Prolotherapy is a form of pain management that involves injecting a sclerosant solution into the region of joints, muscles or ligaments that are thought to cause chronic low back or joint pain. Prolotherapy, also known as reconstructive ligament therapy or joint sclerotherapy, may be used in an attempt to invoke the body’s natural inflammatory response purportedly promoting new collagen growth to increase/improve joint stability or muscle regeneration/strengthening. Examples of injection solutions include, but may not be limited to, sodium morrhuate, dextrose (D50), glycerine, zinc sulfate, fibrin glue or platelet rich plasma (PRP) and often include an anesthetic agent, such as lidocaine.

The effectiveness of prolotherapy has not been verified by scientifically controlled studies. As early as 1978, the Medical Procedures Appropriateness Program of the Council of Medical Specialty Services (CMSS), based on input from the American Academy of Orthopedic Surgeons, the American Association of Neurological Surgeons, and the American College of Physicians, concluded that prolotherapy had not been shown to be effective. Additionally, the Canadian Coordinating Office for Health Technology Assessment (2004) stated that "evidence from further controlled clinical trials of prolotherapy is clearly needed."

An assessment of prolotherapy prepared for the California Technology Assessment Forum (CTAF) concluded that prolotherapy does not meet CTAF's assessment criteria (Feldman, 2004). The assessment concluded "only one early study (Ongley et al, 1987) was able to demonstrate conclusively that prolotherapy was significantly superior to placebo for treatment of chronic low back pain. Subsequent research has not been able to replicate this finding. It is therefore not possible to conclude from the published literature that prolotherapy is superior to placebo injection for the treatment of chronic low back pain".

The findings of the Ongley study were confounded by the use of combinational treatments (including spinal manipulation as well as triamcinolone injections); these findings need to be validated.

Ongley et al (1988) examined the effectiveness of prolotherapy for the treatment of ligament instability of knees. The study was conducted during a 9-month period in a private orthopedic office. A total of 30 patients presented with knee pain during the enrollment period, but 5 knees (in 4 patients) were selected because of substantial and reproducible ligament instability. After informed consent had been given specific measurements were obtained. All measurements were taken by 1 researcher. The patients underwent multiple injections and were followed routinely. After 9 months repeated measurements were obtained. Subjective symptoms were recorded at entry and exit from the study. Ligament stability was measured by a commercially available computerized instrument that measures ligament function objectively and reliably in a complete 3-dimensional format. It consists of a chair equipped with a 6-component force platform and an electrogoniometer. With computer-integrated force and motion measurements, a standardized series of clinical laxity tests can be performed and an objective report obtained. Prior studies have compared clinical testing with objective tests and have established reproducibility. The proliferant solution is made up as follows: Dextrose 25 % (694 mosmol/L), glycerine 25% (2,720 mosmol/L), phenol 2.5 % (266 mosmol/L), and pyrogen-free water to 100 %. At the time of injection it is diluted with an equal volume of 0.5 % lidocaine. The proliferant injections are “peppered” into the lax ligament(s) usually at 2-weekly intervals, each offending ligament being treated an average of 4 times. A total of between 30 and 40 cc of the proliferant solution is injected into the appropriate portion of the joint ligaments. These researchers reported that their protocol was successful in reducing the laxity of unstable knees in this study group. All patients demonstrated improvement in measurable objective data. In addition, the subjective improvement and activity level was markedly improved. They noted that this study was one of the first to measure clinical outcome by the 3-dimensional computerized instrument. They believed this technique will help to evaluate intervention in unstable knees; and prolotherapy provided a well-tolerated new dimension in the treatment of ligamentous instability of the knee. It was well-tolerated, as the preliminary results demonstrated. Moreover, they stated that the drawbacks of this study were the small number of subjects and the study design. They stated that a randomized control without injection therapy and only physiotherapy will be necessary to confirm these findings. The authors believed, however, that these results were very encouraging and provided the scientific format for further research.

An UpToDate review on “Overview of the management of overuse (chronic) tendinopathy” (Khan and Scott, 2014) lists prolotherapy as one of the investigational therapies; it noted that larger, randomized trials are needed to assess this treatment before it can be recommended.

