Prolotherapy  

Lyn Weiss MD, FAAPMR, FAANEM, Julie K. Silver MD, Ted A. Lennard MD, FAAPMR and Jay M. Weiss MD, FAAPMR, FAANEM

Introduction

Prolotherapy, also known as regenerative injection therapy (RIT), is a form of treatment that involves the injection of ligaments or tendons with a proliferation agent such as dextrose. In theory, these ligaments and tendons that are injected are thought to demonstrate laxity or weakness that may be a primary pain generator. The proliferative solution is injected directly into the ligament or tendon at its bony attachment site. This solution is believed to stimulate fibroblast proliferation that restores normal connective tissue strength and length, which, in turn, reduces pain. This chapter will cover the historical aspects of prolotherapy, mechanism of action and clinical effectiveness, patient selection, and basic principles of the injection technique.

History

The principle of prolotherapy originated in the nonsurgical treatment of hemorrhoids, varicose veins, and hernias ( Poritt, 1931 ). These conditions occur because of weakness in the connective tissue structures. Similarly, in ligaments and tendons, degeneration and laxity occur that sometimes results in chronic painful conditions. Early surgeons used a technique known as sclerotherapy on many of these conditions because the injection scarred or “sclerosed” the area. In the seventeenth century, Samuel Sharp taught medical students the technique of sclerotherapy on hydroceles. In 1938 , Steindler and Luck provided strong evidence that ligaments and tendons were pain generators by the use of procaine injections ( Steindler et al ., 1938 ). They were able to locate the noxious pain generators in the spine with the use of carefully injected procaine. In 1937, Schultz treated temporomandibular joint (TMJ) laxity with Synasal, a fatty acid solution. Injections were given into the TMJ joint capsule, and results were found to be effective and safe. This was probably the first true prolotherapy treatment recorded. G. S. Hackett is considered by most to be the father of prolotherapy. He advanced this form of treatment through research and teaching in the 1950s and coined the term “prolotherapy.” He was one of the first to demonstrate ligament and tendon growth after proliferation treatments ( Hackett, 1958;Hackett and Henderson, 1955 ). His student, Gustav Hemwall, MD, further advanced the technique of prolotherapy through his clinical treatments from 1955 until 1996 and has been called by many “the world's greatest prolotherapist.”

Mechanism of Action and Clinical Effectiveness

Prolotherapy injections usually contain various combinations of dextrose, phenol, saline, glycerine, or sodium morrhuate given in multiple sites. These injected sites are within the ligament or tendon proper where it attaches to bone. It is believed by prolotherapists that ligaments and tendons often heal poorly because of a limited blood supply. This incomplete healing may result in a lax or weak band of fibrous or connective tissue that becomes painful. It is postulated that once an injection is given, a localized inflammatory response occurs. This response stimulates a wound-healing cascade that includes an influx of fibroblasts. These fibroblastic cells deposit new collagen where the injection was given. As this new collagen matures, it shortens and strengthens the injected ligament or tendon. Microscopic studies have suggested the newly formed connective tissue has biomechanical properties similar to normal ligaments and tendons ( Maynard et al ., 1985 ). Thus, the goal of prolotherapy is to restore normal tendon and ligament length and strength in the affected area. This restores skeletal support and reduces sources of myofascial trigger perpetuation ( Hackett, 1958;Reeves, 2000 ).

The clinical effectiveness of prolotherapy has been well scrutinized. Its proponents believe it is a safe and effective method to treat chronic musculoskeletal pain, loss of motion, ligament laxity, and swelling. The literature is replete with research that describes its effectiveness on chronic low back pain, peripheral joint arthritis pain, anterior cruciate ligament (ACL) laxity, and temporomandibular joint (TMJ) pain (Hakala, 2005; et al., 2000Hooper and Ding, 2004; et al., 2000Linetsky et al., 2000 ; 2001;Reeves, 2000; et al ., 2005; Yelland et al ., 2004Topol; et al ., 2005; Yelland et al ., 2004[3] et al ., 2005; Yelland et al ., 2004 ). Opponents argue there are limited high-quality data that support the use of prolotherapy in musculoskeletal conditions and that better research is needed (Dagenais et al ., 2005; Hooper and Ding, 2004; Kim et al ., 2004; Rabago et al ., 2005; Yelland, Del Mar et al ., 2004; Yelland, Glasziou et al ., 2004[2] et al ., 2005; Hooper and Ding, 2004; Kim et al ., 2004; Rabago et al ., 2005; Yelland, Del Mar et al ., 2004; Yelland, Glasziouet al ., 2004[3] et al ., 2005; Hooper and Ding, 2004; Kim et al ., 2004; Rabago et al ., 2005; Yelland, Del Mar et al ., 2004; Yelland, Glasziouet al ., 2004[4] et al ., 2005; Hooper and Ding, 2004; Kim et al ., 2004; Rabago et al ., 2005; Yelland, Del Mar et al ., 2004; Yelland, Glasziouet al ., 2004[5] et al ., 2005; Hooper and Ding, 2004; Kim et al ., 2004; Rabago et al ., 2005; Yelland, Del Mar et al ., 2004; Yelland, Glasziouet al ., 2004[6] et al ., 2005; Hooper and Ding, 2004; Kim et al ., 2004; Rabago et al ., 2005; Yelland, Del Mar et al ., 2004; Yelland, Glasziouet al ., 2004). Furthermore, it is thought that prolotherapy literature contains variable protocols, few participants, poorly defined objective measurements, and, often, anecdotal evidence.

