American Association of Orthopaedic Medicine

Position Statement

Prolotherapy for the Treatment of Back Pain

This pronouncement was written for the American Association of Orthopaedic Medicine by

 Robert G. Klein, M.D., Jeffrey Patterson, D.O., Bjorn Eek, M.D. and David Zeiger, D.O.

Summary

It is the position of the American Association of Orthopaedic Medicine that prolotherapy is a safe efficacious therapy for the treatment of selected cases of low back pain and other chronic myofascial pain syndromes.   This is based upon basic science data showing the effects of prolotherapy in animal models, clinical studies, a lengthy history of clinical use and efficacy, and increasingly widespread acceptance within the medical community.   While we recognize that further basic science and clinical studies need to be done and are currently in process, we believe that prolotherapy is a safe, cost effective and efficacious therapy that can provide pain relief and return of function for many patients. 

Introduction

Prolotherapy is an injection therapy used to treat chronic ligament, joint capsule, fascial and tendinous injuries of the low back. The goal of this treatment is to stimulate proliferation of collagen at fibro-osseous junctions to promote non-surgical soft tissue repair and to relieve pain. [1] Animal studies by Liu and others have shown proliferation of collagen with strengthening of ligaments with prolotherapy.[2] Further animal research is currently underway at the University of Wisconsin Medical School.   Prolotherapy is commonly used in veterinary medicine.  

The mechanism of action of ligament proliferation was supported by a pilot study in human volunteers that demonstrated an average increase of 65% in cross-sectional diameter of posterior sacroiliac ligaments 3 months after treatment. Computerized measurements of range of lumbar motion before and after treatment have also demonstrated improvements in motion that are consistent with soft tissue healing.  [3,4]

Scientific Evidence

There have now been 5 randomized clinical trials (RCT'S) of prolotherapy [5-9] for chronic low back pain; their methodology has varied considerably. Two of the trials  [6,7] used similar protocols with well defined injection sites, using dextrose-glycerine-phenol-xylocaine as the solution injected, and 6 weekly injection treatments of 20-30mL each. Both trials used multiple standardized and validated outcome measures to capture changes in pain, disability, and function over a minimum of 6 months, and both trials reported statistically significant improvements in pain and disability in the treatment groups.

The 3 other trials differed considerably. The study by Mathews et al [9] enrolled only 22 patients (16 treatment and 6 controls) and was unlikely to have the statistical power needed to detect a reasonable difference between treatment and placebo. The study by Dechow et al [8] had only 3 weekly injection treatments of 10mL each (total volume 30mL vs. 120-180mL in the two successful trials) of dextrose-glycerine-phenol solution. In addition, the authors attempted to inject all low back ligaments from only 2 injection sites rather than lifting and reinserting the needle at multiple sites as is commonly practiced. This technical difference may have impacted where the solution was injected. Patient selection was also an impediment in this trial, and the authors concluded that: “Many patients were not considered ideal candidates for sclerosing injections by the operator at the time of the treatment for a variety of reasons relating to technical difficulties, deconditioning, patients relying on invalidity benefit, excessive psychological stress, etc. even though they technically fulfilled the inclusion criteria. Therefore, the group of patients recruited into our study was likely to respond poorly to any single intervention in keeping with the relatively poor prognosis in the group of patients today in the UK.”

The most recent study by Yelland from Australia [5] used a 20% dextrose solution that was injected at only 20% of the usual sites and did not include facet joint capsules included in the 2 positive RCT's. Not surprisingly, the study failed to show an advantage of plain dextrose, which is a weak prolotherapy solution, compared to a placebo injection of saline. Despite the shortcomings of this study the results obtained in terms of pain relief and increased function are quite striking. In both the group of prolotherapy patients (mean duration of pain was 14.8 years) and in the saline injection group (mean duration was 13.8 years), there was a statistically significant decrease in pain and disability scores at both 12 and 24 months’ follow-up. In fact, just a fraction less than half of the patients in the prolotherapy group (46%) achieved a greater than 50% reduction of pain and 42% achieved a greater than 50% reduction in disability score. The authors stated that "participants exhibited marked and sustained improvements in their pain and disability, even with saline injections and normal activity." It should be appreciated that the bleeding and tissue disruption associated with needling and saline injections also has a mild proliferant effect so in fact there was no true placebo treatment.  There may also be neurological effects of prolotherapy in relieving pain.  The authors also admitted that "this trial's success rates in reducing pain and improving disability are at least as good as those reported for spinal cord stimulation, surgery or multidisciplinary treatment for patients with low back pain of shorter duration."

