regenerative injection therapy, growth factor stimulation injection, or nonsurgical tendon, ligament, and joint reconstruction. The goal of prolotherapy is to promote tissue repair or growth by prompting release of growth factors, such as cytokines, or by increasing the effectiveness of existing circulating growth factors. The mechanism of action is not well-understood, but may involve local irritation and/or cell lysis. Agents used with prolotherapy include zinc sulfate, psyllium seed oil, combinations of dextrose, glycerine, and phenol, or dextrose alone. Prolotherapy may involve a single injection or a series of injections, often diluted with a local anesthetic.




Prolotherapy has been investigated as a treatment option of various types of pain. Although there is extensive literature regarding prolotherapy, clinical efficacy has not been proven.


American Association of Orthopaedic Medicine. (2013). Prolotherapy for back pain. Retrieved February 25, 2014 from

American College of Rheumatology. (2019). 2019 American College of Rheumatology/Arthritis Foundation guideline for the management of osteoarthritis of the hand, hip, and knee. Retrieved January 7, 2021 from

Arias-Vázquez, P.I., Tovilla-Zárate, C.A., Legorreta-Ramírez, B.G., Fonz, W.B., et al. (2019). Prolotherapy for knee osteoarthritis using hypertonic dextrose vs other interventional treatments: systematic review of clinical trials. Advances in Rheumatology, 59 (1), 39. Abstract retrieved March 20, 2020 from PubMed database.

BlueCross BlueShield Association. Evidence Positioning System. (12:2020). Prolotherapy (2.01.26). Retrieved January 7, 2021 from (23 articles and/or guidelines reviewed)

Catapano, M., Zhang, K., Mittal, N., Sangha, H., Onishi, K., & de Sa, D. (2020). Effectiveness of Dextrose Prolotherapy for Rotator Cuff Tendinopathy: A Systematic Review. PM and R, 12 (3), 288–300. Abstract retrieved March 20, 2020 from PubMed database.

Centers for Medicare & Medicaid Services. NCD for prolotherapy, joint sclerotherapy, and ligamentous injections with sclerosing agents (150.7). Retrieved July 13, 2016 from

Hassan, F., Murrell, W.D., Refalo, A., & Maffulli, N. (2018). Alternatives to biologics in management of knee osteoarthritis: a systematic review. Sports Medicine and Arthroscopic Review, 26 (2), 79-85. Abstract retrieved May 22, 2018 from PubMed database.

Hassan, F., Trebinjac, S., Murrell, W., & Maffulli, N. (2017). The effectiveness of prolotherapy in treating knee osteoarthritis in adults: a systematic review. British Medical Bulletin, 122 (1), 91-108. Abstract retrieved May 24, 2017 from PubMed database.

Hauser, R., Lackner, J., Steilen-Matias, D., & Harris, D. (2016). A systematic review of dextrose prolotherapy for chronic musculoskeletal pain. Clinical Medicine insights: Arthritis and Musculoskeletal Disorders, 9, 139-159. (Level 2 evidence)

Hung, C., Hsiao, M., Chang, K., Han, D., & Wang, T. (2016). Comparative effectiveness of dextrose prolotherapy versus control injections and exercise in the management of osteoarthritis pain: a systematic review and meta-analysis. Journal of Pain Research, 9, 847-858. (Level 2 evidence)

Krstičević, M., Jerić, M., Došenović, S., Jeličić, K., & Puljak, L. (2017). Proliferative injection therapy for osteoarthritis: a systematic review. International Orthopaedics, 41 (4), 671-679. Abstract retrieved May 24, 2017 from PubMed database.

Lin, M.T., Chiang, C.F., Wu, C.H., Huang, Y.T., Tu, Y.K., & Wang, T.G. (2019). Comparative effectiveness of injection therapies in rotator cuff tendinopathy: A systematic review, pairwise and network meta-analysis of randomized controlled trials. Archives of Physical Medicine and Rehabilitation, 100 (2), 336-349. Abstract retrieved March 18, 2019 from PubMed database.

Morath, O., Kubosch, E., Taeymans, J., Zwingmann, J., Konstantinidis, L, Südkamp, N., & Hirschmüller, A. (2017). The effect of sclerotherapy and prolotherapy on chronic painful Achilles tendinopathy – a systematic review including meta-analysis. Scandinavian Journal of Medical & Science in Sports, 28 (1), 4-15. Abstract retrieved May 24, 2017 from PubMed database.

Sanderson, L., & Bryant, A. (2015). Effectiveness and safety of prolotherapy injections for management of lower limb tendinopathy and fasciopathy: a systematic review. Journal of Foot and Ankle Research, 8, 57. (Level 2 evidence)

Sit, R., Chung, V., Reeves, K., Rabago, D., Chan, K., Chan, D., et al. (2016). Hypertonic dextrose injections (prolotherapy) in the treatment of symptomatic knee osteoarthritis: a systematic review and meta-analysis. Scientific Reports, 6:25247. DOI: 10.1038/srep25247. (Level 2 evidence)




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