Prolotherapy and Sclerotherapy

Number: 0207

Policy

Aetna considers prolotherapy (also known as proliferant therapy, proliferation therapy, joint sclerotherapy, or reconstructive ligament therapy) experimental and investigational for all indications, including the following (not an all-inclusive list), because there is inadequate evidence of its effectiveness:

• Achilles tendinosis
• Back pain
• Coccynodynia
• Epicondylitis (lateral epicondylopathy)
• Fasciopathies (including plantar fasciopathy)
• Hand osteoarthritis
• Iliotibial band syndrome
• Ischio-femoral impingement
• Knee ligament instability
• Knee osteoarthritis
• Ligament injuries
• Metatarso-phalangeal joint instability
• Musculoskeletal pain
• Myofascial pain
• Neuropathic pain
• Osgood-Schlatter disease
• Osteomyelitis pubis
• Rotator cuff disease (including bursitis, glenohumeral osteoarthritis, and rotator cuff tendinopathy)
• Sacroiliac joint pain / instability
• Shoulder pain
• Temporomandibular joint syndrome / Temporomandibular joint hypermobility / Temporomandibular joint luxation
• Tendinopathies.

Aetna considers neural prolotherapy (low dose dextrose) experimental and investigational for neurogenic inflammatory pain and all other indications.

Aetna considers prolozone therapy experimental and investigational for any diagnosis because there is no peer-reviewed published clinical literature regarding its effectiveness.

Aetna considers Sarapin, an herbal extract that has been used as a sclerosant in prolotherapy, experimental and investigational for all indications because there is inadequate evidence of its effectiveness.

Aetna considers sclerotherapy medically necessary for the following indications:

• Aneurysmal bone cyst
• Benign cystic thyroid nodules
• Epistaxis due to hereditary hemorrhagic telangiectasia
• Morton's neuroma (intermetatarsal neuroma) when conservative treatments including orthotic use, and corticosteroid injections have failed
• Pediatric rectal prolapse
• Symptomatic orbital varices.

Aetna considers sclerotherapy experimental and investigational for the following indications (not an all-inclusive list) because its effectiveness for these indications has not been established:

• Achilles tendinopathy
• Hepatic cysts
• Patellar tendinopathies
• Prophylaxis of esophageal variceal bleeding
• Seromas
• Use in high varix ligation.

Aetna considers electro-sclerotherapy for capillary malformations experimental and investigational because its effectiveness for this indication has not been established.

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

Background

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".

In the 1960s, Dr. Milne Ongley employed a more sclerosant than proliferative solution, as was common.  Ongley searched the New Zealand Formulary and found an approved solution containing 50 % dextrose, 30 % glycerin, and 2.5 % phenol.  It became known as "Ongley solution" or P2G.  The study by Ongley et al (1987) was one of the few studies in the treatment of LBP to show a dramatic difference between treatment and placebo groups.  There were several major drawbacks with the study by Ongley et al:

1. subjects in the treatment group received an initial treatment of up to 60 ml lidocaine 0.5 % injection into the lumbosacral area compared with only 10 ml for the control group,
2. the treatment group also received 50-mg triamcinolone injection into the gluteus medius compared with lidocaine 0.5 % injection for the control group, and
3. the treatment group received actual spinal manipulation versus sham manipulation for the control group. 

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”.

Sims et al (2014) stated that non-surgical approaches to treatment of lateral epicondylitis are numerous. These investigators examined RCTs of these treatments.  Numerous databases were systematically searched from earliest records to February 2013.  Search terms included "lateral epicondylitis", "lateral elbow pain", "tennis elbow", "lateral epicondylalgia", and "elbow tendinopathy" combined with "randomized controlled trial".  Two reviewers examined the literature for eligibility via article abstract and full text.  A total of 58 articles met eligibility criteria:

1. a target population of patients with symptoms of lateral epicondylitis;
2. evaluation of treatment of lateral epicondylitis with the following non-surgical techniques: corticosteroid injection, injection technique, iontophoresis, botulinum toxin A injection, prolotherapy, platelet-rich plasma or autologous blood injection, bracing, physical therapy, shockwave therapy, or laser therapy; and
3. a randomized controlled trial design. 

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.

Choi et al (2011) examined the most current evidence for treatment options in athletes with osteitis pubis and osteomyelitis pubis, attempting to determine which options provide optimal pain relief with rapid return to sport and prevention of symptom reoccurrence.  Three databases -- MEDLINE, Cochrane Database of Systematic Reviews and CINAHL -- were searched using the OVID interface for all years between 1985 and May 2008.  References were analysed from included studies, and additional relevant articles were obtained for inclusion.  Inclusion criteria included:

1. humans only,
2. subjects had no apparent risk factors for development of osteitis pubis or osteomyelitis of the pubic symphysis other than athletic involvement,
3. both physical examination findings and diagnostic imaging were used to confirm either diagnosis, and
4. a definitive treatment strategy was identifiable for management of osteitis pubis or osteomyelitis of the pubic symphysis. 

In total, 25 articles were included in the review.  There were no RCTs identified with this study's search strategy.  A total of 195 athletes were diagnosed as having osteitis pubis (186 males, 9 females) and treated with either conservative measures/physical therapy, local injection with corticosteroids and/or local anesthetic, dextrose prolotherapy, surgery or antibiotic therapy.  Six case reports/series described conservative treatment measures (physical therapy, rest, non-steroid anti-inflammatory drugs).  Four case series explored the use of corticosteroid injections in treatment.  One case series described the use of dextrose prolotherapy as a treatment modality.  Six case series described various surgical techniques (pubic symphysis curettage, polypropylene mesh placement and pubic bone stabilisation) in treatment.  Ten case reports/series (10 subjects) outlined antibiotic treatment of osteomyelitis of the pubic symphysis.  The authors concluded that current medical literature shows only level 4 evidence of the treatment for osteitis pubis in 24 case reports/series in athletes.  Without any direct comparison of treatment modalities, it is difficult to determine which individual treatment option is the most efficacious.  They stated that further study comparing the different treatment options is needed to determine which modality provides the fastest return to sport.

In a prospective, randomized, double-blind, placebo-controlled clinical study, Rafai et al (2011) evaluated the effectiveness of dextrose prolotherapy for the treatment of temporomandibular joint (TMJ) hypermobility.  A total of 12 patients with painful subluxation or dislocation of the TMJ were randomly assigned to 1 of 2 equal-sized groups.  Patients in the active group received 4 injections of dextrose solution (2 ml of 10 % dextrose and 1 ml of 2 % mepivacaine) for each TMJ, each 6 weeks apart, whereas patients in the placebo group received injections of placebo solution (2 ml of saline solution and 1 ml of 2 % mepivacaine) on the same schedule.  A verbal scale expressing TMJ pain on palpation, maximal mouth opening (MMO), clicking sound, and frequency of luxations (number of locking episodes per month) were assessed at each injection appointment just before the injection procedure and 3 months after the last injection.  The collected data were then statistically analyzed.  By the end of the study, each group showed significant improvement in TMJ pain on palpation and number of locking episodes and insignificant improvement in clicking sound.  With the exception of the MMO, there were no statistically significant differences throughout the study intervals between the active and placebo groups.  The active group showed a significant reduction in MMO at the 12th week post-operatively.  Differences compared with mean baseline value remained significant at the end of the follow-up period.  On the other hand, the placebo group showed an insignificant difference in MMO throughout the study periods.  For the last 2 intervals, the placebo group showed statistically significantly higher mean MMO values than the active group.  By the end of the 12th post-operative week, the percentages of decrease in MMO were significantly greater in the active group.  The authors concluded that prolotherapy with 10 % dextrose appears promising for the treatment of symptomatic TMJ hypermobility, as evidenced by the therapeutic benefits, simplicity, safety, patients' acceptance of the injection technique, and lack of significant side effects.  However, these investigators stated that continued research into prolotherapy's effectiveness in patient populations with large sample sizes and long-term follow-up is needed.