Although there is disagreement among the studies regarding the use of prolotherapy for chronic low back pain, this situation is hardly unique to this specific injection treatment. A recent systematic review of the literature by Nelemans in Spine [10] demonstrates how little evidence there is for the efficacy of a variety of commonly utilized and reimbursed low back treatments including facet injections, trigger point injections, and epidural injections. One of the prolotherapy trials discussed above [6] was included in this review and ranked fourth out of twenty-one randomized trials in terms of study design and is mentioned as the only one with significant follow-up. This study was one of the few that they cited as showing definite statistical efficacy when compared to a control treatment using placebo saline injections.

The literature also indicates that prolotherapy appears to be very safe. None of the clinical trials have reported any serious adverse events with this treatment. In addition, a survey of adverse events related to prolotherapy reported that a group of almost 100 physicians had collectively almost 500,000 patients with this treatment approach and experienced only 66 complications, none of which were life-threatening. This is supported by the low number of serious or adverse reactions documented in the Florida review. 

Although additional studies regarding the use of prolotherapy for chronic low back pain are necessary to address methodological issues of the previous trials, the same is true for all other low back treatment approaches, many of which are commonly utilized and covered by insurers with less documentation than prolotherapy. The reality is that despite the enormous impact of low back pain to our society there are no clearly effective treatments for chronic back pain, at least not in the sense that they are supported by multiple, high-quality randomized clinical trials using multiple validated outcome measures and an appropriate follow-up period. Nevertheless, patients continue to receive care for their chronic low back pain and insurers routinely pay for such care despite a lack of convincing efficacy for all chronic low back pain treatments.  In fact, because of multiple pain generators that may come into play in low back pain, it is quite likely that multiple therapies will be necessary in any one patient or group of patients.  

Recommendations

Prolotherapy should be considered a valid treatment option in a selected group of chronic low back pain patients. As such, it should not be held to a higher standard than other treatments with the same lack of efficacy that are nevertheless covered by insurers, such as epidural injections, steroid injections, and IDET, not to mention surgery for cases in which instability or progressive neurological deficit is absent. The goal of providing access only to the highest quality of treatments supported by the scientific literature is laudable. However, if insurers were to adopt a universal policy of denying payment for chronic low back pain treatments based on lack of definitive evidence, no one with chronic back pain would be able to obtain any treatment. Since this is clearly unacceptable, an alternative is to provide coverage for those treatments that are biologically plausible, supported in the literature by a number of cohort and randomized clinical trials, and have a reasonable safety profile.

Prolotherpy should be performed by well trained providers utilizing selected solutions and techniques. A number of different solutions are used in prolotherapy. The most common ingredients in these solutions are hyperosmolar dextrose and/or glycerine, combined with local anesthetics such as lidocaine or marcaine. A more detailed description of prolotherapy is available in the appended position paper by the Florida Academy of Pain Management and the review in Musculoskeletal Medicine that is also appended.

Conclusions

Vert Mooney, M.D., a prominent orthopedic surgeon and former chairman of orthopedics at the University of California, San Diego, wrote a recent editorial in The Spine Journal concerning prolotherapy [11]. He concluded that "this fringe treatment (prolotherapy) is no longer at the periphery and seems to be at the frontier of a justifiable, rational treatment with a significant potential to avoid destructive procedures."

We therefore urge the California Technical Assessment Forum to provide coverage for prolotherapy for chronic low back pain.

References

1.         Banks, A.R., A Rationale for Prolotherapy. Journal of Orthopaedic Medicine, 1991. 12(3): p. 54-59.

2.         Liu, Y.K. and e. al, An in situ study of the influence of a sclerosing solution in rabbit medial collateral ligaments and its junction strength. Connective Tissue Research, 1983. 11: p. 95-102.

3.         Klein, R.C., T.A. Dorman, and C.E. Johnson, Proliferant injections for low back pain: histologic changes of injected ligaments and objective measurements of lumbar spine mobility before and after treatment. J of Neurol and Ortho Med and Surg, 1989. 10(2): p. 123-126.

4.         Klein, R. and B. Eek, Prolotherapy: an alternative way of managing low back pain. J of musculoskeletal Med, 1997: p. 45-49.

5.         Yelland, M.J. and e. al., Prolotherapy injections, saline injections, and exercises for chronic low back pain: a randomized trial. Spine, 2004. 29(1): p. 9-16.

6.         Ongley, M.J., et al., A new approach to the treatment of chronic low back pain. The Lancet, 1987: p. 143-146.

7.         Klein, R.G., et al., A Randomized double-blind trial of dextrose-glycerine-phenol injections for chronic, low back pain. J. Spinal Disord, 1993. 6(1): p. 23-33.