In a systematic review of prolotherapy for chronic musculoskeletal pain, Rabago et al (2005) concluded that 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 non-randomized and randomized controlled trials (RCTs). Further investigation with high-quality RCTs with non-injection control arms in studies specific to sport-related and musculoskeletal conditions is necessary to determine the effectiveness of prolotherapy.

Guidelines from the Work Loss Data Institute (2011) do not recommend prolotherapy for various pain syndromes.

In a Cochrane review on prolotherapy injections for chronic LBP, Degenais et al (2007) concluded that there is conflicting evidence regarding the effectiveness of prolotherapy injections for patients with chronic LBP. When used alone, prolotherapy is not an effective treatment for chronic LBP. When combined with spinal manipulation, exercise, and other co-interventions, prolotherapy may improve chronic LBP and disability. These researchers noted that conclusions are confounded by clinical heterogeneity among studies and by the presence of co-interventions.

Also, a practice guideline from the American Pain Society on low LBP (Chou et al, 2009) stated that prolotherapy is not recommended for persistent non-radicular LBP.

Furthermore, the clinical practice guideline on "Acute Low Back Problems in Adults" by the Agency for Health Care Policy and Research does not recommend ligamentous and sclerosant injections in the treatment of patients with acute low back pain (LBP). In a report, Yelland et al (2004) concluded that prolotherapy is no more effective than saline injections for the treatment of chronic LBP.

An UpToDate review on “Subacute and chronic low back pain: Nonsurgical interventional treatment” (Chou, 2014) states that “One systematic review included five trials of prolotherapy, compared with local anesthetic or saline injections, for chronic low back pain. There was no difference for short- or long-term pain or disability between prolotherapy and control intervention in three of the trials. Results from one trial that demonstrated short-term benefit for prolotherapy are difficult to interpret, because patients also received a number of co-interventions including forceful manipulation, injection of tender points, and exercise. A fifth trial was confounded by differences in the type of manipulation given to patients in the prolotherapy and control groups. Based on these trial results, a guideline from the American Pain Society recommends against prolotherapy for chronic low back pain”.

In addition, guidelines on low back pain from the American College of Occupational and Environmental Medicine (2007) have concluded that the use of prolotherapy for acute, subacute, chronic or radicular pain syndromes is not recommended.

Dagenais et al (2005) stated that results from clinical studies published to date indicate that prolotherapy 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 (Degenais et al, 2005).

Khan and colleagues (2008) presented the results of dextrose prolotherapy undertaken for chronic non-responding coccygodynia in 37 patients (14 men and 23 women, mean age of 36 years). Patients with chronic coccygodynia not responding to conservative treatment for more than 6 months were included; 27 of them had received local steroid injections. A visual analog score (VAS) was recorded for all patients before and after injection of 8 ml of 25 % dextrose and 2 ml of 2 % lignocaine into the coccyx. In 8 patients with a VAS of more than 4 after the second injection, a third injection was given 4 weeks later. The mean VAS before prolotherapy was 8.5. It was 3.4 after the first injection and 2.5 after the second injection. Minimal or no improvement was noted in 7 patients; the remaining 30 patients had good pain relief. The authors concluded that dextrose prolotherapy is an effective treatment option in patients with chronic, recalcitrant coccygodynia and should be used before undergoing coccygectomy. They stated that randomized studies are needed to compare prolotherapy with local steroid injections or coccygectomies.

