Coverage Policy Manual
Policy #: 1999020
Category: Medicine
Initiated: September 1999
Last Review: August 2023
  Prolotherapy (Sclerotherapy)

Prolotherapy describes a procedure intended for healing and strengthening ligaments and tendons by injecting an agent that induces inflammation and stimulates endogenous repair mechanisms. Prolotherapy may also be referred to as proliferant injection, prolo, joint sclerotherapy, regenerative injection therapy, growth factor stimulation injection, or nonsurgical tendon, ligament, and joint reconstruction.
The goal of prolotherapy is to promote tissue repair or growth by prompting release of growth factors, such as cytokines, or by increasing the effectiveness of existing circulating growth factors. The mechanism of action is not well-understood but may involve local irritation and/or cell lysis. Agents used with prolotherapy have included zinc sulfate, psyllium seed oil, combinations of dextrose; glycerin; and phenol, or dextrose alone, often combined with a local anesthetic. Polidocanol and sodium morrhuate, vascular sclerosants, have also been used to sclerose areas of high intratendinous blood flow associated with tendinopathies. Prolotherapy typically involves multiple injections per session conducted over a series of treatment sessions.
Regulatory Status
The U.S. Food and Drug Administration has approved sclerosing agents for use in treating spider/varicose veins. These sclerosing agents include Asclera® (polidocanol), Varithena® (an injectable polidocanol foam), Sotradecol® (sodium tetradecyl sulfate), Ethamolin® (ethanolamine oleate), and Scleromate® (sodium morrhuate). These agents are not currently approved as joint and ligamentous sclerosing agents.

Effective August 2021
Does Not Meet Primary Coverage Criteria Or Is Investigational For Contracts Without Primary Coverage Criteria
Prolotherapy for the stimulation of tendon/ligament tissue or for pain relief in localized areas of musculoskeletal origin does not meet member benefit certificate primary coverage criteria that there be scientific evidence of effectiveness.
For members with contracts without primary coverage criteria, prolotherapy for the stimulation of tendon/ligament tissue or for pain relief in localized areas of musculoskeletal origin is considered investigational. Investigational services are specific contract exclusions in most member benefit certificates of coverage.
Effective prior to August 2021
Prolotherapy for the stimulation of tendon/ligament tissue or for pain relief in localized areas of musculoskeletal origin is not covered  based on benefit certificate Primary Coverage Criteria.  The Criteria exclude coverage of interventions if there is a lack of scientific evidence regarding the intervention, or if the available scientific evidence is in conflict or the subject of continuing debate.
For members with contracts without Primary Coverage Criteria, prolotherapy for the stimulation of tendon/ligament tissue or for pain relief in localized areas of musculoskeletal origin is considered investigational.  Investigational services are an exclusion in the member certificate of coverage.

Prolotherapy has been investigated as a treatment of various etiologies of pain, including arthritis, degenerative disc disease, fibromyalgia, tendinitis, and plantar fasciitis. As with any therapy for pain, a placebo effect is anticipated, and thus randomized placebo-controlled trials are necessary to investigate the extent of the placebo effect and to determine whether any improvement with prolotherapy exceeds that associated with a placebo. Although there is extensive literature regarding prolotherapy, a literature search revealed only 4 randomized placebo-controlled trials.
Two early trials focused on the use of injections of dextrose, glycerin, and phenol as a treatment of low back pain. In 1987, Ongley et al. reported on a trial of 81 patients with low back pain who were randomized to receive spinal manipulation plus prolotherapy compared to a control group that received less forceful spinal manipulation, less local anesthesia, and placebo injections of saline.  Although improved responses were reported for the treatment group, it is not possible to isolate the possible contribution of the prolotherapy compared to the impact of the different types of spinal manipulation. In 1993, Klein and colleagues reported on a trial that randomized 79 patients with low back pain to receive a series of 6 weekly injections using either saline or a proliferant solution of dextrose, glycerine, and phenol.   Thirty of the 39 patients assigned to the proliferant group achieved a 50% or greater diminution in pain compared to 21 of the 40 in the placebo group. While the incremental benefit of the treatment group was statistically significant (p=0 .04), blinding of the treatment groups was not maintained, since those assigned to the proliferant group experienced a clinically recognizable local inflammatory response.