8.         Dechow, E. and et.al., A randomized, double-blind, placebo-controlled trial of sclerosing injections in patients with chronic low back pain. Rheumatology (Oxford), 1999. 38(12): p. 1255-9.

9.         Mathews, J.A. and et.al., Back pain and sciatica: controlled trials of manipulation, traction, sclerosant and epidural injections. Br J Rheumatol, 1987. 26(6): p. 416-23.

10.       Nelemans, P. and et.al., Injection therapy for subacute and chronic benign low back pain. Spine, 2001. 26(5): p. 501-15.

11.       Mooney, V., Prolotherapy at the fringe of medical care, or is it at the frontier? Spine, 2003. 3(4): p. 253-4.

Appendices

1.         Klein, R. and B. Eek, Prolotherapy: an alternative way of managing low back pain. J of musculoskeletal Med, 1997: p. 45-49.

2.         Nelemans, P. and et.al., Injection therapy for subacute and chronic benign low back pain. Spine, 2001. 26(5): p. 501-15.

3.         Mooney, V., Prolotherapy at the fringe of medical care, or is it at the frontier? Spine, 2003. 3(4): p. 253-4.

4.         The Florida Academy of Pain Medicine (FAPM), Position Paper on Regenerative Injection Therapy (RIT): Effectiveness and Appropriate Usage.  May, 2001.

Originally published in THE LANCET, July 18, 1987, pp. 143 - 146

A NEW APPROACH TO THE TREATMENT OF
CHRONIC LOW BACK PAIN

Department of Rheumatology, Sansum Medical Clinic, and the Sansum Medical Research Foundation, Santa Barbara, California 93102, USA

Summary 81 patients with chronic low back pain (average duration 10 years) were randomised to two treatment groups. 40 received an empirically devised regimen of forceful spinal manipulation and injections of a dextrose-glycerine-phenol ("proliferant") solution into soft-tissue structures, as part of a programme to decrease pain and disability. The other 41 patients received parallel treatment in which the main differences were less extensive initial local anaesthesia and manipulation, and substitution of saline for proliferant. Neither patients nor assessors knew which treatment had been given. When assessed by disability scores the experimental group had greater improvement than the control group at one (p<0·001), three (p<0·004), and six (p<0·001) months from the end of treatment; at six months an improvement of more than 50% was recorded in 35 of the experimental group versus 16 of the control group and the numbers free from disability were 15 and 4, respectively (p<0·003). Visual analogue pain scores and pain diagrams likewise showed significant advantages for the experimental regimen.

Injected Solutions

The experimental solution consisted of dextrose 25% (694 mosmol/1), glycerine 25% (2720 mosmol/1), phenol 2.5% (266 mosmol/1), and pyrogen-free water to 100%. Because this solution may cause a temporary irritation it was diluted with an equal volume of 0·5% plain lignocaine hydrochloride ('Xylocaine') to make it comparable with the placebo injection in terms of initial provocation of post-injection pain. Patients in the placebo group received sterile 0·9% saline. Each patient received six injections of approximately 20 ml of the same solution weekly. The solutions were identical in appearance and were prepared by a pharmacist using sterile techniques. Phenol has a characteristic odour that might be detectable if a drop of solution was spilled. This potential source of bias was eliminated by addition of phenol to the skin preparation throughout the study.

RESULTS

One month after treatment both groups had improved in terms of disability and visual analogue pain scores, but the improvement was significantly greater in the experimental group at this time and at three and six months (table III). 35 of 40 patients in the experimental group had greater than 50% improvement in disability scores, compared with 16 of 41 in the control group; and the numbers with zero disability scores at six months were 15 and 4, respectively (p<0·003).

DISCUSSION

The sacroiliac joint has a small range of motion, and when the joint is at the limit of its range no great force is needed to damage its ligaments.¹⁴ Once the ligaments of the low back and pelvis become incompetent, instability results.

This permits excessive external moments to be transmitted to the three-joint complex of intervertebral disc and zygapophyseal joints,¹⁵ and torsional stresses to be placed on the lumbar vertebrae and sacrum. The former may lead to disc and zygapophyseal joint degeneration and the latter to a slight displacement of the sacrum from its normal anatomic position,¹⁴ placing traction on pain sensitive structures and producing local as well as referred pain.

