Prolotherapy: Potential for the Treatment of Chronic Wounds?

CRITICAL REVIEWS Prolotherapy: Potential for the Treatment of Chronic Wounds? Amir Hossein Siadat1 and Roslyn Rivkah Isseroff2,* 1 2 Roslyn Rivkah Isseroff, MD Submitted for publication September 17, 2018. Accepted November 2, 2018. *Correspondence: Department of Dermatology, University of California, Davis, 3301 C St., Sacramento, CA 95816 (e-mail: ). Department of Dermatology, Isfahan University of Medical Sciences, Isfahan, Iran. Department of Dermatology, University of California, Davis, Sacramento, California. Significance: Chronic skin ulcers, including venous, diabetic, and pressure ulcers, constitute a major health care burden, affecting 2–6 million people in the United States alone, with projected increases in incidence owing to the aging population and rising epidemic of diabetes. The ulcers are often accompanied by pain. Standard of care fails to heal *50% of diabetic foot ulcers and 25% of venous leg ulcers. Even advanced therapies do not heal >60%. Thus there is an unmet need for novel therapies that promote healing and also address the concomitant pain issue. Recent Advances: Prolotherapy involves injection of small amounts of an irritant material to the site of degenerated or painful joints, ligaments, and tendons. Multiple irritants are reported to be efficacious, but the focus here is on dextrose prolotherapy. In vitro and in vivo studies support translation to clinical use. Concentrations as low as 5% dextrose have resulted in production of growth factors that have critical roles in repair. Numerous clinical trials report pro-reparative effects of dextrose prolotherapy in joint diseases, tendon, and ligament damage, and for painful musculoskeletal issues. However, most of the studies have limitations that result in low-quality evidence. Critical Issues: The preclinical data support a role for dextrose prolotherapy in promoting tissue repair that is required for healing chronic wounds and ameliorating the associated pain. Critical issues include provision of evidence of efficacy in human chronic wounds. Another potential obstacle is limitation of reimbursement by third-party payers for a therapy with as yet limited evidence. Future Directions: Preclinical studies in models of chronic wounds would support clinical translation. As dextrose prolotherapy has some mechanistic similarities to already approved honey therapies, it may have a shortened pathway for clinical translation. The gold standard for widespread adoption would be a well-designed clinical trial. Keywords: prolotherapy, chronic wounds, diabetic ulcer, wound healing SCOPE AND SIGNIFICANCE Chronic skin ulcers, including venous, diabetic, and pressure ulcers, constitute a major health care burden, affecting 2–6 million people in the United States alone1 with projected increases in incidence owing to the aging population and the 160 j ADVANCES IN WOUND CARE, VOLUME 8, NUMBER 4 Copyright ª 2019 by Mary Ann Liebert, Inc. increase in incidence of diabetes.2 The ulcers are often accompanied by pain. Standard of care fails to heal *50% of diabetic foot ulcers (DFUs) and 25% of venous leg ulcers.3 Even advanced therapies do not heal *60%, at best.4 Thus, there is an unmet need for novel therapies that DOI: 10.1089/wound.2018.0866 PROLOTHERAPY FOR CHRONIC WOUNDS promote healing and also address the concomitant pain issue. TRANSLATIONAL RELEVANCE Preclinical studies have demonstrated proreparative effects of high-dextrose solutions. These include generation of growth factors critical for tissue repair such as platelet-derived growth factors (PDGFs), transforming growth factor-beta (TGF-b), epidermal growth factor (EGF), basic fibroblast growth factor (b-FGF), insulin-like growth factor (IGF), and connective tissue growth factor (CTGF). In vivo studies have reported increased tendon and ligament repair after hypertonic dextrose injections. Thus these effects have the potential of translation to improved healing in skin wounds. CLINICAL RELEVANCE Prolotherapy is an approach to treatment of painful musculoskeletal issues and for treating injury of tendons, ligaments, and joints.5 Although there are many reports of clinical success using these methods, the quality of the evidence is variable. Dextrose prolotherapy has many mechanistic analogies to honey therapy for wounds, a therapy that is indeed supported by evidence. Therefore, if good quality evidence can be generated for prolotherapy, it may prove to be another approach for improving healing while concomitantly decreasing pain. BACKGROUND Prolotherapy, Definition The term prolotherapy was coined by Dr. George Hackett in 1956 as an approach for healing damaged ligaments and tendons, and derives from the Latin ‘‘proles,’’ offspring or progeny and the English ‘‘therapy.’’6 The medical definition of the prolotherapy in the Merriam-Webster Dictionary is ‘‘an alternative therapy for treating musculoskeletal pain that involves injecting an irritant substance (as dextrose, also known as d-glucose) into a ligament or tendon to promote the growth of new tissue,’’7 although some practitioners object to the ‘‘alternative’’ appelation.8 Multiple agents are used in prolotherapy, some classified as irritants (such as phenol), some as chemoattractants (commonly sodium morrhuate), and others as osmotic agents (commonly dextrose). This review will focus only on dextrose prolotherapy, because of its potential mechanistic analogy to the already approved and widely clinically used, honey in wound therapy. 161 Clinical Uses Since its introduction, perhaps as early as Hippocrates,9 injections of irritants into tissues has been increasingly used to treat various musculoskeletal injuries including osteoarthritis, musculoskeletal pain, low back pain, refractory lateral epicondylosis and joint pain, and laxity.10 Clinical Evidence There are numerous clinical trials proclaiming the efficacy of prolotherapy for treatment of the painful musculoskeletal issues.11–13 For example, prolotherapy for patients with lateral epicondylitis, using a solution with a final concentration of 10% dextrose along with other components, administered at weeks 0, 4, and 8, showed significant improvement in the outcomes of pain and isometric strength, compared with placebo (saline)-treated patients.11 Prolotherapy has also been reported to improve outcomes in knee osteoarthritis. In a systematic review with meta-analysis, prolotherapy was found to be more effective than exercise alone for significantly improving outcomes as measured by standardized scales for pain and functionality.13 Chronic rotator cuff injury is yet another musculoskeletal entity that has been addressed with prolotherapy, with reported significant improvement in the outcomes of pain and functionality as measured by the Western Ontario Rotator Cuff and the Shoulder Pain and Disability Indices. In one study of prolotherapy for rotator cuff injury, injection of 4 mL of a solution with a final concentration of 22% dextro (...truncated)