In 2000, Reeves and Hassanein reported on 2 trials that used dextrose alone as a proliferant, thus eliminating the inflammatory response.  The first trial randomized 68 patients with 111 osteoarthritic knees to receive either 3 bimonthly injections of dextrose or placebo. The patients were evaluated with a visual analogue scale for pain and swelling, frequency of leg buckling, goniometrically measured flexion, and radiographic measures of joint narrowing. As the data are presented, it is clear that there was significant improvement in both the placebo and treatment groups, but it is difficult to determine the comparative magnitude of improvement between the 2 groups. For example, for the various outcome measures of pain, it appears that there are probably no clinically significant incremental effects of prolotherapy compared to the placebo group. However, for other non-pain outcomes, i.e., swelling, buckling, and flexion range, prolotherapy may be associated with a significant incremental improvement. The various outcome measures were combined and assessed using a Hotelling multivariate analysis. With this statistical measurement, prolotherapy demonstrated a statistically superior overall effect (p=0.015) compared to the control group. It should be recognized that the statistical significance of this measure is most likely due to the improvements in the non-pain symptoms (i.e., swelling, buckling, and flexion range). In summary, it is not known whether the incremental improvement in the non-pain-related outcomes of the prolotherapy group compared to the control group is clinically significant.
In a similarly designed study, the same investigators studied the effectiveness of prolotherapy as a treatment of osteoarthritic thumb and finger joints.  A total of 27 patients with 150 osteoarthritic joints were randomized to receive 3 bimonthly injections of either dextrose or water. Patients were evaluated with both visual analogue scale (V AS) for pain and goniometric assessment of joint movement. Since patients had a variable number of joints injected (ranging from 1 to 22), the V AS score for every symptomatic joint in each patient was added together for a total and divided by the number of symptomatic joints to provide an average joint pain score for each patient. There were improvements in pain scores in both the placebo and treatment groups, but the incremental improvement of the treatment group compared to the placebo group did not reach statistical significance. In terms of flexion, the treatment group reported a statistically significant improvement (p=0.043), while the placebo group reported a greater, statistically significant, decrease (p=0.011). Therefore, the statistically significant difference in flexion between the 2 groups (p=.003) was primarily related to the decrease in the control group, with a smaller contribution related to the positive response in the treatment group. In summary, the clinical significance of an isolated finding of improved flexion without a corresponding significant improvement in pain is uncertain.
2002 Update
No articles in the published peer-reviewed literature were identified that would change the above conclusions, therefore the policy statement is unchanged.
2008 Update
A search of PubMed through Aug 2008 did not reveal any results of randomized trials that would change the current policy.  There is no consensus about what should be injected or what patient group would be most likely to be benefited by this therapy.  
Currently there are four ongoing trials recruiting patients for prolotherapy for treatment of chronic lateral epicondylitis, thumb carpo-metacarpal joint arthritis, osteoarthritic knee pain and for tennis elbow.  Relatively low numbers of patients are being recruited for these trials, 40-110 patients.
2010 Update
A review of the literature has been conducted through August 2010.  There was no new literature identified that would prompt a change in the coverage statement.
2012 Update
A search of the MEDLINE database conducted through August 2012 did not reveal any new literature that would prompt a change in the coverage statement. The following is a summary of the key literature identified.
A small (17 subjects) randomized double-blind trial of prolotherapy versus corticosteroid injections for chronic lateral epicondylitis was reported in 2011 (Carayannopoulos, 2011).   Each subject received an injection at baseline followed by a second injection at 1 month. VAS for pain, quadruple VAS (QVAS), and Disabilities of the Arm, Shoulder, and Hand questionnaire (DASH) were measured at baseline and at 1, 3, and 6 months. A change of 2 for VAS and 12 for DASH was considered clinically significant. Per protocol analysis showed a significant improvement in VAS and DASH at both 3 (2.38 and 19.89) and 6 months (2.63 and 21.76, both respectively) for the prolotherapy group, while the corticosteroid group showed significant improvement on the DASH at 3 (13.33) and 6 months (15.56). The study was underpowered to detect a significant difference between the prolotherapy and corticosteroid groups for change in VAS, QVAS, or DASH. Larger controlled trials are needed.