Patient Selection

In general, patients who experience symptoms consistent with joint laxity associated with pain may be candidates for proliferation therapy. These symptoms may include clicking, popping, or stiffness with limited range of joint motion. Many patients give histories of twisting or turning to pop their affected joint or spine for transient pain relief or to improve their range of motion. Some patients demonstrate balance or fatigue problems in certain joints, especially in the cervical spine. Many exhibit referred symptoms from tendons or ligaments that include pseudoradicular pain, tingling, or numbness. Before performing prolotherapy, basic diagnostic studies are necessary. These include plain x-rays and magnetic resonance (MR) imaging. These basic studies help to eliminate underlying fractures, congenital disorders, tumors, vascular anomalies, nerve root, disc, and meniscal injuries. In some cases, an MRI can define specific ligament or tendon disorders that may be a target for future proliferative treatments.

Prolotherapy is generally reserved for patients who have not improved with traditional forms of treatment such as rest, activity modification, medication, corticosteroid injections, physical therapy, and surgery. However, many practicing prolotherapists may begin injections as early as 8 weeks after an injury for strains and sprains, with the goal of reducing protracted treatment. Patients should be instructed to discontinue nonsteroidal anti-inflammatory drugs 3 days before treatment and 10 days afterward. Contraindications to prolotherapy are listed in Table 9–1 . 

Table 9–1

Contraindications to Prolotherapy

1. Allergies to the proliferating agent

2. Acute joint dislocations

3. Septic joint

4. Posttraumatic hemarthrosis

5. Acute soft tissue injury

6. Acute gout or rheumatoid arthritis

7. Undiagnosed concomitant neurological disorder

8. Pregnancy (first trimester)

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Solutions Injected

The type of proliferant solution injected depends on the anatomical site that is being treated and the training and experience of the treating physician. Dextrose is the most commonly used proliferant and is usually recommended for a patient's first treatment session. The Hackett method ( Reeves et al ., 2000; 2003[2] et al ., 2000; 2003 ) uses predominantly dextrose solutions. Phenol-based solutions are commonly used to treat well-localized pain syndromes. The most widely used proliferant is dextrose based. See Table 9–2 for the various types of proliferant agents. 

Table 9–2

Proliferative Solutions

Dextrose-based solutions: Various dilutions with 1% lidocaine makes 10%, 12.5%, or 25% dextrose solutions.

Sodium morrhuate (usually 5%): A mixture of sodium salts of unsaturated and saturated fatty acids of cod liver oil and 2% benzyl alcohol (acts as an anesthetic and preservative).

Dextrose-phenol-glycerine (DPG or P2G) solutions; 25% dextrose/2.5% phenol/25% glycerine. This is usually diluted with a local anesthetic in a 1:1, 1:2, and 2:3 ratio.

Other solutions include 6% phenol in glycerine, tetracycline, chondroitin sulfate–glucosamine sulfate–dextrose solution.

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Injection Sites

The location of injection sites for prolotherapy is based on the knowledge of referral patterns from ligaments and tendons. These referral patterns have been well described ( Reeves, 2000 ). For example, if a patient demonstrates isolated low back pain, the facet, lumbar intertransverse, iliolumbar, and sacroiliac ligaments will be injected. If buttock pain is also present in this example, the gluteal insertions, sacrospinous ligaments, articular hip ligaments, and external rotators of the hip will also be injected. If the pain extends into the thigh, the tendons of the distal knee adductors and hamstrings, knee capsule, and tendon of the vastus medialis may require injection.Figures 9-1 and 9-2 illustrate examples of the technique used for treating low back pain. 

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Fig 9-1

Prolotherapy injection sites.

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Fig 9-2

Prolotherapy injection sites noted on the skin surface.

Injection Technique—Lumbar Spine Example

1 The patient is placed in the prone position with pillows and plinths for comfort.

2 The physician carefully palpates areas of tenderness in the lumbar spine.

3 Landmarks for injections are marked on the patient's low back. This includes the iliac crests, lumbar spinous processes, and PSIS. Avoid marking muscle trigger points.

