Introduction: Prolotherapy for Musculoskeletal Pain

The prevalence of chronic primary musculoskeletal pain has led to a variety of effective non-surgical treatments, including physical therapy, pharmacologic management, and injection-based therapies. Injection therapies are typically utilized after exercise and medication management have failed. Many types of injection therapies exist, including trigger point injections, acupuncture, local anesthetics, corticosteroids, and prolotherapy. Herein, we provide an update on prolotherapy for MSK pain, focusing on osteoarthritis as an example.

Traditional dextrose prolotherapy has become an alternative injection therapy of interest given that is less expensive and easier to prepare than PRP or stem cell sources, making dextrose prolotherapy especially useful in low-income countries.⁴

All types of prolotherapy have become popular because these treatments do not have the deleterious potential side effects of corticosteroid injections, such as focal necrosis, further cartilage damage, ligament and tendon weakening, and even rupture.⁵⁻¹² To the contrary, prolotherapy offers the hope of tissue regeneration and repair.

Test your general clinical knowledge on prolotherapy with these 3 questions. Hit submit to see the answers.

1. Which of the following best describes prolotherapy?
2. In which of the following conditions have clinical studies shown prolotherapy to be effective in reducing pain and improving function?
3. When should prolotherapy be considered as a treatment option?
When Connective Tissue Tears Lead to Chronic Musculoskeletal Pain

It is widely believed that a common cause of chronic MSK pain is the incomplete healing of connective tissue (ligaments and tendons). Connective tissue provides support for the skeleton and joints.¹³⁻¹⁷ However, connective tissue has a poor blood supply, and therefore, when injured, healing can be slow and often incomplete.

Connective tissue injury can occur over many years, such as with repetitive strain, or suddenly, as with trauma.¹⁸˒¹⁹ This leads to connective tissue laxity (looseness), and ultimately pain, chronic sprains/strains, joint instability, tendinopathy, and osteoarthritis (OA).²⁰


As early as 1972, researchers noticed a relationship between ligament injury, joint instability, and the later development of OA.²¹ A very large study examined the trapeziometacarpal joint for stability over 25 years, with regular exams and x-rays. At the beginning of the study, these joints were stable and there was no OA seen in the joint. What was noted, over the years, was that the first thing which occurred was ligament weakness, followed by joint instability – long before any signs of OA in x-rays.²²

It also appears that the more severe the ligament injury is, the more severe the progression of OA.²⁵⁻²⁷ Therefore, prolotherapy can have a role in not only improving connective tissue strength but also in potentially preventing the further development of osteoarthritis.

Prolotherapy Mechanism of Action

Dextrose prolotherapy’s exact mechanism of action is not entirely understood but is likely multifactorial. The primary hypothesis for dextrose prolotherapy is that the hypertonic solution causes an initial cell injury with an ensuing inflammatory response and healing cascade, inducing growth factors and collagen deposition in exposed tissue, resulting in tissue repair.²⁸⁻³²

In a sense, prolotherapy “tricks” the body into thinking it is injured again, which then stimulates a new, directed, healing cascade. This results in repair, regeneration, and stronger connective tissue, and ultimately less pain and more function.

Clinical Applicability of Prolotherapy in Chronic MSK Pain

Dextrose prolotherapy has been studied in multiple human clinical trials, case series, and RCTs for many conditions.⁴³ Evidence from meta-analyses recommends prolotherapy as a potential alternative treatment option for various conditions following failed conservative and medical management, including finger, hand, and knee osteoarthritis, sacroiliac joint pain, low back pain, lateral epicondylitis, plantar fasciitis, temporomandibular laxity/dysfunction and various tendinopathies, including rotator cuff tendinopathy and Achilles tendinopathy.⁴⁴⁻⁵⁰

Other meta-analyses studied prolotherapy’s effectiveness compared to other treatment modalities for MSK pain, regardless of location or etiology. A study of rotator cuff lesions found that while corticosteroid injections gave better short-term relief, prolotherapy injections gave the best long-term benefit.⁴⁶

Adverse Effects of Prolotherapy

Prolotherapy is a low-risk procedure. However, as with any injections, risks include bruising, potential for mild bleeding, and post-injection soreness at the injection site. Less common side effects such as infection, headache, nausea, diarrhea, and minor allergic reactions. Another side effect, which is expected, is a temporary self-limited pain flare for 1 to 4 days produced by the inflammation of the hypertonic dextrose solution,⁵²˒⁵³ representing stimulation of the healing cascade. While expected, the degree of post-treatment pain varies widely among individuals and treatment areas.⁵⁴

Practical Takeaways

Pain physicians should be aware of prolotherapy as an alternative treatment option for chronic musculoskeletal pain in cases where the patient has failed prior conservative, pharmacologic, and interventional management, or where the patient is seeking a regenerative option and/or hopes to avoid surgery. Dextrose prolotherapy has been shown in multiple studies, case reports, and RCTs to be an effective treatment for many kinds of musculoskeletal pain, including tendinopathies, chronic ligament sprains, and osteoarthritis. Dextrose prolotherapy is an inexpensive and readily available alternative modality, that is safe to employ, with minor potential side effects.

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