In a prospective, uncontrolled study with 1-year follow-up, Rabago et al (2012) examined if prolotherapy would improve pain, stiffness, and function in adults with symptomatic knee osteoarthritis (KOA) compared to baseline status.  Adults with at least 3 months of symptomatic KOA, recruited from clinical and community settings, participated in the study.  Participants received extra-articular injections of 15 % dextrose and intra-articular prolotherapy injections of 25 % dextrose at 1, 5, and 9 weeks, with as-needed treatments at weeks 13 and 17.  Primary outcome measure was the validated Western Ontario McMaster University Osteoarthritis Index (WOMAC).  Secondary outcome measure was the validated Knee Pain Scale (KPS).  Tertiary outcome measure was procedure-related pain severity and participant satisfaction.  A total of 36 participants (60 +/- 8.7 years old, 21 females) with moderate-to-severe KOA received an average of 4.3 +/- 0.7 prolotherapy injection sessions over a 17-week treatment period and reported progressively improved scores during the 52-week study on WOMAC and KPS measures.  Participants reported overall WOMAC score improvement 4 weeks after the first injection session (7.6 +/- 2.4 points, 17.2 %), and continued to improve through the 52-week follow-up (15.9 +/- 2.5 points, p < 0.001, 36.1 %).  Knee Pain Scale scores improved in both injected (p < 0.001) and un-injected knees (p < 0.05).  Prescribed low-dose opioid analgesia effectively treated procedure-related pain.  Satisfaction was high and there were no adverse events.  Female gender, age of 46 to 65 years old, and body-mass index of 25 kg/m(2) or less were associated with greater improvement on the WOMAC instrument.  The authors concluded that in adults with moderate-to-severe KOA, dextrose prolotherapy may result in safe, significant, sustained improvement of knee pain, function, and stiffness scores.  Moreover, they stated that randomized multi-disciplinary effectiveness trials including evaluation of potential disease modification are needed to further evaluate the effectiveness of prolotherapy for KOA.

Gross et al (2013) stated that although there has been a recent increase in interest regarding injectable therapy for non-insertional Achilles tendinosis, there are currently no clear treatment guidelines for managing patients with this condition.  These investigators conducted a systematic review of clinical outcomes following injectable therapy of non-insertional Achilles tendinosis, identified patient-specific factors that are prognostic of treatment outcomes, provided treatment recommendations based on the best available literature, and identified knowledge deficits that require further investigation.  They searched Medline (1948 to March week 1 2012) and EMBASE (1980 to 2012 week 9) for clinical studies evaluating the effectiveness of injectable therapies for non-insertional Achilles tendinosis.  Specifically, they included RCTs and cohort studies with a comparative control group.  Data abstraction was performed by 2 independent reviewers.  The Oxford Level of Evidence Guidelines and GRADE recommendations were used to rate the quality of evidence and to make treatment recommendations.  A total of 9 studies fit the inclusion criteria for the review, constituting 312 Achilles tendons at final follow-up.  The interventions of interest included platelet-rich plasma (n = 54), autologous blood injection (n = 40), sclerosing agents (n = 72), protease inhibitors (n = 26), hemodialysate (n = 60), corticosteroids (n = 52), and prolotherapy (n = 20).  Only 1 study met the criteria for a high-quality RCT.  All of the studies were designated as having a low quality of evidence.  While some studies showed statistically significant effects of the treatment modalities, often studies revealed that certain injectables were no better than a placebo.  The authors concluded that the literature surrounding injectable treatments for non-insertional Achilles tendinosis has variable results with conflicting methodologies and inconclusive evidence concerning indications for treatment and the mechanism of their effects on chronically degenerated tendons.  They stated that prospective, randomized studies are needed in the future to guide Achilles tendinosis treatment recommendations using injectable therapies.

An UpToDate review on “Iliotibial band syndrome” (Jackson, 2014) states that “Prolotherapy is the injection of irritants into or adjacent to tendons with the goal of inciting a healing response.  This technique has not been the subject of controlled studies in ITBS”.

According to Martindale's Extrapharmacopoeia, Sarapin is a brand name for an extract of the pitcher plant, or Sarracenia Purpurea.  Martindale's notes that "the roots and leaves of Sarracenia Purpurea have been used in the form of an aqueous distillate, administered by local injection, for neuromuscular or neuralgic pain."

Sarapin is typically administered in conjunction with prolotherapy.  There is inadequate evidence of the effectiveness of Sarapin for pain.  One clinical study involving 180 patients found greater pain relief in patients administered facet blocks with Sarapin than those without (Manchikanti et al, 2000).  Another study, using an animal model, found Sarapin to have no anesthetic effect (Harkins et al, 1997).  Other studies found no effect of the addition of Sarapin on neural blockade (Manchikanti et al, 2004; Manchikanti et al, 2006; Manchikanti et al, 2007).  Levin (2009) stated that injection of corticosteroid or Sarapin on the lumbar medial branch nerves is ineffective for the treatment of acute/subacute lumbo-sacral radicular pain.

Prolozone therapy is an injection technique similar to prolotherapy that uses ozone. According to the practitioners using this technique, the use of ozone causes the joint to heal much more quickly than in traditional prolotherapy because ozone is a highly reactive molecule and when injected into a joint capsule it is able to stimulate the fibroblastic joint repairing abilities.

Metatarso-Phalangeal Joint Instability

Ojofeitimi et al (2016) noted that professional ballet and modern dancers spend an inordinate amount of time on demi pointe (rising onto their forefeet), placing excessive force on the metatarso-phalangeal (MP) joints and putting them at risk of instability.  Surgical treatment of this condition is well-described in the literature.  However, studies describing conservative management particularly in dance populations, are lacking.  These investigators presented the case of a 33-year old dancer with insidious onset of medial arch and 2nd and 3rd MP joint pain.  Functional deficits included the inability to walk barefoot, perform demi releve, or balance in demi pointe.  Imaging studies revealed OA of the 1st MP joint, 2nd MP joint calcification, capsulitis, and plantar plate rupture leading to a diagnosis of instability.  The dancer underwent a treatment program that included taping, padding, physical therapy, a series of prolotherapy injections, and activity modification.  The dancer was seen for a total of 37 physical therapy sessions over the 16-week rehabilitation period.  At the time of discharge, the patient had returned to full duty and performed all choreography with taping and padding.  Repeated single leg jumps and turns on the right foot, however, still caused discomfort.  At her 6 month follow-up, the dancer's total Dance Functional Outcome Score had improved from 11 % to 90 % and her and Short Form 36 (SF-36) physical scores improved from 24 to 47.  One year after discharge, the dancer reported pain-free dancing with no taping or padding.  The authors concluded that this case report described early diagnosis and a multi-modal treatment approach in a professional dancer with significant disability secondary to MTP joint instability.  (Level of Evidence Therapy: Level 4).  This was a single-case study with short-term follow-up (6 months); its finding were confounded by the multi-modality approach.  Thus, the role of prolotherapy in the treatment of MP joint instability has to be determined by well-designed studies.

Osgood-Schlatter Disease and Plantar Fasciopathy

In a systematic review, Sanderson and Bryant (2015) evaluated existing research to determine the safety and effectiveness of prolotherapy injections for treatment of lower limb tendinopathy and fasciopathy.  Nine databases were searched (Medline, Science Direct, AMED, Australian Medical Index, APAIS-Health, ATSIhealth, EMBASE, Web of Science, OneSearch) without language, publication or data restrictions for all relevant articles between January 1960 and September 2014.  All prospective randomized and non-randomized trials, cohort studies, case-series, cross-sectional studies and controlled trials assessing the effectiveness of one or more prolotherapy injections for tendinopathy or fasciopathy at or below the superior aspect of the tibia/fibula were included.  Methodological quality of studies was determined using a modified evaluation tool developed by the Cochrane Musculoskeletal Injuries Group.  Data analysis was performed to determine the mean change of outcome measure scores from baseline to final follow-up for trials with no comparative group, and for RCTs, standardized mean differences between intervention groups were calculated.  Pooled SMD data were calculated where possible to determine the statistical heterogeneity and overall effect for short-, intermediate- and long-term data; adverse events (AEs) were also reported.  A total of 203 studies were identified, 8 of which met the inclusion criteria.  These were then grouped according to tendinopathy or fasciopathy being treated with prolotherapy injections: Achilles tendinopathy, plantar fasciopathy and Osgood-Schlatter disease.  The methodological quality of the 8 included studies was generally poor, particularly in regards to allocation concealment, intention-to-treat analysis and blinding procedures.  Results of the analysis provided limited support for the hypothesis that prolotherapy is effective in both reducing pain and improving function for lower limb tendinopathy and fasciopathy, with no study reporting a mean negative or non-significant outcome following prolotherapy injection.  The analysis also suggested prolotherapy injections provided equal or superior short-, intermediate- and long-term results to alternative treatment modalities, including eccentric loading exercises for Achilles tendinopathy, platelet-rich plasma for plantar fasciopathy and usual care or lignocaine injections for Osgood-Schlatter disease.  No AEs following prolotherapy injections were reported in any study in this review.  The authors stated that the conclusions of this review were derived from the best available scientific evidence.  It was intended that the results of this study would assist clinical decision-making by practitioners.  These investigators stated that the results of this review found limited evidence that prolotherapy injections are a safe and effective treatment for Achilles tendinopathy, plantar fasciopathy and Osgood-Schlatter disease, however more robust research using large, methodologically-sound RCTs is needed to substantiate these findings.