Yelland et al., an author of Cochrane reviews on this topic, reported a multicenter randomized trial of prolotherapy or exercises for Achilles tendonitis in 43 patients (Yelland, 2011). Inclusion criteria were diagnosis of unilateral or bilateral mid-portion Achilles tendinosis with pain between 2 and 7 cm proximal to the calcaneal attachment in adults older than 18 years with activity-related pain for at least 6 weeks. The sample size was limited by the available resources and slow recruitment rate, resulting in 15 participants in the eccentric loading exercise group, 14 in the prolotherapy group, and 14 in the combined treatment group. Randomization was conducted by a central site and resulted in a lower median duration of pain in the combined treatment group (6 months) than in the exercise alone (21 months) or prolotherapy alone (24 months) groups. An average of 4.4 injections per treatment was directed at tender points in the subcutaneous tissues adjacent to the affected tendon, with 4 to 12 weekly treatments until participants attained pain-free activity or requested to cease treatment. The participants were instructed to perform eccentric loading exercises twice daily in 3 sets of 15 repetitions with the knee straight and 3 sets of 15 repetitions with the knee bent for a period of 12 weeks, with the load progressively increased by adding weights to a backpack. Clinical reviews were performed at 3, 6, and 12 weeks to check technique and progress. Mean increases in the validated Victorian Institute of Sport Assessment – Achilles (VISA-A) score were 23.7 for exercise alone, 27.5 for prolotherapy alone, and 41.1 for the combined treatment. At 6 weeks and 12 months, these increases were significantly greater for combined treatment (exercise and prolotherapy) than for exercise alone. The predefined minimum clinically important increase of 20 points or more on the VISA-A was obtained by 12 subjects in the combined treatment group and 11 each in the exercise alone and prolotherapy alone groups. This was not significantly different. The percentage of patients achieving full recovery (VISA-A score of 90 or above at 12 months) was 53% for exercise alone, 71% for prolotherapy alone, and 64% for the combined treatment group, but these differences were not significant. Although the authors concluded that prolotherapy may be a cost-effective method to speed recovery in patients with Achilles tendonitis, this study is limited by the combination of a small number of subjects per group, unequal duration of pain in the treatment groups at baseline, and minimal differences in the number of patients showing recovery (11 vs. 12, of 14 or 15, respectively). Additional randomized trials are needed to replicate and extend these findings.
A 2010 publication by Kim et al. compared intra-articular prolotherapy with intra-articular corticosteroid injection for sacroiliac pain (Kim, 2010).  The randomized double-blind study included 48 patients with sacroiliac joint pain lasting equal to or greater than 3 months, confirmed by equal to or greater than 50% improvement in response to local anesthetic block. The injections were performed on a biweekly schedule (maximum of 3 injections) under fluoroscopic guidance with confirmation of the intra-articular location with an arthrogram. Pain and disability scores were assessed at baseline, 2 weeks, and monthly after completion of treatment. At 2 weeks after treatment, all patients met the primary outcome measure of equal to or greater than 50% reduction in pain scores, and there was no significant difference between the 2 groups. The numerical rating scale for pain was reduced from 6.3 to 1.4 in the prolotherapy group and from 6.7 to 1.9 in the steroid group. The Oswestry Disability Index (ODI) decreased from 33.9 to 11.1 in the prolotherapy group and from 35.7 to 15.5 in the steroid group. Kaplan-Meier survival analysis showed a significantly greater percentage of patients with sustained relief following prolotherapy. At 6 months after treatment, 63.6% of patients in the prolotherapy group reported equal to or greater than 50% improvement from baseline in comparison with 27.2% of the steroid group. At 15 months after treatment, 58.7% of patients in the prolotherapy group reported relief equal to or greater than 50% in comparison with 10.2% of the steroid group. Key differences between this and other studies on prolotherapy were the selection of patients using a diagnostic sacroiliac joint block and the use of an arthrogram to confirm the location of the injection. Additional trials are needed to confirm the safety and efficacy of this procedure.
