An alternative pain management option utilizing injection-based treatment.

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Pain is the most common reason that patients seek healthcare.1 Roughly $100 billion in healthcare costs, lost income and productivity mount annually due to poor pain management.1 The cost and severity of inadequate pain management should prompt consideration of alternative approaches.
Prolotherapy is an injection-based treatment for chronic musculoskeletal pain.2 The name reflects the technique's ability to promote proliferation or regeneration of new cells.3 Prolotherapy involves injection of an irritating solution into tendons, ligaments and joints to prompt white blood cells or platelets to release growth factors that stimulate healing.4 It is based on the idea that chronic pain is often due to ligament laxity that causes muscle spasms, pain and arthritic changes.4

History of the Procedure

The roots of prolotherapy were planted in 1923. Members of the American Society of Herniologists used irritating or sclerosing solutions to stimulate repair and scar tissue formation, making the muscle tissue at the site of abdominal hernias thicker and stronger.5 By the 1930s, this method was being used to repair varicose veins and hemorrhoids as well. In 1936, physician Earl Gedney of Philadelphia sustained an injury that left him with a hypermobile joint in his thumb. Using his knowledge of sclerosing hernia repair, he applied it to the joint in his hand. Pleased with his results, he began further research on the use of sclerosing solutions to treat lax ligaments.5

By the 1950s, surgical hernia repair was much more advanced and practical, so the focus of this therapy shifted from hernia repair to joint injections.5 George Hackett, MD, a trauma surgeon in Ohio, noted that injections made at the junction of ligament and bone resulted in profuse proliferation of new tissue at the site.6 Hackett spent many years developing injection therapy for ligaments and tendons and defined it as "the rehabilitation of an incompetent structure (ligament or tendon) by the generation of new cellular tissue."6

The American Society of Herniologists is now the American Osteopathic Association of Prolotherapy Regenerative Medicine (http://www.acopms.com/).5 Prolotherapy is sometimes referred to as regenerative injection therapy, reconstructive therapy, nonsurgical tendon, ligament and joint reconstruction, or growth factor stimulation therapy.6

Connective Tissue Damage

In patients with chronic pain, it is often difficult to pinpoint the causative structure. The theory of connective tissue damage syndrome states that most tenderness on palpation of painful joints occurs over ligaments and tendons, and therefore these structures must be the source of the problem.4 Connective tissue damage syndrome refers to inadequately repaired connective tissue that results in ligament and tendon laxity.6 This condition can be treated with prolotherapy.

Ligaments and tendons are highly innervated and, when stretched, they can be painful. Some of the smallest nerve fibers within ligaments and tendons carry the pain sensation.4 These fibers are susceptible to the stretching forces associated with a hypermobile joint. Bearing weight on these weakened fibers stimulates pain mechanoreceptors. As long as the connective tissue remains insufficient, the mechanoreceptors continue to fire, creating chronic pain.6 Stretched ligaments and joints result in abnormal mobility of the bones in the joint.4 Hypermobile joints lead to other pathology, such as cartilage damage, osteophyte formation, degenerative disc disease and disc damage.4

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The body's only defense against connective tissue damage is collagen repair.4 This is stimulated by growth factors that reside in white blood cells and platelets. Prolotherapy injections stimulate the white blood cells and platelets to release growth factors and to trigger collagen repair.4 The stimulation of growth factors initiates collagen repair and strengthens lax ligaments and tendons, reducing pain and preventing further damage to the joint.6 Prolotherapy is the only specialty devoted to using this healing system.

Diagnosing connective tissue damage syndrome can be difficult. The provider must recognize that the disease exists and have a good understanding of its symptoms and physical exam findings, such as: pain and tenderness over the affected structure; referred pain; muscle weakness/spasms; cartilage loss; osteogenesis; and palpable joint instability. A good history and physical exam can pinpoint the mechanism of injury, the location of pain and any muscle malfunction. Adequate knowledge of anatomy and pain referral patterns is necessary (Table 1).7

One last area to consider in making the diagnosis of connective tissue damage syndrome is the competence of the patient's healing system. Immunosuppression, chronic nonsteroidal anti-inflammatory therapy and hormonal problems such as growth factor deficiency can reduce the effectiveness of prolotherapy.4

Mechanism of Action

Prolotherapy stimulates the body's inflammatory process to release growth factors that encourage production of new tissue.8 The injected solutions, called proliferants, irritate and break open the surface of cell walls, allowing their contents to spill out into the tissue spaces to begin the healing process.8 The three most common proliferants are hypertonic dextrose, phenol-glycerin-glucose (P2G) and morrhuate sodium. Each of these works via a different pathway. Hypertonic dextrose works by prompting osmotic rupture of local cells.2 The dextrose removes water from the nearby cells, which irritates the tissue and triggers the inflammatory cascade.8 P2G simply acts as a chemical irritant.2 Sodium morrhuate, a derivative of cod liver oil, is a chemotactic activator. Once injected, it directly stimulates the cells that cause inflammation.8

Hypertonic dextrose has two mechanisms of action. It raises extracellular glucose, which increases polypeptide growth factors.9 The exposure of human cells to a hypertonic environment raises DNA levels for growth factors within seconds to minutes.9 The growth factors have the potential to overpower chondrocytes, osteocytes and fibroblasts present in the joint.9 Additionally, dextrose prolotherapy works by tightening loose ligaments. This occurs due to water loss from maturing collagen, which causes ligaments to shorten in length.10 After the treatment is complete, it is normal for the patient to experience heat, pain, swelling and redness, which are signs of inflammation - an indication that the body is working to heal itself.