Rotator Cuff Disease

In a retrospective, case-control study, Lee and colleagues (2015) examined the effectiveness of prolotherapy for refractory rotator cuff disease.  Patients with non-traumatic refractory rotator cuff disease (n = 151) who were unresponsive to 3 months of aggressive conservative treatment.  Of the patients, 63 received prolotherapies with 16.5 % dextrose 10-ml solution (treatment group), and 63 continued conservative treatment (control group).  Main outcome measures included VAS score of the average shoulder pain level for the past 1 week, Shoulder Pain and Disability Index (SPADI) score, isometric strength of the shoulder abductor, active range of motion (AROM) of the shoulder, maximal tear size on ultrasonography, and number of analgesic ingestions per day.  Over 1-year follow-up, 57 patients in the treatment group and 53 in the control group were analyzed.  There was no significant difference between the 2 groups in age, sex, shoulder dominance, duration of symptoms, and ultrasonographic findings at pre-treatment.  The average number of injections in the treatment group was 4.8 ± 1.3.  Compared with the control group, VAS score, SPADI score, isometric strength of shoulder abductor, and shoulder AROM of flexion, abduction, and external rotation showed significant improvement in the treatment group; there were no AEs.  The authors concluded that this was the first study to evaluate the effectiveness of prolotherapy in rotator cuff disease.  Prolotherapy showed improvement in pain, disability, isometric strength, and shoulder AROM in patients with refractory chronic rotator cuff disease.  The authors concluded that the results suggested positive outcomes, but caution is needed in directly interpreting it as an effective treatment option, considering the limitations of this non-randomized retrospective study.  They stated that to show the effectiveness of prolotherapy, further studies on prospective RCTs are needed.

Vanden Bossche and Vanderstraeten (2015) described the protocol of a phase III clinical trial evaluated functional, clinical, and subjective parameters in patients with rotator cuff syndrome and bursitis treated with Traumeel injections versus corticosteroid injections and versus placebo.  This is a multi-center, randomized, double-blind, 16-week, 3-arm, parallel-group, active- and placebo-controlled trial to assess the safety and effectiveness of Traumeel 2-ml injection versus dexamethasone 8-mg injection versus placebo (saline solution).  Patients will be randomly allocated to Traumeel, dexamethasone or placebo in a 2:2:1 randomization.  After 1 week screening, patients will receive 3 injections at weekly intervals (days 1, 8 and 15) with additional follow-up assessments on day 22, a telephone consultation in week 9 and a final visit at week 15.  Male and female patients aged 40 to 65 years, inclusive, will be recruited if they have acute episodes of chronic rotator cuff syndrome and/or bursitis.  Patients with calcifications in the shoulder joint or a complete rotator cuff tear will be excluded.  At least 160 patients will be recruited.  All subacromial injections will be performed under ultrasound guidance utilizing a common technique.  The only rescue medication permitted will be paracetamol (acetaminophen), with usage recorded.  The primary end-point is change from baseline in abduction-rotation pain VAS (0 to 100 mm scale, 0 corresponds to no pain and 100 to extreme pain) at day 22 (Traumeel injections versus dexamethasone injections) for active external rotation.  Secondary effectiveness parameters include ROM, disability of arm, shoulder, hand score and patient's/investigator's global assessment.  Clinical effectiveness will be evaluated as non-inferiority of Traumeel with respect to dexamethasone regarding the primary effectiveness parameter.  The authors stated that it is hoped that the results of this trial will expand the treatment options and evidence base available for the management of rotator cuff disease.

Hand and Knee Osteoarthritis

Sit and associates (2016) stated that prolotherapy is an emerging treatment for symptomatic knee OA but its effectiveness is uncertain.  These investigators conducted a systematic review with meta-analysis to synthesize clinical evidence on the effect of prolotherapy for knee OA.  A total of 15 electronic databases were searched from their inception to September 2015.  The primary outcome of interest was score change on the WOMAC; 3 RCTs of moderate risk of bias and 1 quasi-randomized trial were included, with data from a total of 258 patients.  In the meta-analysis of 2 eligible studies, prolotherapy was superior to exercise alone by a SMD of 0.81 (95 % CI: 0.18 to 1.45, p = 0.012), 0.78 (95 % CI: 0.25 to 1.30, p = 0.001) and 0.62 (95 % CI: 0.04 to 1.20, p = 0.035) on the WOMAC composite scale; and WOMAC function and pain subscale scores, respectively.  Moderate heterogeneity exists in all cases.  The authors concluded that prolotherapy conferred a positive and significant beneficial effect in the treatment of knee OA; adequately powered, longer-term trials with uniform end-points are needed to better elucidate the effectiveness of prolotherapy.

In a systematic review and meta-analysis, Hung and colleagues (2016) compared the effectiveness of dextrose prolotherapy versus control injections and exercise in the management of OA pain.  PubMed and Scopus were searched from the earliest record until February 2016.  One single-arm study and 5 RCTs were included, comprising 326 participants.  These investigators estimated the effect sizes of pain reduction before and after serial dextrose injections and compared the values between dextrose prolotherapy, comparative regimens, and exercise 6 months after the initial injection.  Regarding the treatment arm using dextrose prolotherapy, the effect sizes compared with baseline were 0.65 (95 % CI: 0.14 to 1.17), 0.84 (95 % CI: 0.40 to 1.27), 0.85 (95 % CI: 0.60 to 1.10), and 0.87 (95 % CI: 0.53 to 1.21) after the 1st, 2nd, 3rd, and 4rth or more injections, respectively.  The overall effect of dextrose was better than control injections (effect size, 0.36; 95 % CI: 0.10 to 0.63).  Dextrose prolotherapy had a superior effect compared with local anesthesia (effect size, 0.38; 95 % CI: 0.07 to 0.70) and exercise (effect size, 0.71; 95 % CI: 0.30 to 1.11).  There was an insignificant advantage of dextrose over corticosteroids (effect size, 0.31; 95 % CI: -0.18 to 0.80) which was only estimated from 1 study.  The authors concluded that dextrose injections decreased pain in OA patients; but did not exhibit a positive dose-response relationship following serial injections.  Dextrose prolotherapy was found to provide a better therapeutic effect than exercise, local anesthetics, and probably corticosteroids when patients were re-tested 6 months following the initial injection.  They also noted that The effect of prolotherapy did not differ between hand and knee osteoarthritis.

This study had several drawbacks:

1. the number of trials eligible for meta-analysis was limited, and heterogeneity existed in the patient populations, injection protocols, comparative regimens, and outcome assessment,
2. these researchers did not analyze effect sizes of functional improvements because the data were not available in each retrieved trial.
3. although previous research proposed that the benefit of dextrose prolotherapy derived from its chondo-protective effect or modulation of intra-articular cytokines, these theories could not be proved by this meta-analysis since there were few data about the measurement of cartilage thickness and intra-articular cytokine level in the retrieved articles,
4. hyaluronic acid and platelet-rich plasma are known to counteract OA.  Although dextrose prolotherapy appeared to be more effective than the use of corticosteroids and local anesthetics, the comparison with commonly used regimens like hyaluronic acid or platelet-rich plasma was lacking in this literature search.  This subject should be investigated in future prospective studies,
5. the treatment responsiveness using binary data, which considered the standard outcome variable in pain medicine, is not reported in the included studies. Therefore, these investigators used the effect sizes retrieved from continuous variables like changes in pain or function instead in the quantitative analysis, and
6. the interpretation of the effect of dextrose compared with corticosteroids should be cautious because the finding was derived from only a single study.

Sit and colleagues (2018) noted that KOA is a very common condition with prevalence rising with age.  It is a major contributor to global disability and has a large socioeconomic burden worldwide.  Conservative therapies have marginal effectiveness, and surgery is reserved for severe symptomatic KOA.  Dextrose prolotherapy (DPT) is an evidence-based injection-based therapy for chronic musculoskeletal conditions including KOA.  The standard "whole joint" injection method includes intra-articular injection and multiple extra-articular injections at soft tissue bony attachments.  The procedure is painful and requires intensive procedural training often unavailable in conventional medical education, which potentially limits access.  Intra-articular injection offers the possibility of a less painful, more accessible treatment.  The aim of this project is to assess the clinical efficacy of intra-articular injection of DPT versus normal saline (NS) for KOA.  A total of 76 participants with KOA will be recruited from the community.  These researchers will conduct a single-center, parallel group, superiority RCT comparing DPT and NS injections, with blinding of physician, subjects, outcome assessors and statisticians.  Each group will receive injections at week 0, 4, 8 and 16.  The primary outcome will be the WOMAC, and secondary outcomes include WOMAC composite score, the WOMAC function and stiffness subscale, the VAS of pain, objective physical function tests (the 30 s chair stand, 40-m fast paced walk test, the Timed up and go test) and the EuroQol-5D (EQ-5D).  All outcomes will be evaluated at baseline, and 16, 26 and 52 weeks.  All analyses will be conducted on an intention-to-treat basis using linear mixed regression models.  The authors concluded that this paper presents the rationale, design, method and operational aspects of the trial.  The findings will determine whether intra-articular DPT, an inexpensive and simple injection, is a safe and effective non-surgical option for KOA.  The results can be translated directly to clinical practice, with potentially substantial impact to patient care.