The treatment programme tested here has multiple components. We offer the following speculations as to why it is effective. The dilute lignocaine serves to interrupt the pain reflex arc and facilitate the manipulation. Triamcinolone "disinflames" the gluteal muscles, which are subjected to chronic mechanical strain owing to the incompetence of the lumbar and sacroiliac ligaments. The manipulation moves the sacroiliac joint through a full range of motion, rupturing any microadhesions which may form in response to connective tissue immobilisation,¹⁶ and corrects any minor sacral malalignment present. The transient benefits previously demonstrated with manipulation¹⁷ are usually not sustained unless the supporting ligaments are strengthened. The proliferant induces an inflammatory response which leads to fibroblastic hyperplasia and the growth of collagen.¹ The exercises encourage synthesis of the extracellular connective tissue matrix,¹⁶ increase ligament junction strength,¹⁸ and induce proliferating fibroblasts to line up in parallel to existing connective tissue.¹⁹

Defining worthwhile and desired responses to treatment of chronic low back pain.
Pain Med. 2006 Jan-Feb;7(1):38-45.
Yelland MJ, Schluter PJ.

School of Medicine, Griffith University and Faculty of Health and Environmental Sciences, Auckland University of Technology, Australia.

OBJECTIVE: To describe patients' perceptions of minimum worthwhile and desired reductions in pain and disability upon commencing treatment for chronic low back pain. DESIGN AND SETTING: Descriptive study nested within a community-based randomized controlled trial on prolotherapy injections and exercises. PATIENTS: A total of 110 participants with chronic low back pain. Interventions. Prior to treatment, participants were asked what minimum percentage reductions in pain and disability would make treatment worthwhile and what percentage reductions in pain and disability they desired with treatment. OUTCOME MEASURES: Minimum worthwhile reductions and desired reductions in pain and disability. RESULTS: Median (inter-quartile range) minimum worthwhile reductions were 25% (20%, 50%) for pain and 35% (20%, 50%) for disability. This compared with desired reductions of 80% (60%, 100%) for pain and 80% (50%, 100%) for disability. The internal consistency between pain and disability responses was high (Spearman's coefficient of association of 0.81 and 0.87, respectively). A significant association existed between minimum worthwhile reductions and desired reductions, but no association was found between these two factors and patient age, gender, pain severity or duration, disability, anxiety, depression, response to treatment, or treatment satisfaction. CONCLUSIONS: Inquiring directly about patients' expectations of reductions in pain and in disability is important in establishing realistic treatment goals and setting benchmarks for success. There is a wide disparity between the reductions that they regard as minimum worthwhile and reductions that they hope to achieve. However, there is a high internal consistency between reductions in pain and disability that they expect.

Prolotherapy (proliferation therapy) in the treatment of TMD.
Cranio. 2005 Oct;23(4):283-8.
Hakala RV.

Minnesota Craniofacial Center Midway, 1690 University Avenue West, Suite 390, Saint Paul, MN 55104, USA. drhakala@mncranio.com

Proliferation therapy, or "prolotherapy," is also known as regenerative injection therapy (RIT). Since the 1930s, the technique has been used to stabilize injured joints and to relieve joint pain. This article reviews the history and scientific literature regarding prolotherapy and describes the application of the technique to treat injured or unstable temporomandibular joints (TMJ). Alternative medicaments and the likely mechanisms of action are discussed. A brief preliminary summary of a retrospective clinical study of the efficacy of prolotherapy is included. The study shows that prolotherapy can be an effective therapeutic modality that reduces TMJ pain and joint noise in a majority of patients who have reached a plateau with use of an intraoral appliance, physical therapy, and home care.

A systematic review of prolotherapy for chronic musculoskeletal pain.
Clin J Sport Med. 2005 Sep;15(5):376-80.
Rabago D, Best TM, Beamsley M, Patterson J.

University of Wisconsin-Madison, Madison, WI 53715, USA. David.Rabago@fammed.wisc.edu

OBJECTIVE: Prolotherapy, an injection-based treatment of chronic musculoskeletal pain, has grown in popularity and has received significant recent attention. The objective of this review is to determine the effectiveness of prolotherapy for treatment of chronic musculoskeletal pain. DATA SOURCES: We searched Medline, PreMedline, Embase, CINAHL, and Allied and Complementary Medicine with search strategies using all current and historical names for prolotherapy and injectants. Reference sections of included articles were scanned, and content area specialists were consulted. STUDY SELECTION: All published studies involving human subjects and assessing prolotherapy were included. MAIN RESULTS: Data from 34 case reports and case series and 2 nonrandomized controlled trials suggest prolotherapy is efficacious for many musculoskeletal conditions. However, results from 6 randomized controlled trials (RCTs) are conflicting. Two RCTs on osteoarthritis reported decreased pain, increased range of motion, and increased patellofemoral cartilage thickness after prolotherapy. Two RCTs on low back pain reported significant improvements in pain and disability compared with control subjects, whereas 2 did not. All studies had significant methodological limitations. CONCLUSIONS: There are limited high-quality data supporting the use of prolotherapy in the treatment of musculoskeletal pain or sport-related soft tissue injuries. Positive results compared with controls have been reported in nonrandomized and randomized controlled trials. Further investigation with high-quality randomized controlled trials with noninjection control arms in studies specific to sport-related and musculoskeletal conditions is necessary to determine the efficacy of prolotherapy.