Ongoing Clinical Trials
A search of online site in July 2012 identified the following randomized trials on prolotherapy:
  • The Efficacy of Prolotherapy in Osteoarthritic Knee Pain (NCT00085722) is listed as ongoing but is currently not recruiting participants. This randomized placebo-controlled study is sponsored by the National Center for Complementary and Alternative Medicine (NCCAM) and will determine whether prolotherapy can decrease pain and disability from knee osteoarthritis. The posting lists an estimated enrollment of 111 subjects, with July 2012 as the completion date for primary outcome measures.
  • Prolotherapy for the Treatment of Chronic Lateral Epicondylitis (NCT00674622) is a randomized placebo-controlled trial sponsored by NCCAM. The study is listed as completed as of June 14, 2012 with 67 subjects.
  • NCT01326351 is described as a Phase IV randomized double-blind sham controlled trial of prolotherapy combined with a physiotherapy program for plantar fasciitis. The study is sponsored by Réseau de Santé Vitalité Health Network in Canada. The posting lists an estimated enrollment of 60 subjects with completion expected in 2012. Recruitment for this study had not begun as of October 2012.
  • NCT01402011 is a randomized study of prolotherapy for injured ligaments and tendons of the shoulder. The study is currently recruiting participants and has an estimated enrollment of 74 subjects with completion expected in 2013.
  • NCT01617356 is a randomized trial of prolotherapy versus saline injection for the treatment of temporomandibular dysfunction. The study began enrollment of a projected 42 subjects in June 2012 and has an estimated study completion date in 2014.
 2013 Update
A search of the MEDLINE database through August 2013 did not reveal any new information that would prompt a change in the coverage statement. One published report of a randomized, controlled trial was identified.
Rabago et al. reported a randomized controlled trial of prolotherapy for knee osteoarthritis in 2013 (Rabago, 2013). This study was supported by the National Center for Complementary and Alternative Medicine (NCCAM). Ninety patients were randomized to blinded injections (3-5 treatments with dextrose prolotherapy or saline) or at-home exercise. All 3 groups showed improvements on the composite Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC), with significantly greater improvement in the prolotherapy group (15.3 points) compared to saline and exercise groups (7.6, and 8.2 points, respectively). At 52 weeks, 50% of prolotherapy patients achieved the minimum clinically important difference (MCID) of a 12-point change in WOMAC, compared to 30% of saline-treated patients and 24% of exercise participants. Knee pain scores also improved more in the prolotherapy group. Although the results of this study are promising; the author states, “Determination of clinical utility of prolotherapy will require confirmation in a larger effectiveness trial that includes biomechanical and imaging outcome measures to assess potential disease modifi cation. Clinical trials designed to optimize dose and assess biological mechanism of action are also warranted” (Rabago, 2013).
2014 Update
A literature search conducted through July 2014 did not reveal any new information that would prompt a change in the coverage statement.
2015 Update
A literature search conducted through July 2015 did not reveal any new information that would prompt a change in the coverage statement.  The key identified literature is summarized below.
In 2015, Rabago and colleagues reported 2.5-year telephone follow-up from prolotherapy-treated patients in their randomized trial and from 2 uncontrolled open-label studies (Rabago, 2015). The 3 prolotherapy groups were comparable, having undergone similar treatment courses and showing similar improvements in WOMAC score at 52 weeks (15.3, 12.4, 15.9 points, respectively). At a mean 2.5-year follow-up (range, 1.5-3.5 years), the 65 patients who agreed to participate in this follow-up study had a mean 20.9-point improvement in the WOMAC score. There is a risk of bias due to the open-label design and the relatively high proportion (10%) of prolotherapy-treated patients who declined to participate in the telephone interview.
In 2014, Jahangiri and colleagues reported a double-blind randomized trial that compared prolotherapy versus corticosteroid for the treatment of osteoarthritis in the first carpometacarpal joint (Jahangiri, 2014). Sixty patients were randomized to 3 monthly prolotherapy injections or to 2 monthly saline injections plus a corticosteroid injection in the third month. The groups were comparable at baseline, with a VAS for pain on pressure of 6.7 in the prolotherapy group and 6.4 in the corticosteroid group. At the 6-month follow-up, pain had decreased more (by »2 cm VAS; final score, <2) in the prolotherapy group compared with the corticosteroid-treated group (p<0.001). Pain on movement and hand function had also improved to a greater extent in the prolotherapy group.
