Prolotherapy for Chronic Musculoskeletal Pain

By Dónal P. O'Mathúna, PhD Dr. O'Mathúna is a lecturer in Health Care Ethics, School of Nursing, Dublin City University, Ireland; he reports no consultant, stockholder, speaker's bureau, research, or other financial relationships with companies having ties to this field of study.

Each Olympics brings thrills, triumphs, tears, and, nowadays, tales of the latest controversial drugs among athletes. This year's Winter Olympics in Turin, Italy, was no exception. As the athletes made final preparations to hit the slopes, news hit the airwaves of an injectable treatment for injuries. Two prominent U.S. skiers were injected for knee injuries at a Mexican clinic. The treatment does not contain banned substances, but remains controversial.1 So too is its most high-profile practitioner, Milne Ongley. A physician from New Zealand, Ongley's license to practice medicine was revoked for malpractice in 1973. He moved to the United States where he was later barred from practicing medicine; then he moved to Mexico.2

Ongley injects a solution of dextrose, glycerin, and phenol. Other prolotherapists use different mixtures. Prolotherapy is or has been known by other names, including reconstructive therapy, proliferative therapy, or sclerotherapy. The latter also refers to a completely different procedure used for vessel occlusion in gastroenterology and surgery.3 One review found 21 different names for prolo-therapy.4 While media attention has focused on prolotherapy for sports injuries, other uses include treating chronic back pain and osteoarthritis. Physicians should be aware of this increasingly popular therapy.


Prolotherapy was developed in the 1930s by Louis Schultz, an oral surgeon. He described the injection of psyllium seed extracts for temporomandibular joint pain.5 He conducted animal experiments which led George Hackett, a general surgeon, to apply the injection protocols more generally in the 1950s.3 Hackett proposed that some chronic musculoskeletal pain arose from ligamentous laxity which led to joint instability.5 The laxity could arise from injury, poor posture, or age-related degeneration. Hackett also changed the name from sclerotherapy (derived from the idea that the injections cause scarring to overcome joint laxity) to prolotherapy (from the idea that the injections promote proliferation of new tissue).6

Prolotherapy injections are currently used to treat various musculoskeletal injuries. Among athletes, 85% of sprains are due to ligamentous injuries and the injections reportedly strengthen ligaments that have been stretched or torn.

Prolotherapy is practiced in many different ways. The injections are administered at different intervals, for different lengths of time, and with various co-interventions, including exercise regimens, physical manipulations, and vitamin supplements.7 A review of clinical trials found that 20 different mixtures had been used in the studies.4 Sixteen solutions used dextrose and nine combined dextrose, glycerin, and phenol. Most procedures also used a local anesthetic because of the discomfort caused by the injections. Although various mixtures are used, almost half the studies injected "P2G," which contains dextrose 12.5%, glycerin 12.5%, phenol 1.25%, and lidocaine 0.25%. The solution is typically prepared by compound pharmacists using USP-grade ingredients and autoclaved to ensure sterility. Several injections of around 1-2 mL are made into the ligament(s) at the site of pain or tenderness, with total volumes ranging from 5 to 30 mL.

Mechanism of Action

Prolotherapy solutions are believed to cause a local inflammatory reaction that leads to growth and strengthening of collagenous structures. The three commonly used components are believed to act in different ways to promote this response. One component is an irritant, such as phenol, guaiacol, or tannic acid.5 This causes local oxidative damage, which initiates an inflammatory cascade. Pumice flour is sometimes used as a particulate irritant.4 The second component is an osmotic agent, such as dextrose, glycerin, or zinc sulfate. This causes cell dehydration or damage, which further promotes the inflammatory response. The third component is a chemotactic agent, usually sodium morrhuate. This fatty acid salt is derived from cod liver oil and is a precursor of inflammatory mediators, including prostaglandins and thromboxanes.5 The mixture is believed to bring various growth factors to the site of injury. These promote growth and strengthening of collagenous structures, which is hypothesized to reduce joint laxity, improve biomechanics, and reduce pain.3