Temporomandibular Joint Hypermobility

Comert Kilic and Gungormus (2016) performed a randomized clinical trial involving adult patients with bilateral TMJ hypermobility referred for treatment.  The sample comprised 30 consecutive patients, who were divided randomly into 2 groups.  The TMJ hypermobility was treated with either saline (placebo group) or dextrose injections (study group).  The solution was injected into 5 different TMJ areas in 3 sessions at monthly intervals.  The predictor variable was the treatment technique.  The outcome variables were VAS evaluations and maximum inter-incisal opening (MIO).  Outcome variables were recorded pre-operatively and at 12 months post-operatively.  Descriptive and bivariate statistics were computed, and significance was set at a p-value of less than 0.05.  The follow-up sample comprised 26 subjects: 12 in the placebo group and 14 in the study group.  Masticatory efficiency increased and general pain complaints and joint sounds decreased significantly in both groups; MIO decreased significantly only in the study group.  Insignificant changes in the other parameters were found for both groups.  After estimating differences between follow-up and baseline outcomes, the mean change in primary outcome variables showed no statistically significant difference between the 2 groups.  The authors concluded that these findings suggested that dextrose prolotherapy is no more effective than placebo treatment for any of the outcome variables of TMJ hypermobility assessed.

Reeves and colleagues (2016) stated that prolotherapy involves the injection of non-biologic solutions, typically at soft tissue attachments and within joint spaces, to reduce pain and improve function in painful musculoskeletal conditions.  A variety of solutions have been used; dextrose prolotherapy is the most rigorously studied and is the focus of this review.  Although the mechanism of action is not clearly known, it is likely to be multifactorial.  The authors concluded that data on effectiveness for temporomandibular dysfunction are promising but insufficient for recommendations; research on the mechanism of action and clinical effects of dextrose prolotherapy are under way.

In a systematic review and meta-analysis, Nagori and colleagues (2018) examined the available evidence on the efficacy of DPT in improving outcomes in TMJ hypermobility patients as compared to placebo.  An electronic search of PubMed, Scopus, CENTRAL and Google scholar databases was performed for English language papers published up to February 2018; RCTs and controlled clinical trials (CCTs) comparing DPT with placebo for TMJ hypermobility were included.  A total of 3 RCTs were included in the review.  Frequency of subluxation/dislocation was reported by 2 trials, which found no difference between dextrose and placebo.  A statistical significant difference in reduction of MMO with the use of DPT was seen on pooling of data (random: MD = -3.32, 95 % CI -5.26 to -1.28; p = 0.0008; I2  = 0 %).  A statistical significant difference in pain reduction was also seen with dextrose as compared to placebo (random: MD = -1, 95 % CI -1.58 to -0.42; p = 0.0007; I2  = 0 %).  The authors concluded that within the limitations of the study, DPT may cause significant reduction in mouth opening and pain associated with TMJ hypermobility.  Conclusions with regard to reduction of episodes of subluxation/dislocation could not be drawn.  These researchers stated that there is a need of more high-quality RCTs with larger sample size and homogenous prolotherapy protocol to draw stronger conclusions on the effect of DPT in patients with TMJ hypermobility.

Prolotherapy for Shoulder Pain

Seenauth and colleagues (2018) noted that shoulder pain is one of the most common pain complaints reported by patients.  Consensus is lacking on its ideal treatment, and many different treatments are available and used.  These researchers examined the use of dextrose prolotherapy in the treatment of shoulder pain.  The study occurred at the Medical Center at Southwest College of Naturopathic Medicine (Tempe, AZ).  The participant was a middle-aged man with a long-term history of untreated shoulder pain.  Injections were administered in the patient's glenohumeral joint space, the acromioclavicular joint, the subacromial space, and the insertion of the supraspinatus.  Each location was injected with a solution of 50 % dextrose diluted with 1 % lidocaine, 0.25 % bupivacaine, and 1 mg methylcobalamin.  The final concentration of dextrose in the solution was approximately 22.8 %.  The patient completed questionnaires (numerical rating scale, verbally reported at the beginning of each visit) indicating his level of pain on a scale of 0 to 10, with 0 = no pain and 10 = worst pain.  Following 3 sessions of prolotherapy, the patient reported a 90 % reduction in pain and full restoration of normal activity.  The authors concluded that the findings of this single-case study suggested that dextrose prolotherapy may be an effective treatment for chronic shoulder pain and may be an alternative to surgery or other more costly and invasive interventions.

Sclerotherapy for Achilles Tendinopathy

Morath and colleagues (2018) stated that chronic painful Achilles tendinopathy (AT) is a common disorder among athletes.  Sclerotherapy (ST) and prolotherapy (PT) are 2 promising options among the numerous other conservative therapies.  As their efficacy and potential AEs are still unclear, these researchers systematically searched, analyzed, and synthesized the available literature on ST and PT for treating AT.  Electronic databases, Google Scholar and articles' reference lists were searched according to PRISMA guidelines.  Eligibility criteria were set up according to the PICOS-scheme including human and animal studies.  Three authors independently reviewed the results and evaluated methodological quality (Coleman Methodology Score and Cochrane Risk of Bias Assessment).  The initial search yielded 1,104 entries.  After screening, 18 articles were available for qualitative synthesis, 6 of which were subjected to meta-analysis.  The mean Coleman Score of the 13 human studies was 50; 4 RCTs were ranked as having a low risk of selection bias; 3 of those reported a statistically significant drop in the VAS score, one a significant increase in the VISA-A Score; 12 of 13 human studies reported positive results in achieving pain relief and patient satisfaction, whereas only 1 study's finding differed.  Meta-analysis revealed an unambiguous result in favor of the intervention (weighted mean difference [WMD] = -4.67 cm, 95 % CI -5.56 to -3.76 cm [p < 0.001]).  Only 1 serious AE and 2 minor AEs were reported in the entire literature.  The authors concluded that the findings of this systematic review suggested that ST and PT may be effective treatment options for AT and that they can be considered safe.  Moreover, they stated that long-term studies and RCTs are still needed to support their recommendation.

Sclerotherapy for Aneurysmal Bone Cysts

Park et al (2016) noted in a review of aneurysmal bone cysts, that local control of aneurysmal bone cysts can be achieved by inducing sclerosis of the aneurysmal bone cyst vascular network. In a randomized trial, Varshney et al. (2010) compared polidocanol sclerotherapy with curettage, high-speed burr, and bone graft: polidocanol had a healing rate of 93.3 % compared with 84.8 % for curettage, although this difference did not reach statistical significance. There was no statistical difference in healing rates; however, sclerotherapy with polidocanol provided faster pain relief, better functional outcomes, and avoided the morbidity and costs associated with surgery

Ghanem and colleagues (2017) reviewed the findings of sclerotherapy using Surgiflo in addition to alcohol in the treatment of primary aneurysmal bone cysts (ABC).  A total of 16 consecutive patients with histologically confirmed diagnosis of primary ABC were treated by percutaneous Surgiflo and alcohol injection.  Clinical follow-up included the assessment of pain, swelling, limping and functional impairment.  Radiological parameters included tumor volume, physis-cyst distance, thickness of cyst cortex, and presence of intra-cystic septations.  Mean follow-up was 35.6 months (range of 24 to 71 months).  Treatment was considered successful when the cyst volume decreased by a minimum of 10 %, the bone cortex became thicker, and the distance to physis increased.  Mean age at presentation was 9.5 years (range of 5.16 to 13.84 years).  All ABC's were primary and all patients underwent a single Surgiflo and alcohol session except for 2 (12.5 %) who required a 2nd session.  All patients had a good clinical result at final follow-up.  Satisfactory cyst healing was achieved in 11 cases according to radiological parameters.  Tumor volume decreased from a mean of 122 cm3 (range of 111 to 133) before injection to 86 cm3 (range of 76 to 96) at last follow-up (p < 0.01).  Physis-cyst distance increased from a mean of 1 cm (0.1 to 2) to 2.1 cm (0.5 to 4) at last follow-up (p < 0.01).  Cortical thickness improved from 1 mm (0.5 to 1.5) to 2 mm (1 to 3.5) at last follow-up (p < 0.01).  There were no treatment related complications.  Surgery was performed in 1 patient having a C3 vertebra ABC after developing quadriparesis due to tumor progression.  The authors concluded that sclerotherapy using Surgiflo and alcohol may be used as an efficient, safe and minimally invasive alternative for the treatment of primary ABCs.  These preliminary findings need to be validated by well-designed studies.