Ongoing and Unpublished Clinical Trials
Some currently unpublished trials that might influence this policy are listed below:
(NTC01897259) Comparison of conservative Methods for the Treatment of Lateral Epicondylitis: A Randomized Prospective Study; planned enrollment 200; projected completion date June 2016.
(NCT01617356) Treatment of Temporomandibular Dysfunction With Hypertonic Dextrose Injection: A Randomized Clinical Trial Efficacy; planned enrollment 42; projected completion date December 2016.
(NCT01934868) A Comparison of the Long Term Outcomes of Prolotherapy Versus Interlaminar Epidural Steroid Injections (ESI) for Lumbar Pain Radiating to the Leg; planned enrollment 160; projected completion date May 2017.
(NCT01326351) Plantar Fasciitis: Pain Relief and Improvement of Foot Function With Prolotherapy; planned enrollment 60; projected completion date February 2012
(NCT00674622) Prolotherapy for the Treatment of Chronic Lateral Epicondylitis; planned enrollment 67; projected completion date October 2011.
(NCT01402011) Prolotherapy in the Treatment of Rotator Cuff Tendinopathy, a Randomized Double-blind Placebo-controlled Study; planned enrollment 72; projected completion date June 2013.
2018 Update
A literature search was conducted through July 2018.  There was no new information identified that would prompt a change in the coverage statement.  The key identified literature is summarized below.
American Association of Orthopedic Medicine
The American Association of Orthopedic Medicine currently has a recommendation posted online for the use of prolotherapy for back pain (AAOM, 2017). The Association has indicated that “…prolotherapy should be considered a valid treatment option in a selected group of chronic low back pain patients.”
2019 Update
Annual policy review completed with a literature search using the MEDLINE database through July 2019. No new literature was identified that would prompt a change in the coverage statement.
2020 Update
Annual policy review completed with a literature search using the MEDLINE database through July 2020. No new literature was identified that would prompt a change in the coverage statement.
2021 Update
Annual policy review completed with a literature search using the MEDLINE database through July 2021. No new literature was identified that would prompt a change in the coverage statement. The key identified literature is summarized below.
Sert et al reported on an RCT of prolotherapy in symptomatic knee osteoarthritis refractory to conservative therapy (Sert, 2020). A total of 66 patients between the ages of 40 to 70 years were randomized to dextrose prolotherapy, saline injection, or a control group. Injections were blinded and given at week 0, 3, and 6, while the control group was not blinded. All groups performed an at home exercise program. At 18 weeks, the primary outcome, the Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) pain subscale score was significantly improved in all groups, with the change in the prolotherapy group (-7.2 points) showing a significant improvement compared to the saline (-3.5 points; p<0.002) and control groups (-3 points; p<0.001). The WOMAC Total Score and pain VAS scores were also significantly improved in all treatment groups at 18 weeks, with a greater improvement in the prolotherapy group (WOMAC: -36 points and VAS: -6 points) compared to the saline group (WOMAC: -22.5 points, p<0.001; VAS: -2.8 points, p<0.001) and the control group (WOMAC: -9 points, p=0.002; VAS: -2.4 points, p<0.001). Rates of patients achieving a minimum clinically important difference of a 12-point change in the WOMAC score were not reported. There were no significant differences between the prolotherapy and saline groups on changes in Short Form 36 (SF-36) mental or physical component scores at 18 weeks. This study was limited by its small sample size and relatively short follow-up. The majority of the included population was composed of women (85.7 to 90.9% of groups) and adhered to the at home exercise regimen (85 to 87% of groups); both of these factors have been shown to increase benefit of prolotherapy limiting generalizability of the findings to all osteoarthritis patients.
A double-blind RCT reported by Bayat et al compared dextrose prolotherapy with corticosteroid injection for chronic lateral epicondylitis (Bayat, 2019). Patients (n=28) received a single injection during the treatment period. There was a significant improvement in VAS pain score at 1- and 3- month follow-up in both the prolotherapy group (mean difference: 1.9 and 4.4 points, respectively) and the corticosteroid group (mean difference: 1.5 and 1.9 points, respectively). No difference was observed between groups in VAS score at 1 month (p=0.74); however, prolotherapy resulted in significantly better scores at 3 months (p=0.03). At 1 month follow-up, no statistically significant difference was observed between the prolotherapy and corticosteroid groups in the Quick Disabilities of the Arm, Shoulder, and Hand (QuickDASH) score (24.3 vs 34.8, respectively; p=0.14); however, Quick DASH score was significantly better with prolotherapy compared to corticosteroid at 3 months (score=14.7 vs 34.6, respectively; p=0.01). Results of this study are limited by a short follow-up, use of a single injection regimen, small sample size, and a notable non-significant difference in baseline symptom duration and QuickDASH score.
