Coverage Policy Manual
Policy #: 1999020
Category: Medicine
Initiated: September 1999
Last Review: August 2018
  Prolotherapy (Sclerotherapy)

Description:
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.
 
Background
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.

Policy/
Coverage:
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.

Rationale:
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 ClinicalTrials.gov 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:
 
Ongoing
(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.
 
Unpublished
(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.
 
PRACTICE GUIDELINES AND POSITION STATEMENTS
 
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.”

CPT/HCPCS:
M0076Prolotherapy

References: American Association of Orthopedic Medicine, Klein RG, Patterson J, et al.(2017) Prolotherapy for Back Pain Treatment. n.d.; http://www.aaomed.org/prolotherapy-back-pain. Accessed September 19, 2017.

Carayannopoulos A, Borg-Stein J, Sokolof J et al.(2011) Sokolof J et al. Prolotherapy versus corticosteroid injections for the treatment of lateral epicondylosis: a randomized controlled trial. PMR 2011; 3(8):706-15.

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

Dagenais S, Mayer J, et al.(2008) Evidence-informed management of chronic low back pain with prolotherapy. Spine J. 2008;8(1):203-12.

Jahangiri A, Moghaddam FR, Najafi S.(2014) Hypertonic dextrose versus corticosteroid local injection for the treatment of osteoarthritis in the first carpometacarpal joint: a double-blind randomized clinical trial. J Orthop Sci. Sep 2014;19(5):737-743. PMID 25158896

Kim WM, Lee HG, Jeong CW et al.(2010) A randomized controlled trial of intra-articular prolotherapy versus steroid injection for sacroiliac joint pain. J Altern Complement Med 2010; 16(12):1285-90.

Klein RG, EEK B.(1997) Prolotherapy: An Alternative Approach to Managing Low Back Pain. J Musculo Med 1997.

Klein RG, Eek BC, DeLong WB, Mooney V.(1993) A randomized double blind trial of dextrose-glycerine-phenol injections for chronic, low back pain. J Spinal Disord 1993; 6:23-33.

Ko G.(1998) Prolotherapy: A new "old" Treatment for chronic back pain (clinical commentary). Natural Med J 1998.

Prolotherapy for treatment of joint and ligamentous conditions. Hayes Directory, Sep 2008.

Rabago D, Best TM, et al.(2005) A systematic review of prolotherapy for chronic musculoskeletal pain. Clin J Sport Med. 2005l 15(5):376-80.

Rabago D, Mundt M, Zgierska A, et al.(2015) Hypertonic dextrose injection (prolotherapy) for knee osteoarthritis: Long term outcomes. Complement Ther Med. Jun 2015;23(3):388-395. PMID 26051574

Rabago D, Patterson JJ, Mundt M et al.(2013) Dextrose prolotherapy for knee osteoarthritis: a randomized controlled trial. Ann Fam Med 2013; 11(3):229-37.

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

Reeves KD, Hassanein K.(2000) 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; 6:311-20.

Staal JB, de Bie R, et al.(2008) Injection therapy for subacute and chronic low-back pain. Cochrane Database of Systematic Reviews. 2008; Issue 3:art no:CD0018242.

www.clinicaltrials.gov.

Yelland MJ, Del Mar C, et al.(2004) Prolotherapy injections for chronic low back pain: A systematic review. Spine 2004; 29:2126-33.

Yelland MJ, Glasziou PP, et al.(2004) Prolotherapy injections, saline injections, and exercise for chronic low-back pain: a randomized trial. Spine. 2004; 29(1):9-16.

Yelland MJ, Sweeting KR, Lyftogt JA et al.(2011) Prolotherapy injections and eccentric loading exercises for painful Achilles tendinosis: a randomised trial. Br J Sports Med 2011; 45(5):421-8.


Group specific policy will supersede this policy when applicable. This policy does not apply to the Wal-Mart Associates Group Health Plan participants or to the Tyson Group Health Plan participants.
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