Sclerotherapy for Cystic Thyroid Nodules

Guidelines on thyroid nodules from the American Thyroid Association (Haugen, et al., 2015) state that "recurrent cystic thyroid nodules with benign cytology should be considered for surgical removal or percutaneous ethanol injection (PEI) based on compressive symptoms and cosmetic concerns. Asymptomatic cystic nodules may be followed conservatively. (Weak recommendation, Low-quality evidence)." Guidelines on thyroid nodules from the American Association of Clinical Endocrinology (2016) state that percutaneous ethanol injection (PEI) is the first-line treatment of relapsing benign cystic thyroid lesions.

Gong and colleagues (2017) evaluated the safety and efficacy of percutaneous polidocanol injection (PPI) in treating cystic thyroid nodules.  A total of 158 cystic or predominantly cystic thyroid nodules (greater than 80 % cystic component) in 143 patients were evaluated; 114 patients with compressive symptoms or aesthetic complaints were offered PPI; 44 individuals without compressive symptoms and aesthetic complaints who were only followed-up clinically were used as the control group.  The safety and efficacy of PPI were evaluated for 1-, 3-, 6-, 9-, and 12-month follow-ups.  In the PPI group, the mean baseline volume of 15.6 ± 18.9 cm3 reduced at the 1-month follow-up to 5.1 ± 5.6 cm3 (p < 0.001) and 0.6 ± 0.9 (p < 0.001), and nodules shrunk according to the time after PPI (p < 0.001).  A complete response (if greater than or equal to 70 % decrease) to PPI at the 12-month follow-up occurred in 100 % of the cystic or predominant cystic nodules.  None of the nodules recurred at the 12-month follow-up after PPI.  The side effects were mild; 20 patients (17.5 %) developed mild localized pain, and 14 cases (12.3 %) experienced mild or moderate fever after PPI.  The authors concluded that PPI is a safe and effective alternative to treat benign cystic or predominant cystic thyroid nodules; moreover, further studies with larger patient samples are needed to confirm these findings.  This study had 2 main drawbacks:

1. these investigators did not compare PPI treatment with a control group treated with ethanol because they could not obtain absolute ethanol, and
2. patients were followed-up only for 1 year.

Sclerotherapy for Epistaxis due to Hereditary Hemorrhagic Telangiectasia

In a pilot study, Boyer et al (2011) evaluated office-based sclerotherapy using sodium tetradecyl sulfate (STS) for epistaxis due to hereditary hemorrhagic telangiectasias (HHT).  Patients with HHT suffer from unpredictable, recurrent, severe nasal bleeding necessitating emergency care, nasal packing, blood transfusions, and invasive procedures.  In this retrospective study, a total of 7 patients with a history of treatment for recurrent epistaxis due to HHT were treated in an office-based setting with intra-lesional injection of STS.  Treatment results were evaluated using a questionnaire.  All patients had undergone multiple prior procedures attempting to control epistaxis.  Patients had an average of 5 sclerotherapy treatments for HHT.  Patients were treated using topical and/or local anesthesia with no reports of discomfort.  Bleeding requiring intervention did not occur during the procedures.  After the procedure all patients (100 %) reported significantly less frequent and less severe nasal bleeding.  A total of 83 % reported that their need for nasal packing was reduced.  All patients were willing to undergo the same treatment again.  No complications such as perforation, crusting, or foul smell were reported.  The authors concluded that this was the first clinical experience demonstrating that office-based sclerotherapy with STS was a safe, tolerable, and useful alternative for the treatment of epistaxis due to HHT.

In a prospective randomized trial, Boyer et al (2015) examined the effectiveness of sclerotherapy with STS versus standard treatment for the treatment of HHT.  This study (conducted from November 1, 2011, through January 31, 2014) involved 17 patients with recurrent epistaxis due to HHT.  These researchers defined standard treatment as continuation of any treatment that the patient had previously undergone, such as moisturization, packing, and cautery.  They used a cross-over design, so study participants were randomized to either sclerotherapy or standard treatment during the first time period, and then to the other during the second period.  The primary outcome measure was frequency and severity of epistaxis, as measured by the epistaxis severity score (ESS).  The ESS is a 10-point scale, with higher scores corresponding to more bleeding.  After controlling for treatment order, bleeding was substantially better controlled after sclerotherapy; the ESS after sclerotherapy was nearly 1 point lower than after standard treatment (-0.95, 1-sided p = 0.027).  Treatment order, baseline ESS, the number of lesions, moisturization practices, and a history of previous blood transfusions did not significantly affect the results.  The authors concluded that the findings of this trial demonstrated that sclerotherapy with STS (versus standard treatment) significantly reduced epistaxis due to HHT. 

The authors noted that this study had several drawbacks:

1. lack of randomization and blinding,
2. the sample size (n = 17) was smaller than what these investigators had originally planned (nearly 40 patients).  They found that many patients were unwilling to be randomized, because they had been referred for treatment with sclerotherapy.  However, the authors believed that their findings were perhaps even more meaningful because their observed effect reached statistical significance, even in enrolling 50 % the anticipated number of patients.  They believed that this supported their assertion that the observed impact was strongly clinically significant, and
3. these researchers recognized that some may criticize their definition of standard therapy.  They chose to define standard therapy as it is largely used in the community, with a potpourri of treatments.  These investigators felt that patients had been managed as best as possible by referring otolaryngologists, and the authors therefore kept standard therapy to what had been optimized prior to their referral.  They also recognized that the treatment periods could have been lengthened, and they could not offer a true washout period because that would require no treatment for their epistaxis, which would not be reasonable. 

However, the authors had to balance study optimization with study enrollment.  Patients were not willing to wait more than 2 months for sclerotherapy.

In an evidence review of treatments for epistaxis in HHT, Chin et al (2016) stated that sclerotherapy with STS was described for use in HHT in 2011.  A follow-up prospective trial recently demonstrated the efficacy of sclerotherapy when compared to “standard therapy” (defined in this study as any treatment that the patient had previously undergone, such as packing or cautery).  Sclerotherapy works via injection of STS into the vascular lesion, which theoretically leads to thickening of the vessel wall and subsequently less bleeding.  The authors notes that this is a promising new treatment that can be considered in HHT patients.  The authors concluded that the existing studies showed benefit for sclerotherapy; moreover, they stated that further research into this treatment modality is needed. This recommendation had Level of Evidence: Level 1b (1 RCT); level 4 (1 case series).

Grigg et al (2017) states that HHT is a disease more commonly associated with significant morbidity rather than mortality.  The morbidity of the disease and decreased quality of life are the result of the recurrent and potentially severe epistaxis a majority of patients with HHT experience … Recent research has involved comparison of new therapies including laser photocoagulation, electrosurgical plasma coagulation, and sclerotherapy … During active epistaxis, the effective emergency techniques of locally applied pressure, nasal packing anteriorly and/or posteriorly, and cauterization will likely remain paramount.  Medical treatment with anti-estrogen therapy has shown promising results in trials from Israel, but further research is needed to determine the long-term side effects and the limitations of lifelong therapy.  Research directed toward bleeding reduction and prevention has yet to have a breakthrough.  Although initial reports suggested that intranasal bevacizumab is an effective agent, with some studies resulting in decreased ESS and manageable side effects, further research with longer treatment periods and follow-up is needed.  In the meantime, appropriate management of acute epistaxis coupled with early diagnosis and referral to an ear, nose, and throat specialist should be the mainstay of treatment.

Sclerotherapy for High Varix Ligation

In a prospective, randomized comparative study, Abdelsalam and co-workers (2017) compared the results of high varix ligation with and without sclerotherapy.  Between November 2014 and December 2015, a total of 60 patients with varicocele were included in this study.  Patients were divided into 2 equal groups: group I (underwent high varix ligation), and group II (underwent high varix ligation with a retrograde injection of 2 ml of 5 % ethanolamine oleate in the lower end of the bisected gonadal vein).  The operative time, intra- and post-operative complications, post-operative pain, improvement of semen parameters, incidence of recurrence and achieving of unassisted pregnancy were recorded for both groups.  The age range was 19 to 34 years in group I and 21 to 37 years in group II.  The operative time was shorter in group I (34.6 ± 7.81 mins) than group II (43.3 ± 8.5 mins) (p < 0.001).  Improvement of semen parameters and the occurrence of spontaneous pregnancy were insignificant between both groups.  No intra-operative complications occurred.  The post-operative complications were statistically insignificant in both groups.  The authors concluded that combined varix ligation with retrograde sclerotherapy did not offer significant advantages over high varix ligation alone with a longer operative time and prolonged post-operative pain.