Bertrand et al reported on an RCT of prolotherapy in rotator cuff tendinopathy with supraspinatus pathology (Bertrand, 2016). A total of 73 participants were randomized to a blinded injection of dextrose prolotherapy (n=27), entheses saline injection (n=20), or superficial saline injection (n=27), all of which were given at months 0, 1, and 2, along with physical therapy. The primary outcome was achieving at least a 2.8 point improvement on the Numeric Rating Scale (NRS), which was obtained by phone by a blinded evaluator. Because the NRS rates pain in only whole numbers, pain levels are typically rated higher than with the VAS. For this reason, the improvement threshold was set as twice the minimal clinically important difference for VAS change in rotator cuff tendinopathy. After 9 months, the primary outcome occurred in 59% of patients in the prolotherapy group, which was significantly higher than in the superficial saline group (27%; p=0.017) and similar to the enthesis saline group (37%; p=0.088). Patient satisfaction at 9 months, assessed using a 10-point satisfaction scale (0=not satisfied, 10=completely satisfied), revealed highest satisfaction in the prolotherapy group (6.7 points), followed by enthesis saline (4.7 points; p=0.079 compared to prolotherapy) and superficial saline (3.9 points; p=0.003 compared to prolotherapy). Scores from the Ultrasound Shoulder Pathology Rating Scale did not differ significantly between groups (p=0.734). Important limitations of this study are the single-center design, which may limit generalizability to all patients. Additionally, the enthesis saline injection group was not sufficiently powered to find a difference from the prolotherapy group. Finally, the use of the NRS as an alternative to the VAS may have biased the measurement of pain improvement.
The 2019 American College of Rheumatology/Arthritis Foundation guideline for osteoarthritis of the hand, hip, and knee conditionally recommends against the use of prolotherapy in patients with knee and/or hip osteoarthritis, given limited number of trials involving small sample sizes showing limited effect (Kolasinski, 2020). The guideline does not make any recommendation regarding hand osteoarthritis, given lack of trials.
2022 Update
Annual policy review completed with a literature search using the MEDLINE database through July 2022. No new literature was identified that would prompt a change in the coverage statement. The key identified literature is summarized below.
Wee et al published a systematic review and meta-analysis involving 11 RCTs (N=837) that evaluated the use of dextrose prolotherapy in knee osteoarthritis (Wee, 2021).
Goh et al conducted a systematic review and network meta-analysis of the efficacy of prolotherapy in comparison to other treatments for patients with chronic soft tissue injuries (e.g., tendinopathies and enthesopathies) having a mean symptom duration lasting at least 6 weeks (Goh, 2021). The review included 91 articles (87 RCTs with 5859 subjects) involving upper limb (74%), lower limb (23%), and truncal/hip (3%) injuries. The "other treatments" within the network meta-analysis were primarily injections such as blood derivatives, corticosteroid, hyaluronic acid, and botulinum toxin. The primary outcome of interest was pain, evaluated mainly at a measurement time point 6 months post-intervention. If a 6-month time point was not available then measurements of pain at other times were evaluated. Results revealed that prolotherapy had no statistically significant benefits over other therapies with regard to pain relief at all assessed time points. However, prolotherapy was associated with better pain improvement over placebo at selected time points and injuries, primarily shoulder (<4 and >8 months) and elbow (4 to 8 months) injuries. The authors noted that more than 50% of included studies had a high overall risk of bias and some comparisons were connected by a small number of RCTs.