Intraligamentous injection of sclerosing solutions (prolotherapy) for spinal pain: a critical review of the literature.
Spine J. 2005 May-Jun;5(3):310-28.
Dagenais S, Haldeman S, Wooley JR.

Department of Environmental Health, Science, and Policy, University of California, Irvine, CA 92697, USA. Simon@CamResearch.com

BACKGROUND CONTEXT: The injection of various solutions aimed at producing a sclerosing effect has been used to treat soft tissues injuries (eg, inguinal hernia) for more than 100 years. In the 1930s, this treatment approach was applied to injured joints in an attempt to stimulate connective tissue repair. Although several studies have been published about this method of treatment for various orthopedic and spinal indications (termed prolotherapy), its use remains controversial. PURPOSE: To conduct a critical review of the literature on prolotherapy for spinal pain. STUDY DESIGN/SETTING: Critical review of the literature. METHODS: Computerized medical literature databases (Medline, CINAHL, Mantis, Cochrane Central Register of Controlled Trials) were searched to uncover all published information about the use of sclerosing injections in humans with spinal pain disorders. Search results were reviewed for relevance, and information was abstracted from full-text articles. RESULTS: Our search uncovered almost 200 reference materials in various media related to prolotherapy, including 31 clinical studies related to spinal pain. There were 26 observational cohorts and 5 randomized clinical trials (RCTs). Indications in these studies were low back pain (22), neck pain (3), cervical headaches (3) and dorsal or thoracic pain (3). A total of 20 sclerosing solutions were used in these studies; the most common was a mixture of dextrose 12.5%, glycerin 12.5%, phenol 1.25% and lidocaine 0.25%. Wide variations were found in treatment protocols, such as dose, number of treatments and use of adjunct therapies. Most cohort studies were only of moderate quality and varied greatly in the substances injected and the use of co-interventions. Most clinical studies reported positive results such as decreased pain or disability, although differences between treatment and control groups did not always reach statistical significance. Commonly reported adverse reactions to this treatment include temporary postinjection pain and stiffness. A handful of more serious adverse events were reported in the 1950s and 1960s with stronger or unknown solutions. CONCLUSION: Prolotherapy describes a variety of treatment approaches rather than a specific protocol. Results from clinical studies published to date indicate that it may be effective at reducing spinal pain. Great variation was found in the injection and treatment protocols used in these studies that preclude definite conclusions. Future research should focus on those solutions and protocols that are most commonly used in clinical practice and have been used in trials reporting effectiveness to help determine which patients, if any, are most likely to benefit from this treatment.

Efficacy of dextrose prolotherapy in elite male kicking-sport athletes with chronic groin pain.
Arch Phys Med Rehabil. 2005 Apr;86(4):697-702.
Topol GA, Reeves KD, Hassanein KM.

Physical Medicine and Rehabilitation Service, Jaime Slullitel Rosario Orthopedic and Trauma Institute, Argentina.

OBJECTIVE: To determine the efficacy of simple dextrose prolotherapy in elite kicking-sport athletes with chronic groin pain from osteitis pubis and/or adductor tendinopathy. DESIGN: Consecutive case series. SETTING: Orthopedic and trauma institute in Argentina. PARTICIPANTS: Twenty-two rugby and 2 soccer players with chronic groin pain that prevented full sports participation and who were nonresponsive both to therapy and to a graded reintroduction into sports activity. INTERVENTION: Monthly injection of 12.5% dextrose and 0.5% lidocaine into the thigh adductor origins, suprapubic abdominal insertions, and symphysis pubis, depending on palpation tenderness. Injections were given until complete resolution of pain or lack of improvement for 2 consecutive treatments. MAIN OUTCOME MEASURES: Visual analog scale (VAS) for pain with sports and the Nirschl Pain Phase Scale (NPPS), a measure of functional impairment from pain. RESULTS: The final data collection point was 6 to 32 months after treatment (mean, 17 mo). A mean of 2.8 treatments were given. The mean reduction in pain during sports, as measured by the VAS, improved from 6.3+/-1.4 to 1.0+/-2.4 ( P <.001), and the mean reduction in NPPS score improved from 5.3+/-0.7 to 0.8+/-1.9 ( P <.001). Twenty of 24 patients had no pain and 22 of 24 were unrestricted with sports at final data collection. CONCLUSIONS: Dextrose prolotherapy showed marked efficacy for chronic groin pain in this group of elite rugby and soccer athletes.