Prolotherapy Technique

A standard protocol for prolotherapy has not been developed. Specific approaches differ according to the type of solution used, the volume and frequency of injections, needle size, and whether or not co-interventions are used.11 Generally, patients receive injections every 2 to 6 weeks over the course of several months.2 Patient response to treatment varies. Some experience improvement in pain after one session of prolotherapy, while others may need several sessions. If pain does not improve after three sessions, treatment should be stopped because additional sessions are not likely to make a difference.8

There is no limit to the number of prolotherapy treatments that can be delivered and the risks, which are similar to those associated with any injection, do not increase with the number of treatment sessions.8

Many prolotherapists modify their methods for patients on an individual basis. Prolotherapy injections consist of a small amount of proliferant solution, usually 0.5 to 1 mL.12 NSAID use is prohibited for 2 days prior to prolotherapy and for 2 weeks afterward, in order to allow the body's own inflammatory process to work efficiently. The length and gauge of the needle used varies depending on the anatomic location being treated.

The procedure begins with manual palpation to find tender landmarks to inject. The areas are marked with a pen, and the skin is then cleansed with an antiseptic solution. Injection of subcutaneous wheals of local anesthetic can be helpful. Another choice is to mix the anesthetic with the proliferant solution.11 Whether treating a tendon or ligament, the injection is given at the point where tissue meets bone. This is because bone has the blood supply that tendons and ligaments are lacking. This site is also chosen for safety reasons. If the needle is resting on a bone, it is not in the middle of an artery or nerve, which is where complications can arise.13 Common indications for prolotherapy are listed in Table 2.


Several research studies have examined the effectiveness and safety of prolotherapy. Hauser and colleagues documented the outcomes of 40 patients who underwent dextrose prolotherapy for chronic hand and finger pain.7 The patients had experienced pain for an average of 55 months. They were treated four times and contacted 18 months after their last treatment. Ninety-eight percent of the patients reported improvement in pain. Thirty-nine patients decreased the amount of pain medications they were taking, and all 40 said they would recommend prolotherapy.7

In another study, Grote and colleagues followed the nonsurgical repair of a torn anterior cruciate ligament (ACL) using prolotherapy and at-home exercise.14 The study was performed on an 18-year-old woman who sustained a torn ACL while downhill skiing. Magnetic resonance imaging (MRI) revealed a high-grade partial rupture of the ACL. On physical exam, the Lachman test suggested a complete rupture. Twenty-one weeks after the injury, the patient had unstable gait and was unable to ascend or descend stairs. The patient received seven prolotherapy sessions over 15 weeks, and she began at-home exercises after the third week of prolotherapy. Four weeks after prolotherapy was initiated, the patient's gait had improved on flat ground. By 12 weeks, she could ride a stationary bicycle for 30 minutes. At 15 weeks, the patient had no instability ascending and descending stairs. Also at 15 weeks, the Lachman test was negative on physical exam and MRI showed an intact ACL with fibrosis.14

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A pilot study completed by Scarpone and colleagues sought to assess whether prolotherapy would improve elbow pain, grip strength and extension strength in patients with lateral epicondylitis.15 Twenty-four patients were treated with three injections at zero, 4 and 8 weeks. The results revealed that compared to controls, the patients who received prolotherapy reported improved pain scores. Prolotherapy patients also displayed increased grip and extension strength compared to controls. The researchers concluded that prolotherapy with dextrose and sodium morrhuate was well tolerated and effective in improving symptoms of lateral epicondylosis.15

A study by Reeves and Hassanein determined the effects of dextrose prolotherapy on knee osteoarthritis with or without ACL laxity in patients at an outpatient physical medicine clinic.9 The physicians followed 111 knees in 68 patients. All patients had experienced 6 months or more of pain and had grade 2 or higher joint narrowing or other osteophytic changes in any knee compartment. Patients received three bimonthly injections of a prolotherapy mixture or a control mixture. The study concluded that dextrose prolotherapy injection resulted in clinically and statistically significant improvement in knee osteoarthritis. Radiographic readings 1 year post-treatment showed improvement in several measures of osteoarthritic severity, such as osteophyte grade, cartilage thickness and joint space narrowing. ACL laxity that had been present in the osteoarthritic patients also showed clinical improvement.9