Sclerotherapy for Orbital Varices

An overview of orbital vascular malformations from the North American Society of Academic Orbital Surgeons (Subramanian, 2016) state that orbital varices are a type of venous malformations of the orbit where venous walls are thinned and distended. They commonly present in the second or third decade of life and are usually unilateral. Clinical presentation includes stress proptosis –proptosis that increases with maneuvers that rise venous pressure like coughing, straining, forward bending or Valsalva. Complications like hemorrhage and thrombosis are rare but may lead to rapid proptosis, pain, diplopia and optic nerve compression. Most patients do not need treatment; indications for treatment are recurrent thrombosis, severe proptosis or optic nerve compression. Treatment options include scleroterapy, electrothrombosis, emboliztion and surgical resection.

Yang and colleagues (2018) stated that until now, no study has focused exclusively on low-flow retrobulbar intraconal venous malformations (RIVMs), which may require treatment due to cosmetic defect, pain, and visual dysfunction.  The treatment for RIVMs, which surround the optic nerve remains challenging.  In a prospective, non-comparative, single-center, interventional case-series study, these investigators evaluated the technical feasibility, effectiveness, and safety of percutaneous sclerotherapy with polidocanol for low-flow RIVMs, using local anesthesia.  All patients signed informed consent forms; 7 patients with RIVMs were treated with percutaneous sclerotherapy with polidocanol/air foam using CT guidance.  Primary end-points were reduction in the volume of RIVMs and pain relief assessed by VAS; secondary end-points were exophthalmos and recording AEs obtained in clinical follow-up during out-patient visits.  Results revealed that the mean volume of RIVMs was decreased from 12.05 ± 6.35 cm3 pre-operatively to 1.56 ± 0.43 cm3 post-operatively, (p = 0.005), with a mean decrease of 87.05 %.  The intra-ocular pressure (IOP) was lowered from 14.19 ± 2.99 to 11.79 ± 1.25 mmHg, (p = 0.043).  The mean VAS score was reduced from 3.43 ± 2.37 pre-operatively to 1.29 ± 0.76 post-operatively, (p = 0.023).  The exophthalmos score was decreased from 1.75 ± 0.27 to 1.34 ± 0.31 cm, (p = 0.005).  All patients were satisfied with the treatment, which did not leave a post-operative scar.  The authors concluded that the results of percutaneous intra-lesion injection of polidocanol for RIVMs are encouraging.  They stated that these findings suggested that this method could be a safe and effective treatment option for patients with RIVMs.  These preliminary findings need to be validated by well-designed studies.

Sclerotherapy for Seromas

Sood and co-workers (2017) stated that despite improved recognition of risk factors, plastic surgeons commonly encounter seromas post-operatively and must decide upon management.  Current recommendations for minimally invasive, chemical management originate from the literature on management of pneumothorax and pleural effusions.  A handful of published reports have suggested the efficacy of sclerotherapy in seroma management.  These researchers evaluated the literature on the use of sclerosants to treat subcutaneous fluid collections.  A systematic review of the literature was performed on the PubMed, Medline, and Cochrane databases for primary research articles on sclerotherapy for seroma treatment between January 1975 and January 2017.  Exclusion criteria were surgical treatment, sclerotherapy for seroma prevention, hematoma, or absence of detailed documentation.  Data related to seroma location, sclerosant, and resolutions were extracted.  The literature search yielded 7 relevant articles of level IV evidence and 12 case reports, with a total of 84 patients treated with sclerotherapy for persistent seromas.  Sclerosant included talc, tetracycline antibiotics, ethanol, polidocanol, erythromycin, OK-432, fibrin glue, and povidone-iodine.  All agents achieved high rates of success.  Repeat aspirations and instillations were easily performed when needed.  Complications, while uncommon, included pain, tightness or discomfort of the treated area, and infection.  The authors concluded that sclerotherapy appeared to be safe and effective for recurrent seromas.  While a variety of sclerosing agents may be applied successfully, talc and tetracyclines remain popular choices.  Moreover, they stated that because of the small scale, heterogeneity, and retrospective nature of the studies, the reproducibility and generalizability of the reported outcomes cannot be determined; larger, randomized, comparative studies are needed to ascertain and optimize this therapeutic approach.

Electro-Sclerotherapy for Capillary Malformations

Horbach and associates (2017) noted that the current state-of-the-art treatment modality for hypertrophic capillary malformations (CMs), laser therapy, has a considerable rate of non-responders and recurrence.  Electroporation -- an electric field applied to the tissue -- could increase the permeability of endothelial cells, which could theoretically facilitate targeted localized bleomycin delivery.  These researchers hypothesized that bleomycin injections in combination with electroporation – “electro-sclerotherapy (EST)”, also known as “electro-chemotherapy” -- could potentially be a novel alternative therapeutic option for CMs.  In this randomized within-patient controlled pilot trial, 20 patients with hypertrophic CMs will be enrolled.  Three regions of interest (ROIs) within the CM will be randomly allocated for treatment with

1. EST,
2. bleomycin sclerotherapy without electroporation, and
3. no treatment. 

Patients and outcome assessors are blinded for the treatment allocation.  Treatment outcome for each ROI will be measured approximately 7 weeks after the treatment procedure, using patient-reported and physician-reported global assessment scores, colorimetry, laser speckle imaging and reporting of AEs.  The authors concluded that the study protocol is approved by the ethics review committee of the Academic Medical Center, Amsterdam.  They stated that in this feasibility trial, the safety and effectiveness of EST as a therapeutic option for hypertrophic CMs will be explored.  When the results of this study provide preliminary evidence for the safety and effectiveness of EST in hypertrophic CMs, a larger ensuing hypothesis-testing trial will be conducted.

Sclerotherapy for the Treatment of Morton’s Neuroma

Fanucci et al (2004) stated that Morton's neuroma (MN) is a frequent cause of metatarsalgia.  These investigators evaluated the efficacy of neuroma alcohol-sclerosing therapy (NAST) under ultrasound (US) guidance in MN after a 10-month follow-up.  A total of 40 inter-metatarsal neuromas underwent alcohol-sclerosing therapy after US evaluation of their dimensions and echotexture.  After subcutaneous anesthesia, a sclerosing solution composed of anesthetic (carbocaine-adrenaline 70 %) and ethylic alcohol (30 %) was injected inside the mass under US guidance.  The procedure was repeated at intervals of 15 days until the resolution of the symptoms.  A total or partial symptomatic relief was obtained in 36 cases (90 %).  No procedure-related complications were observed.  Transitory plantar pain, due to the flogistic reaction induced by the sclerosing solution, occurred in 6 cases (15 %).  The 10-month follow-up revealed a 20 to 30 % mass volume reduction and an adiposus-like change in echotexture.  In the 4 cases (10 %) of therapeutic failure, the preliminary US demonstrated a hypoechoic echotexture with a strong US beam attenuation corresponding to a highly fibrous neuroma after surgical resection.  The authors concluded that NAST is a feasible and cost-efficient procedure with high rates of therapeutic success.

Magnan et al (2005) noted that the symptomatic treatment of Civinini-Morton syndrome (inter-digital neuritis: IDN) may be performed directly on the nervous trunk involved using orthotic, local pharmacological or surgical methods.  Alcoholization with phenol in the percutaneous treatment of IDN has the purpose of provoking a permanent chemical neurolysis, obtaining remission of the neuritic pain symptoms.  A total of 71 cases were treated by a dorsal approach to the inter-metatarsal space using a needle-electrode connected to the electro-stimulator.  Once the nervous trunk with a reproduction of the paresthesia to the fingers was localized, 2.5 ml of phenol at 5 % water solution was injected, immediately followed by local anesthetic with a post-surgical analgesic purpose.  Mean follow-up was 36 +/- 8 months.  The patients were evaluated by visual analog scale for pain (VAS).  Alcoholization of the common inter-digital nerve proved to be effective in treating pain in 80.3 % of cases (57/71).  Treatment must be considered a percutaneous mini-invasive surgical procedure.  The authors concluded that the results were better than those reported in the literature with conservative and infiltrative treatment and they appeared to be comparable today with those obtained when surgical treatment was used, with no complications occurring.