Retrospective case series on patients with chronic spinal pain treated with dextrose prolotherapy.
J Altern Complement Med. 2004 Aug;10(4):670-4.
Hooper RA, Ding M.

Advanced Spinal Care Centre, Calgary, Alberta, Canada. ahooper@ucalgary.ca

OBJECTIVES: To determine the clinical benefits of dextrose prolotherapy in patients with chronic spinal pain. DESIGN: Retrospective case series. SETTING/LOCATION: During the first 2 years at an outpatient prolotherapy clinic. SUBJECTS: One hundred and seventy-seven (177) consecutive patients with a history of chronic spinal pain completed prolotherapy treatment and were followed for a period ranging from 2 months to 2.5 years. INTERVENTIONS: Patients were treated with a proliferant solution containing 20% dextrose and 0.75% xylocaine. One half milliliter (0.5 mL) of proliferant was injected into the facet capsules of the cervical, thoracic, and lumbar spine, or combinations of the three areas. The iliolumbar and dorsal sacroiliac ligaments were also injected in patient with low back pain. Injections were typically done on a weekly basis for up to 3 weeks. A set of three injections was repeated in 1 month's time if needed. OUTCOME MEASURES: Level of pain, and improvement in activities of daily living were measured on a five-point scale. Improvement in ability to work was also assessed. RESULTS: Ninety-one percent (91.0%) of patients reported reduction in level of pain; 84.8% of patients reported improvement in activities of daily living, and 84.3% reported an improvement in ability to work. Women required on average, three more injections than men. Cervical spine response rates were lower than thoracic or lumbar spine. No complications from treatment were noted. CONCLUSIONS: Dextrose prolotherapy appears to be a safe and effective method for treating chronic spinal pain that merits further investigation. Future studies need to consider differences in gender response rates.

Prolotherapy injections for chronic low back pain: a systematic review.
Spine. 2004 Oct 1;29(19):2126-33.
Yelland MJ, Del Mar C, Pirozzo S, Schoene ML.

Discipline of General Practice, University of Queensland, Brisbane, Queensland, Australia. myelland@bigpond.com

STUDY DESIGN: A systematic review of randomized and quasi-randomized controlled trials. OBJECTIVES: To determine the efficacy of prolotherapy injections in adults with chronic low back pain. SUMMARY OF BACKGROUND DATA: Prolotherapy is an injection-based treatment for chronic low back pain. Proponents of prolotherapy suggest that some back pain stems from weakened or damaged ligaments. Repeatedly injecting them with irritant solutions is thought to strengthen the ligaments and reduce pain and disability. Prolotherapy protocols usually include co-interventions to enhance the effectiveness of the injections. METHODS: The authors searched MEDLINE, EMBASE, CINAHL, and Science Citation Index up to January 2004, and the Cochrane Controlled Trials Register 2004, issue 1, and consulted content experts. Both randomized and quasi-randomized controlled trials comparing prolotherapy injections to control injections, either alone or in combination with other treatments, were included. Studies had to include measures of pain and disability before and after the intervention. Two reviewers independently selected the trials and assessed them for methodologic quality. Treatment and control group protocols varied from study to study, making meta-analysis impossible. RESULTS: Four studies, all of high quality and with a total of 344 participants, were included. All trials measured pain and disability levels at 6 months, three measured the proportion of participants reporting a greater than 50% reduction in pain or disability scores from baseline to 6 months. Two studies showed significant differences between the treatment and control groups for those reporting more than 50% reduction in pain or disability. Their results could not be pooled. In one, co-interventions confounded interpretation of results; in the other, there was no significant difference in mean pain and disability scores between the groups. In the third study, there was little or no difference between groups in the number of individuals who reported more than 50% improvement in pain and disability. The fourth study reporting only mean pain and disability scores showed no differences between groups. CONCLUSIONS: There is conflicting evidence regarding the efficacy of prolotherapy injections in reducing pain and disability in patients with chronic low back pain. Conclusions are confounded by clinical heterogeneity among studies and by the presence of co-interventions. There was no evidence that prolotherapy injections alone were more effective than control injections alone. However, in the presence of co-interventions, prolotherapy injections were more effective than control injections, more so when both injections and co-interventions were controlled concurrently.