In a pilot study, Scarpone et al (2008) examined the effectiveness of prolotherapy in the treatment of lateral epicondylosis. Subjects received injections of a solution made from 1 part 5 % sodium morrhuate, 1.5 parts 50 % dextrose, 0.5 parts 4 % lidocaine, 0.5 parts 0.5 % sensorcaine and 3.5 parts normal saline. Controls received injections of 0.9 % saline. Three 0.5-ml injections were made at the supracondylar ridge, lateral epicondyle, and annular ligament at baseline and at 4 and 8 weeks. The primary outcome was resting elbow pain (0 to 10 Likert scale). Secondary outcomes were extension and grip strength. Each was performed at baseline and at 8 and 16 weeks. One-year follow-up included pain assessment and effect of pain on activities of daily living. The groups were similar at baseline. Compared to controls, prolotherapy-treated subjects reported improved pain scores (4.5 +/- 1.7, 3.6 +/- 1.2, and 3.5 +/- 1.5 versus 5.1 +/- 0.8, 3.3 +/- 0.9, and 0.5 +/- 0.4 at baseline and at 8 and 16 weeks, respectively). At 16 weeks, these differences were significant compared to baseline scores within and among groups (p < 0.001). Prolotherapy subjects also reported improved extension strength compared to controls (p < 0.01) and improved grip strength compared to baseline (p < 0.05). Clinical improvement in prolotherapy-treated subjects was maintained at 52 weeks. There were no adverse events. The authors concluded that prolotherapy with dextrose and sodium morrhuate was well-tolerated, effectively decreased elbow pain, and improved strength testing in subjects with refractory lateral epicondylosis compared to control group injections. The findings of this pilot study (with a small sample size) need to be validated by more research.

In a systematic review on injection therapies for lateral epicondylosis (LE), Rabago and colleagues (2009) stated that there is strong pilot-level evidence supporting the use of prolotherapy in the treatment of LE. Moreover, they noted that rigorous studies of sufficient sample size, assessing these injection therapies using validated clinical, radiological and biomechanical measures, and tissue injury/healing-responsive biomarkers, are needed to determine the long-term effectiveness and safety, and whether these techniques can play a definitive role in the management of LE and other tendinopathies.

In a systematic review and meta-analysis, Krogh et al (2013) evaluated the comparative effectiveness and safety of injection therapies in patients with lateral epicondylitis. Randomized controlled trials comparing different injection therapies for lateral epicondylitis were included provided they contained data for change in pain intensity (primary outcome). Trials were assessed using the Cochrane risk of bias tool. Network (random effects) meta-analysis was applied to combine direct and indirect evidence within and across trial data using the final end point reported in the trials, and results for the arm-based network analyses are reported as standardized mean differences (SMDs). A total of 17 trials (1,381 participants; 3 [18 %] at low-risk of bias) assessing injection with 8 different treatments -- glucocorticoid (10 trials), botulinum toxin (4 trials), autologous blood (3 trials), platelet-rich plasma (2 trials), and polidocanol, glycosaminoglycan, prolotherapy, and hyaluronic acid (1 trial each) -- were included. Pooled results (SMD [95 % confidence interval (CI)]) showed that beyond 8 weeks, glucocorticoid injection was no more effective than placebo (-0.04 [-0.45 to 0.35]), but only 1 trial (which did not include a placebo arm) was at low-risk of bias. Although botulinum toxin showed marginal benefit (-0.50 [-0.91 to -0.08]), it caused temporary paresis of finger extension, and all trials were at high-risk of bias. Both autologous blood (-1.43 [-2.15 to -0.71]) and platelet-rich plasma (-1.13 [-1.77 to -0.49]) were also statistically superior to placebo, but only 1 trial was at low-risk of bias. Prolotherapy (-2.71 [-4.60 to -0.82]) and hyaluronic acid (-5.58 [-6.35 to -4.82]) were both more efficacious than placebo, whereas polidocanol (0.39 [-0.42 to 1.20]) and glycosaminoglycan (-0.32 [-1.02 to 0.38]) showed no effect compared with placebo. The criteria for low-risk of bias were only met by the prolotherapy and polidocanol trials. The authors concluded that this systematic review and network meta-analysis of RCTs found a paucity of evidence from unbiased trials on which to base treatment recommendations regarding injection therapies for lateral epicondylitis.

