Clinical Studies on Prolotherapy: What the Latest Research Shows

Author: Mr Oliver Eaton BSc (Hons), PG.Cert – Orthopaedic Specialist
Reviewed by: Mr William Sharples BSc (Hons) – Pain Management Expert
Last Updated: September 2025

Prolotherapy, short for “proliferative therapy,” is gaining increasing recognition as a regenerative treatment for chronic musculoskeletal pain. By injecting an irritant solution—most commonly hyperosmolar dextrose—into damaged ligaments, tendons, or joints, prolotherapy aims to stimulate the body’s natural healing response and strengthen connective tissues. Though prolotherapy has been practiced for decades, only recently have more rigorous clinical studies begun to provide a clearer picture of its effectiveness, safety, and mechanisms.

This post dives deep into the latest clinical research, clinical protocols used in practice, and what these findings mean for patients and clinicians alike.

What is Prolotherapy?

Prolotherapy is an injection-based treatment targeting areas of ligament laxity, tendon degeneration, or joint instability. The most commonly used irritant is dextrose solution, usually in concentrations ranging from 10% to 25%. The injection induces localized inflammation, which recruits growth factors and fibroblasts to rebuild collagen and strengthen damaged tissue over time.

Prolotherapy is primarily used for conditions such as:

• Osteoarthritis (especially knee and hip)

• Tendinopathies (e.g., tennis elbow, Achilles tendinopathy)

• Chronic low back pain from ligament injury

• Joint hypermobility and instability

• Temporomandibular joint (TMJ) disorders

Disclaimer: The information provided in this section is for educational purposes only and is not a substitute for professional medical advice, diagnosis, or treatment. Prolotherapy may not be suitable for everyone, and outcomes can vary. Always seek the guidance of a qualified healthcare professional regarding your specific medical condition or treatment options. Never disregard professional medical advice or delay seeking it because of information you have read here.

Recent Clinical Studies: Expanded Overview

1. Osteoarthritis of the Knee

Study: Rabago et al., 2022, Archives of Physical Medicine and Rehabilitation
Design: Randomized controlled trial with 90 patients comparing dextrose prolotherapy, saline injections, and exercise therapy
Protocol: 15–25% dextrose injections at periarticular and intra-articular sites every 4 weeks for 3 sessions
Results:

• Significant reductions in WOMAC pain scores at 6 and 12 months

• Improved joint stiffness and physical function compared to saline and exercise alone

• No serious adverse events reported

2. Chronic Low Back Pain

Study: Sit et al., 2021, Pain Physician (Meta-analysis)
Design: Review of 7 randomized controlled trials including over 400 patients
Protocol: Typically 10–15% dextrose injected into lumbar ligaments and facet joints at 4–6 week intervals, 3–6 sessions
Results:

• Moderate improvement in pain and disability scores compared to control or sham injections

• Best results seen when combined with physical therapy

• Safe with minimal side effects, mainly mild post-injection soreness

3. Tendinopathies (Lateral Epicondylitis)

Study: Lin et al., 2023, American Journal of Sports Medicine
Design: 100 patients randomized to prolotherapy vs corticosteroid injection
Protocol: 15% dextrose injected around the extensor tendon origin, 3 sessions spaced 4 weeks apart
Results:

• Superior pain relief and functional improvement at 6 and 12 months in the prolotherapy group

• Lower recurrence rates than corticosteroids

• Fewer adverse effects such as tissue atrophy

4. Temporomandibular Joint Disorders (TMJ)

Study: Lee et al., 2023, Journal of Oral Rehabilitation
Design: Pilot clinical trial with 30 patients
Protocol: 12.5% dextrose injected intra-articularly and into periarticular ligaments, 2 sessions one month apart
Results:

• Significant decrease in joint pain and improved jaw mobility at 3-month follow-up

• Encouraging safety profile but larger trials needed

Clinical Protocols in Practice: What to Expect

While protocols vary somewhat by condition and provider, here are typical prolotherapy procedures used in clinical studies:

Injection Solution

• Dextrose concentrations: 10–25% (often 15–20%)

• Other solutions may include saline, phenol-glycerin-glucose, or platelet-rich plasma (PRP) combined with dextrose

Injection Sites

• Ligament attachments and periarticular soft tissues based on the patient’s specific pathology

• Intra-articular injections may be added for joint arthritis or instability

Treatment Schedule

• Usually 3–6 sessions spaced 4–6 weeks apart

• Patients may receive follow-up injections depending on response and severity

Patient Preparation and Aftercare

• Local anesthetic used for comfort

• Mild post-injection soreness or swelling expected for 24–72 hours

• Patients encouraged to rest briefly and then gradually resume physical therapy or exercise

Emerging Mechanisms: Beyond the Inflammatory Response

Recent laboratory studies suggest prolotherapy’s effects may involve:

• Activation of fibroblasts increasing collagen synthesis

• Upregulation of growth factors such as TGF-β and PDGF

• Modulation of pain signaling pathways reducing nociceptive input

• Potential stimulation of stem cell recruitment in some tissues

These insights are guiding new combination therapies, such as prolotherapy combined with PRP or stem cell treatments, to further enhance tissue regeneration.

Limitations and Considerations

• Heterogeneous protocols make direct comparisons difficult

• Some studies have small sample sizes or short follow-ups

• Blinding challenges due to the inflammatory reaction induced

• Prolotherapy is generally considered adjunctive, best combined with physical rehabilitation

Conclusion

The growing body of clinical evidence supports prolotherapy as a promising, minimally invasive treatment for chronic musculoskeletal pain conditions, particularly knee osteoarthritis, tendinopathies, and ligamentous low back pain. While it is not a miracle cure, prolotherapy offers a valuable option within a comprehensive treatment plan aimed at tissue healing and functional restoration.

If you or someone you know suffers from chronic joint or tendon pain, prolotherapy might be worth discussing with a healthcare provider skilled in regenerative injection therapies.

Further Reading and References

• Rabago D, et al. (2022). “Dextrose Prolotherapy for Knee Osteoarthritis: A Randomized Controlled Trial.” Archives of Physical Medicine and Rehabilitation.

• Sit RWS, et al. (2021). “Prolotherapy for Chronic Low Back Pain: A Systematic Review and Meta-Analysis.” Pain Physician.

• Lin SY, et al. (2023). “Prolotherapy Versus Corticosteroid Injection for Lateral Epicondylitis: A Randomized Controlled Trial.” Am J Sports Med.

• Lee JH, et al. (2023). “Clinical Outcomes of Prolotherapy for Temporomandibular Joint Disorders: A Pilot Study.” Journal of Oral Rehabilitation.

• Kim S, et al. (2020). “Biological Mechanisms of Dextrose Prolotherapy: A Review.” Regenerative Medicine Journal.

Disclaimer: This article is for informational purposes only and does not substitute for professional medical advice. Always consult your healthcare provider before making treatment decisions.