Intra-articular therapy in osteoarthritis.
Postgrad Med J. 2003 Aug;79(934):449-53.
Uthman I, Raynauld JP, Haraoui B.

Department of Internal Medicine, Faculty of Medicine, American University of Beirut, Beirut, Lebanon. iuthman@aub.edu.lb

The medical literature was reviewed from 1968-2002 using Medline and the key words "intra-articular" and "osteoarthritis" to determine the various intra-articular therapies used in the treatment of osteoarthritis. Corticosteroids and hyaluronic acid are the most frequently used intra-articular therapies in osteoarthritis. Other intra-articular substances such as orgotein, radiation synovectomy, dextrose prolotherapy, silicone, saline lavage, saline injection without lavage, analgesic agents, non-steroidal anti-inflammatory drugs, glucosamine, somatostatin, sodium pentosan polysulfate, chloroquine, mucopolysaccharide polysulfuric acid ester, lactic acid solution, and thiotepa cytostatica have been investigated as potentially therapeutic in the treatment of arthritic joints. Despite the lack of strong, convincing, and reproducible evidence that any of the intra-articular therapies significantly alters the progression of osteoarthritis, corticosteroids and hyaluronic acid are widely used in patients who have failed other therapeutic modalities for lack of efficacy or toxicity. As a practical approach for a knee with effusion, steroid injections should be considered while the presence of symptomatic "dry" knees may favour the hyaluronic acid approach. The virtual absence of serious side effects, coupled with the perceived benefits, make these approaches attractive.

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

Department of Biometry, University of Kansas Medical Center, Kansas City, Kan., USA.

CONTEXT: Use of dextrose prolotherapy. Prolotherapy is defined as injection that causes growth of normal cells or tissue. OBJECTIVE: Determine the 1 and 3 year efficacy of dextrose injection prolotherapy on anterior cruciate ligament (ACL) laxity. After year 1, determine patient tolerance of a stronger dextrose concentration (25% versus 10%). DESIGN: Prospective consecutive patient trial. SETTING: Outpatient physical medicine clinic. PATIENTS OR OTHER PARTICIPANTS: Eighteen patients with 6 months or more of knee pain plus ACL knee laxity. This laxity was defined by a KT1000 anterior displacement difference (ADD) of 2 mm or more. INTERVENTION: Intraarticular injection of 6-9 cc of 10% dextrose at months 0, 2, 4, 6, and 10. Injection with 6 cc of 25% dextrose at 12 months. Then, depending on patient preference, injection of either 10% or 25% dextrose every 2-4 months (based on patient preference) through 36 months. MAIN OUTCOME MEASURES: Visual analogue scale (VAS) for pain at rest, pain on level surfaces, pain on stairs, and swelling. Goniometric flexion range of motion, and KT1000-measured ADD were also measured. All measurements were obtained at 0, 6, 12 and 36 months. RESULTS: Two patients did not reach 6 month data collection, 1 of whom was diagnosed with disseminated cancer. The second was wheelchair-bound and found long-distance travel to the clinic problematic. Sixteen subjects were available for data analysis. KT1000 ADD, measurement indicated that 6 knees measured as normal (not loose) after 6 months, 9 measured as normal after 1 year (6 injections), and 10 measured as normal at 3 years. At the 3 year follow-up, pain at rest, pain with walking, and pain with stair use had improved by 45%, 43%, and 35% respectively. Individual paired t tests indicated subjective swelling improved 63% (P = .017), flexion range of motion improved by 10.5 degrees (P = .002), and KT1000 ADD improved by 71% (P = .002). Eleven out of 16 patients preferred 10% dextrose injection. CONCLUSION: In patients with symptomatic anterior cruciate ligament laxity, intermittent dextrose injection resulted in clinically and statistically significant improvement in ACL laxity, pain, swelling, and knee range of motion.

Randomized, prospective, placebo-controlled double-blind study of dextrose prolotherapy for osteoarthritic thumb and finger (DIP, PIP, and trapeziometacarpal) joints: evidence of clinical efficacy.
J Altern Complement Med. 2000 Aug;6(4):311-20.
Reeves KD, Hassanein K.