Studies to assess the efficacy of prolotherapy for chronic low back pain (CLBP) are inconclusive. A review by Dagenais et al stated that two randomized clinical trials of prolotherapy for CLBP found no evidence of efficacy for prolotherapy injections alone without the use of co-interventions.11 A study by Yelland et al sought to determine the quality of improvement in CLBP among adult patients who received prolotherapy.16 Three hundred forty-four patients were enrolled. The authors found conflicting evidence about the efficacy of prolotherapy in reducing pain and disability. The research produced no evidence that prolotherapy alone was any more effective than control injections. In the presence of co-interventions, however, prolotherapy injections were more effective than controls.16

Much more research is necessary to determine the efficacy and safety of prolotherapy. One reason that research lags is the low price of prolotherapy solutions. No pharmaceutical company will benefit financially from funding research involving such common and cheaply available solutions.13

Looking Ahead

Prolotherapy is an unregulated procedure, and no formal training is offered by medical schools, residencies or fellowships.2 However, the procedure requires specialized training. This can be obtained through organizations such as the American Academy of Musculoskeletal Medicine (http://www.aamsm.com/Public/Home/index.cfm), the American Osteopathic Association of

Prolotherapy Regenerative Medicine (http://www.acopms.com/), and the American Association of Orthopedic Medicine (http://www.aaomed.org/Prolotherapy-Certification).2,6 Some physicians who practice prolotherapy offer preceptor training in their offices.6,8

Today, prolotherapy is being performed by a growing number of family and sports medicine physicians, orthopedic surgeons, neurologists and anesthesiologists. It is usually reserved for patients who are not surgical candidates or who have not responded adequately to other treatments.2 As more quality research is published and more physicians become skilled in prolotherapy, the treatment should become more accepted as an alternative for patients with chronic pain.8

Most insurance plans do not cover prolotherapy. Depending on the location and number of prolotherapy sessions a patient undergoes, the cost ranges between $75 and $400 per session.8 When a patient does not respond to conventional treatments such as corticosteroid injection and physical therapy, a case may be made for reimbursement or prolotherapy treatment.

In the past, prolotherapy was mainly used to treat chronic musculoskeletal issues. The future of prolotherapy appears to be headed toward the treatment of athletes in the acute phase of injury to speed up their return to play.13

In the United States, healthcare providers who are authorized to deliver joint injections can perform prolotherapy. NPs and PAs whose scope of practice permits them to perform corticosteroid injections are therefore usually permitted to perform prolotherapy.


1. Physician assistant's prescribing reference. New drug information. Product: Embeda. JAAPA. 2009;22(11):12.

2. Rabago D, et al. Prolotherapy in primary care practice. Prim Care. 2010;37(1):65-80.

3. Hauser RA. The regeneration of articular cartilage with prolotherapy. J Prolotherapy. 2009;1:39-44.

4. Johnson M. Prolotherapy and connective tissue damage syndrome: why am I hurting, and no one seems to know what is wrong? J Prolotherapy. 2009;1:45-53.

5. Alderman D. A history of the American College of Osteopathic Sclerotherapeutic Pain Management, the oldest prolotherapy organization. J Prolotherapy. 2009;4:200-204.

6. Alderman D. Prolotherapy for musculoskeletal pain: a primer for pain management physicians on the mechanism of action and indications for use. Practical Pain Management. 2007;7(1):10-15.

7. Hauser R, et al. A retrospective observational study on Hackett-Hemwall dextrose prolotherapy for unresolved hand and finger pain at an outpatient charity clinic in rural Illinois. J Prolotherapy. 2010;2(4):480-486.

8. Tortland P, et al. Regenerative injection therapy. Valley Sports Physicians and Orthopedic Medicine. http://www.jockdoctors.com/library/documents/Prolotherapy.pdf

9. Reeves KD, Hassanein K. Randomized prospective double-blind placebo-controlled study of dextrose prolotherapy for knee osteoarthritis with or without ACL laxity. Altern Ther Health Med. 2000;6(2):68-80.

10. Reeves KD, Hassanein K. Long term effects of dextrose prolotherapy for anterior cruciate ligament laxity. Altern Ther Health Med. 2003;9(3):58-62.

11. Dagenais S, et al. Evidence-informed management of chronic low back pain with prolotherapy. Spine J. 2008;8(1):203-212.

12. Fullerton BD. High-resolution ultrasound and magnetic resonance imaging to document tissue repair after prolotherapy: a report of 3 cases. Arch Phys Med Rehabil. 2008;89(2):377-385.

13. Anderson RJ. Vaulting over pain. Training and Conditioning. 2007;17(7):15-19.

14. Grote W, et al. Repair of a complete anterior cruciate tear using prolotherapy: a case report. Int Musculoskel Med. 2009;31(4):159-165.

15. Scarpone M, et al. The efficacy of prolotherapy for lateral epicondylosis: a pilot study. Clin J Sports Med. 2008;18(3):248-254.

16. Yelland MJ, et al. Prolotherapy injections for chronic low-back pain. Cochrane Datab Syst Rev. 2004;(2):CD004059.

Michele Kauffman is a physician assistant who is chairwoman of the physician assistant department at Gannon University in Erie, Pa. Stevie Lynn Crisci is a physician assistant at Three Rivers Orthopedic Associates in Pittsburgh. The authors have completed disclosure statements and report no relationships related to this article.


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