Musson et al (2012) evaluated the efficacy of US-guided alcohol injection as a treatment for Morton's neuroma.  Data from 87 treatment courses (85 patients) were included in this study with a mean follow of 14.3 months.  Technical success was 100 %; 1 patient developed symptoms consistent with an allergic reaction to the injection and 1 patient declined further injection because of peri-procedural pain.  Partial or total treatment response was achieved in 66 %, with 32 % of patients having complete resolution of pain.  The median VAS decreased from 8 pre-procedure to 4 post-procedure (p < 0.0001).  Procedural success was greater in patients under 55 years old and in those with solitary neuromas; 17 patients (20 %) went on to have surgery due to continuing pain.  The authors concluded that US-guided alcohol ablation for the treatment of Morton's neuroma was a safe procedure that significantly reduced pain and may offer an alternative therapy to surgery.

In a retrospective, case-series study, Pasquali et al (2015) evaluated the effectiveness of US-guided alcohol injection (USGAI) to treat Morton's neuroma in 508 patients at 2 medical centers.  Between January 2001 and January 2012, 508 patients with 540 Morton's neuroma had USGAI for Morton's neuroma.  Only 2nd and 3rd web-space neuromas were included in this study.  A mean number of 3.0 (range of 1 to 4) injections were performed for each neuroma.  Mean local inflammatory reaction was 0.7 (range of 0 to 2).  There were no other local or systemic complications.  The overall mean pre-USGAI VAS score was 8.7 (range of 6 to 10), while the post-USGAI VAS score at 1 year was 3.6 (range of 0 to 9).  The delta VAS between the pre- and post-USGAI was statistically significant (p < 0.0001).  At 1-year follow-up 74.5 % of patients were satisfied with the procedure.  The authors concluded that USGAI produced encouraging results in over 500 patients affected by Morton's neuroma.; the procedure proved to be safe in all patients. 

Furthermore, an UpToDate review on “Evaluation and diagnosis of common causes of forefoot pain in adults” (Fields, 2018) states that “Other treatments, including injection of alcohol and radiofrequency therapy to ablate the neuroma, have shown promise in observational case series”.

Prolotherapy for Ischio-Femoral Impingement

Nakano and colleagues (2020) noted that there has been relatively little information about the treatment for ischio-femoral impingement (IFI) because of its rarity as well as the uncertainty of diagnosis In a systematic review, these investigators evaluated the available treatment strategies and their related outcomes for IFI based on the best available evidence, while high-lighting classically accepted ways of treatment as well as relatively new surgical and non-surgical techniques.  They carried out a systematic review of the literature from Medline, Embase, AMED, Cochrane and Google Scholar since inception to December 2017 following the PRISMA guidelines.  Clinical outcome studies, prospective/retrospective case series and case reports that described the treatment outcome for IFI were included.  Animal or cadaveric studies, trial protocols, diagnostic studies without any description of treatments, technical notes without any results, and review articles were excluded.  These researchers found 17 relevant papers.  No comparative studies were included in the final records for qualitative assessment, which meant all the studies were case-series and case-reports; 8 studies (47.1 %) employed non-surgical treatment including injection and prolotherapy, followed by endoscopic surgery (5 studies, 29.4 %) then open surgery (4 studies, 23.5 %).  Mean age of the subjects was 41 years (11 to 72).  The mean follow-up was 8.4 months (range of 2 weeks to 2.3 years).  No complications or adverse effects were reported.  The authors concluded that several treatment strategies had been reported for IFI, and most of them had good short- to medium-term outcomes with a low rate of complications.  However, there were no comparative studies to evaluate the superiority of one technique over another, thus further research with RCTs is needed.  This study  provided level III evidence; these findings need to be validated by well-designed studies.

Prolotherapy for Sacroiliac Joint Instability

In a retrospective cohort study, Hoffman and Agnish (2018) examined the effectiveness of sacro-iliac (SI) joint prolotherapy for SI joint instability, and characterized the patients most likely to benefit from this treatment.  Patients referred for LBP and diagnosed with SI joint instability received a series of 3 SI joint prolotherapy injections (15 % dextrose in lidocaine) at approximately a 1-month interval.  The outcome of those completing treatment was retrospectively examined, and characteristics were compared between those with at least a minimum clinically important improvement and those without improvement.  Patients completed the Oswestry Disability Index (ODI) before treatment was initiated, immediately preceding each prolotherapy injection, and at 3 to 4 month follow-up.  Of 103 treated patients returning for post-treatment follow-up at a median of 117 days, 24 (23 %) showed a minimum clinically important improvement despite a median of 2 years with LBP and a mean (± SD) pre-intervention ODI of 54 ± 15 points.  Much of the improvement was evident after the initial prolotherapy injection, and a 15-point improvement in ODI prior to the 2nd prolotherapy injection had a sensitivity of 92%  and specificity of 80 % for determining which patients would improve.  The authors concluded that a satisfactory proportion of patients with symptomatic SI joint instability as an etiology of LBP could have clinically meaningful functional gains with prolotherapy treatment.  The patients who were not likely to improve with prolotherapy were generally evident by lack of improvement following the initial prolotherapy injection.  This was a retrospective study with relatively short-term follow-up (3 to 4 months); and less than 25 % of participants attained minimum clinically important improvement.  These findings need to be validated by well-designed studies with long-term follow-up.

Prolotherapy for the Treatment of Chronic Musculoskeletal Pain

In a systematic review and meta-analysis, Bae and colleagues (2020) examined the effectiveness of dextrose prolotherapy as a long-term treatment for chronic musculoskeletal pain.  Medline, Embase, Cochrane Central, KoreaMed, and KMbase databases were searched for studies published up to March 2019.  These researchers included RCTs that compared the effect of dextrose prolotherapy with that of other therapies such as exercise, saline, platelet-rich plasma (PRP), and steroid injection.  The primary outcome was pain score change during daily life.  A total of 10 studies involving 750 participants were included in the final analysis.  Pain scores from 6 months to 1 year after dextrose prolotherapy were significantly reduced compared to saline injection (SMD -0.44; 95 % CI: -0.76 to -0.11, p = 0.008) and exercise (SMD -0.42; 95 % CI: -0.77 to -0.07, p = 0.02).  Prolotherapy yielded results similar to PRP or steroid injection, that it showed no significant difference in pain score.  The authors concluded that dextrose prolotherapy was more effective in the treatment of chronic pain compared to saline injection or exercise.  Its effect was comparable to that of PRP or steroid injection.  Moreover, these investigators stated that adequately powered, homogeneous, and longer-term trials are needed to better ascertain the efficacy of prolotherapy.

Prolotherapy for the Treatment of Bursitis, Fasciopathy, Glenohumeral Osteoarthritis,  Ligament Injuries, and Tendinopathy

In a systematic review and meta-analysis, Chung and colleagues (2020) examined the effectiveness and superiority of prolotherapy separately in treating dense fibrous connective tissue injuries.  PubMed, Scopus, and Embase were searched from the earliest record to February 18, 2019.  This study included RCTs; both analysis at individual studies level and pooled meta-analysis were carried out.  A total of 10 trials involving 358 participants were included for review.  At study level, the majority of comparisons did not reveal significant differences between dextrose prolotherapy and placebo regarding pain control.  The meta-analysis showed dextrose prolotherapy was effective in improving activity only at immediate follow-up (i.e., 0 to 1 month) (SMD: 0.98; 95 % CI: 0.40 to 1.50; I = 0 %); and superior to corticosteroid injections only in pain reduction at short-term follow-up (i.e., 1 to 3 month) (SMD: 0.70; 95 % CI: 0.14 to 1.27; I = 51 %).  No other significant SMDs were found in this analysis.  The authors concluded that there is insufficient evidence to support the clinical benefits of dextrose prolotherapy in managing dense fibrous tissue injuries.  These researchers stated that more high-quality RCTs are needed to establish the benefits of dextrose prolotherapy.

The authors stated that this study had several drawbacks.  The involved study population differed in diagnosis, durations of symptoms, mechanisms, severity of injuries, and methods of injection, which potentially contributed to the evident heterogeneity.  Although the fascia, ligaments, and tendons shared many common features, the surrounding environment, vasculature, and tensile loads within these structures vary.  Finally, only 3 databases were searched, and only a limited number of trials and participants were available for this analysis.