In a pilot study, Rabago et al (2013) evaluated the effectiveness of 2 prolotherapy (PrT) solutions for chronic lateral epicondylosis. This study was a 3-arm RCT. A total of 26 adults (32 elbows) with chronic lateral epicondylosis for 3 months or longer were randomized to ultrasound-guided PrT with dextrose solution, ultrasound-guided PrT with dextrose-morrhuate sodium solution, or watchful waiting ("wait-and-see"). The primary outcome was the Patient-Rated Tennis Elbow Evaluation (100 points) at 4, 8, and 16 weeks (all groups) and at 32 weeks (PrT groups). The secondary outcomes included pain-free grip strength and magnetic resonance imaging severity score. The participants receiving PrT with dextrose and PrT with dextrose-morrhuate reported improved Patient-Rated Tennis Elbow Evaluation composite and subscale scores at 4, 8, and/or 16 weeks compared with those in the wait-and-see group (p < 0.05). At 16 weeks, compared with baseline, the PrT with dextrose and PrT with dextrose-morrhuate groups reported improved composite Patient-Rated Tennis Elbow Evaluation scores by a mean (SE) of 18.7 (9.6; 41.1 %) and 17.5 (11.6; 53.5 %) points, respectively. The grip strength of the participants receiving PrT with dextrose exceeded that of the PrT with dextrose-morrhuate and the wait-and-see at 8 and 16 weeks (p < 0.05). There were no differences in magnetic resonance imaging scores. Satisfaction was high; there were no adverse events. The authors concluded that PrT resulted in safe, significant improvement of elbow pain and function compared with baseline status and follow-up data and the wait-and-see control group. They stated that the findings of this pilot study suggested the need for a definitive trial.

An UpToDate review on “Epicondylitis (tennis and golf elbow)” (Jayanthi, 2014) states that “The role of prolotherapy in the treatment of epicondylitis warrants further investigation”.

Lateral epicondylitis is a condition that is usually self-limited. There may be a short-term pain relief advantage found with the application of corticosteroids, but no demonstrable long-term pain relief. Injection of botulinum toxin A and prolotherapy are superior to placebo but not to corticosteroids, and botulinum toxin A is likely to produce concomitant extensor weakness. Platelet-rich plasma or autologous blood injections have been found to be both more and less effective than corticosteroid injections. Non-invasive treatment methods such as bracing, physical therapy, and extra-corporeal shockwave therapy do not appear to provide definitive benefit regarding pain relief. Some studies of low-level laser therapy show superiority to placebo whereas others do not. The authors concluded that there are multiple RCTs for non-surgical management of lateral epicondylitis, but the existing literature does not provide conclusive evidence that there is one preferred method of non-surgical treatment for this condition. Moreover, they stated that lateral epicondylitis is a condition that is usually self-limited, resolving over a 12- to 18-month period without treatment.

In a triple-blinded RCT, Akcay and colleagues (2020) compared the effect of DPT with saline in the treatment of chronic lateral epicondylopathy (LE). A total of 60 cases of patients with chronic LE were included in the study. Subjects were randomly divided into 2 groups as DPT and normal saline. Saline or hypertonic dextrose (15 %) was injected at the baseline, and at the end of the 4th and 8th week. Evakuations were carried out at baseline, and at the end of the 4th, 8th, and 12th week. Primary outcome measures were VAS for pain, Patient Rated Tennis Elbow Evaluation (PRTEE-Total [PRTEE-T], PRTEE-Pain, PRTEE-Function); secondary outcome measures were Disabilities of the Arm, Shoulder, and Hand Score (DASH) and pain-free handgrip strength. Intra-group analysis demonstrated that both groups significantly improved in VAS, PRTEE, DASH scores, and handgrip strength during the study period (p < 0.001, for all outcome measurements in both groups). Inter-group analysis showed that PRTEE-T score changes between baseline-4th and -12th week; VASrest change between baseline and 4th week in the DPT group were significantly higher than the saline group (p = 0.041, p = 0.038, p = 0.013 respectively). There was no significant difference between groups in VAS, DASH scores, and handgrip strength between any time points, in terms of improvement (p > 0.05). The authors concluded that the findings of this study showed that DPT outperformed saline in PRTEE-T score. Moreover, these researchers stated that although saline appeared to be a comparable clinical effect with DPT, further studies comparing the effects of saline injection and DPT are needed in chronic LE.

An evidence review of prolotherapy from the Veterans Administration Technology Assessment Program (VATAP) (Adams, 2008) stated: "Although proponents have advocated the use of prolotherapy for a range of indications, relatively few clinical uses have been studied systematically or published in the peer-reviewed literature. Results of the most recent systematic reviews are inconclusive for demonstrating the effectiveness of prolotherapy for treatment of musculoskeletal pain, and new evidence from case series would not alter these conclusions. The majority of published experimental studies have included conservative therapy with prolotherapy for relief of chronic low back pain, and to a lesser extent, osteoarthritis of the knee with varying results. Sample sizes have been insufficient on which to base national policy decisions."