Meadowbrook Rehabilitation Hospital, Gardner, Kansas, USA. dreeves1@kc.rr.com

OBJECTIVES: To determine the clinical benefit of dextrose prolotherapy (injection of growth factors or growth factor stimulators) in osteoarthritic finger joints. DESIGN: Prospective randomized double-blind placebo-controlled trial. SETTINGS/LOCATION: Outpatient physical medicine clinic. SUBJECTS: Six months of pain history was required in each joint studied as well as one of the following: grade 2 or 3 osteophyte, grade 2 or 3 joint narrowing, or grade 1 osteophyte plus grade 1 joint narrowing. Distal interphalangeal (DIP), proximal interphalangeal (PIP), and trapeziometacarpal (thumb CMC) joints were eligible. Thirteen patients (with seventy-four symptomatic osteoarthitic joints) received active treatment, and fourteen patients (with seventy-six symptomatic osteoarthritic joints) served as controls. INTERVENTION: One half milliliter (0.5 mL) of either 10% dextrose and 0.075% xylocaine in bacteriostatic water (active solution) or 0.075% xylocaine in bacteriostatic water (control solution) was injected on medial and lateral aspects of each affected joint. This was done at 0, 2, and 4 months with assessment at 6 months after first injection. OUTCOME MEASURES: One-hundred millimeter (100 mm) Visual Analogue Scale (VAS) for pain at rest, pain with joint movement and pain with grip, and goniometrically-measured joint flexion. RESULTS: Pain at rest and with grip improved more in the dextrose group but not significantly. Improvement in pain with movement of fingers improved significantly more in the dextrose group (42% versus 15% with a p value of .027). Flexion range of motion improved more in the dextrose group (p = .003). Side effects were minimal. CONCLUSION: Dextrose prolotherapy was clinically effective and safe in the treatment of pain with joint movement and range limitation in osteoarthritic finger joints.

Randomized prospective double-blind placebo-controlled study of dextrose prolotherapy for knee osteoarthritis with or without ACL laxity.
Altern Ther Health Med. 2000 Mar;6(2):68-74, 77-80.
Reeves KD, Hassanein K.

Bethany Medical Center, Kansas City, Kan., USA.

CONTEXT: Use of prolotherapy (injection of growth factors or growth factor stimulators). OBJECTIVE: Determine the effects of dextrose prolotherapy on knee osteoarthritis with or without anterior cruciate ligament (ACL) laxity. DESIGN: Prospective randomized double-blind placebo-controlled trial. SETTING: Outpatient physical medicine clinic. PATIENTS OR OTHER PARTICIPANTS: Six months or more of pain along with either grade 2 or more joint narrowing or grade 2 or more osteophytic change in any knee compartment. A total of 38 knees were completely void of cartilage radiographically in at least 1 compartment. INTERVENTION: Three bimonthly injections of 9 cc of either 10% dextrose and .075% lidocaine in bacteriostatic water (active solution) versus an identical control solution absent 10% dextrose. The dextrose-treated joints then received 3 further bimonthly injections of 10% dextrose in open-label fashion. MAIN OUTCOME MEASURES: Visual analogue scale for pain and swelling, frequency of leg buckling, goniometrically measured flexion, radiographic measures of joint narrowing and osteophytosis, and KT1000-measured anterior displacement difference (ADD). RESULTS: All knees: Hotelling multivariate analysis of paired observations between 0 and 6 months for pain, swelling, buckling episodes, and knee flexion range revealed significantly more benefit from the dextrose injection (P = .015). By 12 months (6 injections) the dextrose-treated knees improved in pain (44% decrease), swelling complaints (63% decrease), knee buckling frequency (85% decrease), and in flexion range (14 degree increase). Analysis of blinded radiographic readings of 0- and 12-month films revealed stability of all radiographic variables except for 2 variables which improved with statistical significance. (Lateral patellofemoral cartilage thickness [P = .019] and distal femur width in mm [P = .021]. Knees with ACL laxity: 6-month (3 injection) data revealed no significant improvement. However, Hotelling multivariate analysis of paired values at 0 and 12 months for pain, swelling, joint flexion, and joint laxity in the dextrose-treated knees, revealed a statistically significant improvement (P = .021). Individual paired t tests indicated that blinded measurement of goniometric knee flexion range improved by 12.8 degrees (P = .005), and ADD improved by 57% (P = .025). Eight out of 13 dextrose-treated knees with ACL laxity were no longer lax at the conclusion of 1 year. CONCLUSION: Prolotherapy injection with 10% dextrose resulted in clinically and statistically significant improvements in knee osteoarthritis. Preliminary blinded radiographic readings (1-year films, with 3-year total follow-up period planned) demonstrated improvement in several measures of osteoarthritis severity. ACL laxity, when present in these osteoarthritic patients, improved.