Clinical Studies

A number of animal studies with prolotherapy have been conducted since the 1930s. While the early studies found improved ligament size and strength, study design was often poor compared to more recent methodology.4 The older studies were carried out with healthy animals, while more recent studies with injured animals have not found statistically significant improvements.4

A comprehensive review of prolotherapy for chronic musculoskeletal pain identified 42 clinical studies.3 Of these, 34 were case reports or case series studies involving a wide variety of indications. Low back pain was studied in almost three-quarters of the cases. The results were consistently positive as measured by pain reduction and improved function. However, methodology quality was often poor and none of these 34 studies included randomized control groups. The review also identified six randomized controlled trials (RCT), two involving intra-articular injections for osteoarthritis and four involving low back pain. Only the studies involving low back pain will be reviewed here as they fit into the general claim that prolotherapy is effective for conditions caused by ligament laxity and resulting joint instability. Three other systematic reviews identified the same four RCT and one additional one.4,5,8

The first published RCT was carried out by the man at the center of the skiing controversy, Milne Ongley.9 He recruited 81 patients who had chronic back pain for an average of 10 years. On the first day, both groups received a 0.5% lidocaine injection and a spinal manipulation. However, the treatment group received a manipulation of typical force while the control group received one of suboptimal force. On the second day, both groups began a series of weekly low back injections for six weeks and were taught flexion exercises. The treatment group received the P2G solution and the control received saline injections. The treatment group also received steroid injections (triamcinolone) into the gluteus medius muscles. After six months, the treatment group had significantly better outcomes than the control group for pain scores (P < 0.001) and disability rating (P < 0.003).

Another RCT involved 22 patients with low back pain, with 16 in the treatment group and six in the control group.10 The prolotherapy solution contained dextrose 10%, glycerin 12%, phenol 1%, and procaine 0.3%, with saline as the control. The prolotherapy injections were given into the lumbosacral ligaments and the saline injections into an unspecified tender spot. A total of three injections were given on a biweekly schedule. After 12 months, the percentage of patients reporting no pain, occasional pain, or constant pain did not differ significantly between the two groups.

A third RCT sought to remove some of the co-intervention differences in Ongley's study.11 Seventy-nine patients with chronic, unresponsive back pain received typical spinal manipulations under local anesthetic and intravenous sedation. All were instructed to perform daily flexion and extension exercises. Patients in both groups with hyperirritable areas were injected with triamcinolone or corticosteroid. On the next day, six weekly injections commenced with patients receiving either P2G or lidocaine 0.25% in saline. After six months, both groups had improved significantly on two pain scales and a disability score, but the improvements did not differ significantly between the two groups. The treatment group contained significantly more patients reporting more than 50% reduction in pain (P < 0.05).

The next RCT randomly assigned 74 patients with chronic low back pain to three weekly injections of either P2G or lidocaine 0.25% in saline.12 Outcomes were measured at one, three, and six months. Steroid injections, spinal manipulation, and exercises were not included, and the injections were given to a limited area of the spine. No significant differences were found between the two groups in pain, disability, and range of motion scores.

The most recent RCT included 110 patients averaging 14 years with chronic back pain.7 Patients were randomly assigned to receive either dextrose 20% and lidocaine 0.2% or saline and then randomized again to either perform flexion and extension exercises or maintain normal activity. All patients were given vitamin and mineral supplements and compliance was checked. Follow-up was continued for two years. Pain and disability scores dropped significantly in all groups (P < 0.05), with no statistical differences between the groups based on injection solution or type of activity.

Adverse Effects

Initial pain at prolotherapy injection sites is commonly reported, which is why local anesthetics are used.4 A small number of patients have withdrawn from some studies because of the intensity of this pain. Cases of radiating leg pain and nausea have been reported. Usually, the pain subsides within a few days, but can be accompanied by local stiffness and headache. Apart from the initial reaction, prolotherapy is reported to be relatively free of adverse effects.