4 Conscious sedation (optional) is given IV.

5 The patient's vital signs are closely monitored throughout the procedure.

6 The skin is cleaned with Betadine or Hibiclens.

7 Advance a 2- to 3-inch 25-gauge needle to bone adjacent to the desired ligament to be injected. Reposition the needle slightly into the ligament. In large patients, a 6-inch needle may be required.

8 Inject 1.5 mL of proliferative solution.

9 Withdraw the needle, and repeat the injection at multiple sites within the same ligament.

10 Repeat the same technique in other ligaments in the lumbar spine.

11 The patient is monitored after the procedure until stable and is discharged with a responsible driver.

12 The patient is encouraged to apply ice to the affected areas.

This same principle can be performed for most ligaments or tendons in other areas of the spine, peripheral joints, and soft tissue.

Conclusion

Prolotherapy has been used for decades for the treatment of painful musculoskeletal conditions. Its use requires proper patient selection and a good working knowledge of anatomy. One should always carefully examine and image the patient with chronic painful conditions before instituting proliferation therapy. Additional research is needed to further delineate proper patient selection and to verify outcomes after this form of treatment.

References

Dagenais 2005. Dagenais S., Haldeman S., and Wooley J.R.: Intraligamentous injection of sclerosing solutions (prolotherapy) for spinal pain: A critical review of the literature. Spine J. 2005; 5: pp. 310-328

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Hackett 1958. Hackett G.: In (eds): Ligament and Tendon Relaxation (Skeletal Disability) Treated by Prolotherapy (Fibro-osseous Proliferation), 3rd ed. Springfield, IL: Charles C. Thomas, 1958.

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Hackett 1955. Hackett G., and Henderson D.: Joint stabilization: An experimental, histologic study with comments on the clinical application in ligament proliferation. Am. J. Surg. 1955; 89: pp. 968-973

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Hakala 2005. Hakala R.V.: Prolotherapy (proliferation therapy) in the treatment of TMD. Cranio. 2005; 23: pp. 283-288

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Hooper 2004. Hooper R.A., and Ding M.: Retrospective case series on patients with chronic spinal pain treated with dextrose prolotherapy. J. Altern. Complement Med. 2004; 10: pp. 670-674

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Kim 2004. Kim S.R., Stitik T.P., Foye P.M., Greenwald B.D., and Campagnolo D.I.: Critical review of prolotherapy for osteoarthritis, low back pain and other musculoskeletal conditions: A physiatric perspective. Am. J. Phys. Med. Rehabil. 2004; 83: pp. 379-389

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Linetsky 2000. Linetsky F., et al: Regenerative injection therapy: History of application in pain management, Part I 1930s–1950s. Pain Clinic 2000; 2: pp. 8-13

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Maynard 1985. Maynard J., et al: Morphological and biochemical effects of sodium morrhuate on tendons. J. Ortho. Res. 1985; 3: pp. 234-248

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Poritt 1931. Poritt A.: The injection treatment of hydrocele, varicocele, bursae and nevi. Proc. R. Soc. Med. 1931; 24: pp. 81

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Rabago 2005. Rabago D., Best T.M., Beamsley M., and Patterson J.: A systematic review of prolotherapy for chronic musculoskeletal pain. Clin. J. Sport. Med. 2005; 15: pp. E376

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Reeves 2000. Reeves K.D.: Prolotherapy: Basic science, clinical studies, and technique. In Lennard T.A. (eds): Pain Procedures in Clinical Practice, 2nd ed. London: Hanley and Belfus, 2000. pp. 172-190

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Reeves 2000. Reeves K.D., and 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: pp. 68-74

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Reeves 2000. Reeves K.D., and Hassanein K.: Randomized, prospective, placebo-controlled double-blind study of dextrose prolotherapy for osteoarthritic thumb and finger joints: Evidence of clinical efficacy. J. Altern. Complement Med. 2000; 6: pp. 311-320

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Reeves 2003. Reeves K.D., and Hassanein K.: Long-term effects of dextrose prolotherapy for anterior cruciate ligament laxity. Altern. Ther. Health Med. 2003; 9: pp. 58-62

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Steindler 1938. Steindler A., et al: Differential diagnosis of pain low in the back; allocation of the source of pain by the procaine hydrochloride method. JAMA 1938; 110: pp. 106-113

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Topol 2005. Topol G.A., Reeves K.D., and Hassanein K.M.: Efficacy of dextrose prolotherapy in elite male kicking-sport athletes with chronic groin pain. Arch. Phys. Med. Rehabil. 2005; 86: pp. 697-702

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Yelland 2004. Yelland M.J., Del Mar C., Pirozzo S., and Schoene M.L.: Prolotherapy injections for chronic low back pain: A systematic review. Spine 2004; 29: pp. 2126-2133

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Yelland 2004. Yelland M.J., Glasziou P.P., Bogduk N., Schluter P.J., and McKernon M.: Prolotherapy injections, saline injections, and exercises for chronic low-back pain: A randomized trial. Spine 2004; 29: pp. 9-16

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