Chung et al published a systematic review and meta-analysis involving 10 RCTs (N=358) that analyzed the effects of dextrose prolotherapy on tendinopathy, fasciopathy, and ligament injuries (Chung, 2020). Included studies compared the effects of hypertonic dextrose prolotherapy to placebo, no prolotherapy, or corticosteroids and evaluated either pain or activity level at follow-up. Results revealed that there were no significant differences between dextrose prolotherapy and no treatment or placebo with regard to pain control for the majority of studies. Dextrose prolotherapy was effective in improving activity only at an immediate follow-up period of 0 to 1 month (standardized mean difference [SMD], 0.98; 95% CI, 0.40 to 1.50) and was superior to steroid injections only in pain reduction at short-term follow-up (1 to 3 months; SMD, 0.70; 95% CI, 0.14 to 1.27). The authors concluded there was insufficient evidence to support the clinical benefits of dextrose prolotherapy in managing dense fibrous tissue injuries.
Two RCTs were published in 2020 evaluating the efficacy of dextrose prolotherapy in the treatment of lateral epicondylopathy/epicondylalgia. Both of these trials were conducted in Turkey in small patient populations. Akcay et al enrolled 60 subjects with chronic lateral epicondylopathy with randomization to dextrose 15% prolotherapy or normal saline injection (Akcay, 2020). Results revealed that there was no significant difference between groups in VAS scores at rest or in motion, Disabilities of the Arm, Shoulder, and Hand (DASH) score, and handgrip strength at any time points in terms of improvement (p>.05). Dextrose prolotherapy was noted to outperform normal saline with regard to effect on the Patient Rated Tennis Elbow Evaluation (PRTEE). Additionally, a significant percentage of patients in both groups achieved an MCID for all outcome measurements at the end of 12 weeks with no significant difference among the groups in terms of MCID achievement (p>.05 for VAS at rest and motion, DASH, and PRTEE). Apaydin et al compared the effects of dextrose prolotherapy to hyaluronic acid injection in 32 patients with lateral epicondylalgia (Apaydin, 2020). Overall, dextrose prolotherapy was favored over hyaluronic acid for improvements in pain with activity, at night, and at rest from baseline to 12 weeks. Dextrose prolotherapy was also associated with a significant improvement in in quick-DASH scores. No between-group improvement in grip pain was observed. Results of both studies were limited by a short follow-up time, small sample size, and non-US-based, single center design.
Kazempour Mofrad et al compared periarticular (neurofascial) dextrose prolotherapy and physiotherapy for the short-term treatment of chronic rotator cuff tendinopathy in 66 patients with associated symptoms lasting >3 months (Kazempour Mofrad, 2021). Patients were randomly assigned to physiotherapy, involving 20 minutes of superficial heat using a hot pack followed by transcutaneous electrical nerve stimulation as well as pulsed ultrasound and exercise (n=33), or prolotherapy with hypertonic dextrose 12.5% and 40 mg of 2% lidocaine (n=33). This mixture was injected twice over a 1 week interval around the shoulder joint and to tender joints along the suprascapular nerve. Study outcomes included change in shoulder pain and in a disability index. Overall, 23 patients (70%) in the physiotherapy group and 29 (91%) patients in the prolotherapy group experienced a decrease in pain of 2.8 or greater on a VAS at study end. The difference between the groups was not significant (p=.072). Dextrose prolotherapy was more effective than physiotherapy at alleviating pain at 2 weeks (p<.001) after the intervention; however, both treatments were found to alleviate pain similarly at 3 months (p=.055). Regarding improvement in disability, dextrose prolotherapy was more effective than physiotherapy at 2 weeks and 3 months post-intervention (both p<.001); however, the changes in the physiotherapy group were more sustained. The authors concluded that both treatments were beneficial for chronic rotator cuff tendinopathy, at least in the short term; long-term research is needed to effectively track the pattern of clinical benefits for prolotherapy.
2023 Update
Annual policy review completed with a literature search using the MEDLINE database through July 2023. No new literature was identified that would prompt a change in the coverage statement. The key identified literature is summarized below.