As noted above, a number of different formulations are used. The most commonly used solution is P2G, containing dextrose 12.5%, glycerin 12.5%, phenol 1.25%, and lidocaine 0.25% made to USP standards. Injection volumes and frequency of administration are also highly variable, with six weekly injections delivering 30 mL solution being the most common regimen.4


The evidence regarding prolotherapy is unclear. RCTs of prolotherapy have focused mainly on low back pain. Three found no benefit compared to control, and two found some benefit. The results of the first RCT were "some of the most impressive ever reported in any RCT on chronic low back pain and need to be repeated to increase their credibility."4 However, the two groups differed in several ways in addition to prolotherapy (concurrent exercise, steroid injections, and type of manipulation).9 The other positive study eliminated these differences, but only found significant differences when subgroup analysis was conducted.11

The studies reporting no significant benefits also had limitations. The earliest had a very small number of participants unevenly distributed between the two groups.10 The next did not follow the usual injection pattern12 and the most recent used a solution not typically used in prolotherapy.7 However, these studies did report improvements in both groups. Case reports and cohort studies on low back pain report consistent improvements in patients who have been unresponsive to other therapies for many years.

RCTs for athletic ligamentous injuries were not found, though a recent consecutive case series examined prolotherapy for chronic groin strain in 24 rugby and soccer players.13 Dextrose 12.5% and lidocaine 0.5% injections were given monthly until pain resolved or no further improvement occurred for two consecutive treatments. Participants received an average of 2.8 injections and were followed up for an average of 17 months. At last assessment point, 20 players had no groin pain and 22 of 24 had unrestricted sports involvement. Such impressive results warrant further controlled investigations.


Clarification of what precisely constitutes prolotherapy is urgently needed. The injected solutions vary widely, are administered in different ways, and are combined with various co-interventions. Such variety makes it difficult to identify the critical components. A consistent finding is that some people with unresponsive chronic musculoskeletal pain are helped by injections, regardless of what they contain. Prolotherapy may be worth a trial for those with refractory low back pain. However, the injections should be presented to patients as experimental. Until further RCTs provide better evidence on which solutions and protocols are effective for particular forms of musculoskeletal pain, recommendations must remain tentative.


1. Dufresne C, Roan S. A ski run for border. LA Times. Feb. 9, 2006. Available at,1,6914731,full.story?coll=la-headlines-sports&ctrack=1cset=true. Accessed Feb. 22, 2006.

2. NZPA. NZ-born therapist in Olympic row. New Zealand Herald. Feb. 2, 2006. Available at Accessed Feb. 22, 2006.

3. Rabago D, et al. A systematic review of prolotherapy for chronic musculoskeletal pain. Clin J Sport Med 2005;15:376-380.

4. Dagenais S, et al. Intraligamentous injection of sclerosing solutions (prolotherapy) for spinal pain: A critical review of the literature. Spine J 2005;5:310-328.

5. Kim SR, et al. Critical review of prolotherapy for osteoarthritis, low back pain, and other musculoskeletal conditions: A physiatric perspective. Am J Phys Med Rehabil 2004;83:379-389.

6. Mooney V. Prolotherapy at the fringe of medical care, or is it the frontier? Spine J 2003;3:253-254.

7. Yelland MJ, et al. Prolotherapy injections, saline injections, and exercises for chronic low-back pain: A randomized trial. Spine 2004;29:9-16.

8. Yelland MJ, et al. Prolotherapy injections for chronic low back pain: A systematic review. Spine 2004;29:2126-2133.

9. Ongley MJ, et al. A new approach to the treatment of chronic low back pain. Lancet 1987;2:143-146.

10. Mathews JA, et al. Back pain and sciatica: Controlled trials of manipulation, traction, sclerosant and epidural injections. Br J Rheumatol 1987;26:416-423.

11. Klein RG, et al. A randomized double-blind trial of dextrose-glycerine-phenol injections for chronic, low back pain. J Spinal Disord 1993;6:23-33.

12. Dechow E, et al. A randomized, double-blind, placebo-controlled trial of sclerosing injections in patients with chronic low back pain. Rheumatology 1999;38:1255-1259.

13. Topol GA, et al. Efficacy of dextrose prolotherapy in elite male kicking-sport athletes with chronic groin pain. Arch Phys Med Rehabil 2005;86:697-702.