The VATAP assessment also noted that the existing evidence base for prolotherapy shows wide variation in patient selection criteria (Adams, 2008). The review noted that, in case series, findings from physical examination by a prolotherapist are part of the inclusion criteria, whereas all entry criteria from randomized controlled clinical trials were diagnosis-driven. The positive results seen in these case series may, in part, reflect careful selection criteria that a prolotherapist would employ in clinical practice using both diagnostic and examination findings.

The VATAP assessment stated that greater attention needs to be paid to using an appropriate control group (Adams, 2008). The report found that RCTs to date have employed control therapies with injection, which may invoke a response irrespective of injectant used, resulting in similar clinical improvement observed across study arms, while other RCTs have used control groups with very different treatment regimens such that it is not possible to attribute improvement in outcomes to prolotherapy alone.

The VATAP found that prolotherapy appears to have a safety profile comparable to that of other needling procedures, when performed by a skilled prolotherapist, but treatment protocols varied considerably across studies (Adams, 2008). The VATAP notes that, up to now, education and training for prolotherapists have relied on continuing education programs and mentoring and have not been standardized.

The VATAP report stated that prolotherapy along with conservative interventions (e.g., physiotherapy) appears to offer some pain relief when administered by a skilled prolotherapist in patients with LBP who are refractory to other treatments, but its independent role in these patients remains to be determined (Adams, 2008). The report stated that, given the increasing interest in this intervention, additional research and monitoring are warranted to clarify the safety profile and to determine the optimal proliferant, dosage and schedule, appropriate patient selection criteria, and the independent role of prolotherapy for a number of indications for which there are limited nonsurgical options for persons seeking chronic pain relief. The report stated that ongoing clinical trials of prolotherapy should help define its clinical use.

Guidelines on chronic pain from the American College of Occupational and Environmental Medicine (2008) have concluded that the use of prolotherapy for neuropathic or myofascial pain is not recommended. American College of Occupational and Environmental Medicine (2011) guidelines on hand, wrist, and forearm disorders were unable to make a recommendation about the use of prolotherapy because of insufficient evidence.

In a prospective RCT, Kim and colleagues (2010) evaluated the efficacy and long-term effectiveness of intra-articular prolotherapy in relieving sacroiliac joint pain, compared with intra-articular steroid injection. The study included patients with sacroiliac joint pain, confirmed by greater than or equal to 50 % improvement in response to local anesthetic block, lasting 3 months or longer, and who failed medical treatment. The treatment involved intra-articular dextrose water prolotherapy or triamcinolone acetonide injection using fluoroscopic guidance, with a bi-weekly schedule and maximum of 3 injections. Pain and disability scores were assessed at baseline, 2 weeks, and monthly after completion of treatment. The numbers of recruited patients were 23 and 25 for the prolotherapy and steroid groups, respectively. The pain and disability scores were significantly improved from baseline in both groups at the 2-week follow-up, with no significant difference between them. The cumulative incidence of greater than or equal to 50 % pain relief at 15 months was 58.7 % (95 % CI: 37.9 % to 79.5 %) in the prolotherapy group and 10.2 % (95 % CI: 6.7 % to 27.1 %) in the steroid group, as determined by Kaplan-Meier analysis; there was a statistically significant difference between the groups (log-rank p < 0.005). The authors concluded that intra-articular prolotherapy provided significant relief of sacroiliac joint pain, and its effects lasted longer than those of steroid injections. They stated that further studies are needed to confirm the safety of the procedure and to validate an appropriate injection protocol.

Scope of Policy

This Clinical Policy Bulletin addresses prolotherapy and sclerotherapy.

Medical Necessity

Aetna considers sclerotherapy medically necessary for the following indications:

Ongley solution (also known as P2G) is a proliferant solution.

Experimental and Investigational

The following procedures are considered experimental and investigational because the effectiveness of these approaches has not been established (not an all-inclusive list):