Cortez et al conducted a systematic review involving 8 RCTs (N=660) that compared dextrose prolotherapy with other substances for pain relief (e.g., platelet-rich plasma, exercise programs, hyaluronic acid, saline) in patients with primary knee osteoarthritis (Cortez, 2022). Study size ranged from 42 to 120 patients with gender distribution leaning heavily toward the female sex (61% of the total population). Study assessments ranged from 0 to 52 weeks with the majority of study investigators performing assessments at months 1, 3, and 6. Only 2 studies continued assessments up to the 52 week mark. Dextrose intra-articular injections were primarily applied at weekly or monthly intervals and most studies performed a total of 3 injections. Concentrations of dextrose injections ranged from 12.5% to 25% with 10 mL as the most prevalent volume injected. Overall, patients who underwent dextrose prolotherapy had numerical improvements between baseline and posterior assessments when compared to saline injections regarding pain and function with between-group differences of 7.73 to 14 points on the Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) scale and 1.06 to 3.5 points on visual analogue scale (VAS). However, the results were unclear when comparing dextrose prolotherapy to other substances. The included studies were limited by small sample sizes and the limited time frame for patient assessment. Due to significant heterogeneity of the studies, the intended meta-analysis could not be performed, and no conclusions can be drawn based on these findings.
Arias-Vazquez et al completed a systematic review and meta-analysis involving 6 studies (5 clinical trials and an observational study) of 395 patients with knee osteoarthritis comparing the effectiveness of hypertonic dextrose prolotherapy with intra-articular hyaluronic acid injections on pain reduction and improvement of function (Arias-Vazquez, 2022). The primary outcomes were pain control (as measured by VAS or the pain subscale score of validated questionnaires) and improvement in function (as measured by scores on validated questionnaires). Both outcomes were assessed at 3 months follow-up. Two hundred patients were treated with hypertonic dextrose prolotherapy and 195 were administered intra-articular hyaluronic acid injections. The groups who received hypertonic dextrose prolotherapy used a solution of hypertonic dextrose combined with local anesthetics, with up to 3 intra-articular injections dependent on study design. For those who received hyaluronic acid, up to 5 intra-articular injections were administered dependent on study design. Pooled results of the clinical trials revealed no significant difference in pain reduction between hypertonic dextrose prolotherapy and hyaluronic acid in the short-term (3 months; p=.06); however, a significant difference in improvement of function was observed in favor of the hypertonic dextrose prolotherapy group (p=.03). No major adverse effects were reported in the 3 studies reporting adverse reactions. Limitations included the small total number of studies, short-term follow-up, unclear or high risk of study bias, and significant data heterogeneity. Better quality clinical trials are necessary to corroborate these results.
Zhu et al conducted a systematic review and meta-analysis involving 8 parallel or crossover RCTs (N=354) that evaluated the efficacy or effectiveness of dextrose prolotherapy on pain intensity and physical functioning in patients with lateral elbow tendinosis as compared to other active non-surgical treatments (Zhu, 2022). The majority of the included RCTs are summarized below (Scarpone, 2008; Akcay, 2020; Apaydin, 2020; Bayat, 2019; Carayannopoulos, 2011). Study sample sizes of the included RCTs ranged from 24 to 120 patients. The study periods ranged from 8 to 52 weeks with an injection frequency of 1 to 4 injections, weekly to 4 weeks apart; dextrose concentrations ranged from 12.5% to 50%. Comparison controls were classified into active (e.g., various injection solutions or therapies such as exercise, shock wave, laser, or manual therapy) or inactive (e.g., no treatment, watchful waiting, bracing) categories. The primary outcome of interest was pain reduction, measured by VAS, numerical rating scale (NRS), or algometry. Secondary outcomes included handgrip strength, the Disabilities of the Arm, Shoulder, and Hand (DASH) score, and the Patient Rated Tennis Elbow Evaluation (PRTEE) score. Pooled results revealed dextrose prolotherapy to be significantly more effective than active controls at reducing pain intensity (p=.04) and improving DASH cumulative score (p<.001) at 12 weeks. However, dextrose prolotherapy had no significant effect on PRTEE cumulative score (p=.70) at 12 weeks or grip strength (p=.90) at 12 to 16 weeks. There were no significant related adverse events of dextrose prolotherapy. The overall quality of evidence ranged from very low to moderate with a high heterogeneity across the RCTs. Additionally, the number of studies included, and the total participant sample size were small, the time frame available for pooling data was short (12 to 16 weeks), and quantitative syntheses included only a small number of studies in most comparisons (2, 3, or 4 RCTs).


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