In a systematic review, Catapano and associates (2020) examined the efficacy and complication profile of prolotherapy using hyperosmolar dextrose solution injection for rotator cuff tendinopathy.  Data sources included Medline, Embase, CINAHL, and the Cochrane Central Register of Controlled Trials (from inception to July 1, 2019).  These researchers carried out a comprehensive search to identify RCTs addressing prolotherapy using hyperosmolar dextrose solution for rotator cuff tendinopathy.  Two reviewers independently screened the titles, abstracts, and full texts, and then extracted data from eligible studies.  All reported outcome measures and complications were analyzed descriptively.  A total of 5 studies satisfied inclusion criteria.  Included studies analyzed a total of 272 participants with a final follow-up ranging from 6 weeks to 12 months.  Prolotherapy differed greatly among studies; 2 studies used a multi-site enthesis injection protocol while the other 3 used US-guided protocols; 2 of the studies used an intra-substance supraspinatus injection and 3 used a supraspinatus enthesis injection.  Control groups consisted of non-operative rehabilitation including physical therapy and medical management in 3 studies, supraspinatus saline enthesis injection in 1 study, and corticosteroid injection in 1 study.  There was statistically significant improvement in pain intensity with multi-site injection protocols compared to physical therapy and medical management in both studies; US-guided supraspinatus injection trials did not find any statistically significant difference in pain intensity, range of motion (ROM), strength, function, or US characteristics compared to controls of enthesis saline injection or corticosteroid.  The complication rate was low, with only 6/272 participants experiencing AEs consisting of transient increase in pain for 1 to 2 days post-intervention.  The authors concluded that prolotherapy with hyperosmolar dextrose solution was a potentially effective adjuvant intervention to physical therapy for patients with rotator cuff tendinopathy ranging from tendinosis to partial-thickness and small full-thickness tears.  Moreover, these researchers stated that further studies are needed to determine effects in sub-populations as well as optimal technique including dextrose concentration, volume, and location.

Robinson and co-workers (2020) noted that shoulder pain from rotator cuff pathology and glenohumeral osteoarthritis (OA) is a common entity encountered in musculoskeletal practices.  Ortho-biologic agents are being increasingly used as a therapeutic option and understanding their safety and efficacy is necessary.  These investigators systematically evaluated the available evidence for ortho-biologic use in rotator cuff and glenohumeral pathology.  They carried out a systematic review following PRISMA guidelines; RCTs and prospective cohort studies evaluating non-operative treatment with prolotherapy, PRP, or medicinal signaling cells (MSCs) for rotator cuff pathology and glenohumeral OA were included.  Bias risk assessments used were the Cochrane tool and Newcastle-Ottawa score.  The search yielded 852 potential articles, of which 20 met the inclusion criteria with a breakdown of 5 prolotherapy, 13 PRP, and 2 MSC; 16 studies were RCTs and 4 were cohort studies; 6 studies were deemed "low risk of bias or good quality".  Efficacy results were mixed, and no serious AEs were reported from ortho-biologic treatment.  The authors concluded that ortho-biologics offered a relatively safe therapeutic option with inconclusive evidence for or against its use for rotator cuff pathology.  No studies on glenohumeral OA met the inclusion criteria.  Adoption of standardized preparation reporting and consistent use of functional outcome measures is imperative for future studies to consider.

In a double-blinded RCT, Chang et al (2020) examined if DPT offers clinical benefits in patients with shoulder pain and bursitis.  Subjects were patients (n = 50) who had received a diagnosis of shoulder pain and bursitis through clinical tests and US examination.  They were randomly assigned to the 15 % dextrose injection (D15W) group or the placebo group to receive either D15W or normal saline injection, respectively.  All subjects received US-guidance bursal injection every 2 weeks for a total of 3 injections.  The primary outcome was maximal pain level while performing activities.  The secondary outcomes included resting pain level, function and disability assessment results, and US parameters.  Subjects were followed-up for 3 months after completion of the injection course.  No significant differences in baseline characteristics were observed between the D15W and placebo groups.  Significant time effects were observed for all outcome parameters (all p < 0.05); however, time × group effects were non-significant for all outcomes, except for tissue elasticity (p = 0.026).  The authors concluded that supporting evidence was insufficient regarding the clinical benefits of 15 % dextrose bursal injection administered through 3 sessions in patients with chronic shoulder pain and bursitis.  These researchers stated that the findings indicated that these injections may increase the tissue stiffness of the supraspinatus tendon, as indicated by elastography assessment results; however, further research is needed to determine the nature of such changes in elastography findings.

Prolotherapy for the Treatment of Temporomandibular Joint Luxation

In a systematic review, Abrahamsson and colleagues (2020) examined the effectiveness of surgical and non-surgical treatment of TMJ luxation.  These investigators searched PubMed, the Cochrane Library, and Web of Science databases to identify RCTs on TMJ luxation treatment published between the inception of each database and March 26, 2018.  Two authors evaluated 113 unique abstracts according to the inclusion criteria and read 9 articles in full text; 8 articles comprising 338 patients met the inclusion criteria, but none of these evaluated surgical techniques; 3 studies including 185 patients concerned acute treatment with manual reduction of luxation while 5 studies including 153 patients evaluated minimally invasive methods with injection of autologous blood or dextrose prolotherapy for recurrent TMJ luxation.  These studies reported that mouth opening after treatment was reduced and that independent of type of injection, recurrences of TMJ luxation were rare in most patients.  The authors concluded that in the absence of randomized studies on surgical techniques, autologous blood injection in the superior joint space and peri-capsular tissues with intermaxillary fixation appeared to be the treatment for recurrent TMJ luxation that at present has the best scientific support.  Moreover, these researchers stated that well-designed studies on surgical techniques with sufficient numbers of patients, long-term follow-ups, and patient experience assessment are needed for selection of the optimal surgical treatment methods.

Neural Prolotherapy

Neural prolotherapy involves low dose dextrose Prolotherapy in the treatment of neurogenic inflammatory pain.

Ficarrotta et al (2010) noted that a study using unblinded block performance and subjective outcome measurements suggested that "opening the space" surrounding the femoral nerve with 10 ml dextrose 5 % in water (D5W) before catheter placement facilitated placement and improved the quality of the nerve block.  These researchers conducted a double-blind, prospectively randomized study to evaluate this suggestion by adding objective measurements to the original subjective measurements.  A Tuohy needle was directed toward the femoral nerve under ultrasound and nerve stimulator guidance.  A quadriceps femoris motor response was identified by cephalad patellar movements with a maximum nerve stimulator output of 0.5 mA.  The primary anesthesiologist either injected D5W or made no injection through the needle, depending on patient randomization.  A second anesthesiologist, unaware of randomization, placed the stimulating perineural catheter.  The primary measurement was the procedure time (in seconds) for threading the catheter.  Additional measurements included total nerve block time (in minutes), number of attempts passing the catheter, subjective ease of placement by the second anesthesiologist, depth of needle and catheter, minimum stimulating current through needle and catheter, and the quality of the nerve block.  Two groups of 35 patients were enrolled.  Statistically significant differences were found in the median (5th to 95th confidence intervals [CI]) catheter threading time (21.0 [9.6 to 118] and 33.0 [13.4 to 193] secs in the control and D5W groups, respectively; p = 0.03).  Significant difference was also found in the number of attempts at passing the catheter (1 [1 to 2] and 2 [1 to 4] in the control and D5W groups, respectively; p = 0.03).  The authors concluded that the findings of this study did not support the concept that opening the space surrounding the femoral nerve with D5W before femoral catheter placement added value to perineural catheter placement.

Lam et al (2017) stated that deep nerve hydro-dissection uses fluid injection under pressure to purposely separate nerves from areas of suspected fascial compression, which are increasingly viewed as potential perpetuating factors in recalcitrant neuropathic pain/complex regional pain.  The usage of D5W as a primary injectate for hydro-dissection, with or without low dose anesthetic, could limit anesthetic-related toxicity.  An analgesic effect of D5W upon perineural injection in patients with chronic neuropathic pain has recently been described.  These researchers described ultrasound (US)-guided methods for hydro-dissection of deep nerve structures in the upper torso, including the stellate ganglion, brachial plexus, cervical nerve roots, and paravertebral spaces.  They retrospectively reviewed the outcomes of 100 hydro-dissection treatments in 26 consecutive cases with a neuropathic pain duration of 16 ± 12.2 months and the mean Numeric Pain Rating Scale (NPRS) 0 to 10 pain level of 8.3 ± 1.3.  The mean percentage of analgesia during each treatment session involving D5W injection without anesthetic was 88.1 %  ±  9.8 %.  The pre-treatment NPRS score of 8.3 ± 1.3 improved to 1.9 ± 0.9 at 2 months after the last treatment.  Patients received 3.8 ± 2.6 treatments over 9.7 ± 7.8 months from the 1st treatment to the 2-month post-treatment follow-up.  Pain improvement exceeded 50 % in all cases and 75 % in half.  The authors concluded that these findings confirmed the analgesic effect of D5W injection and suggested that hydro-dissection using D5W provided cumulative pain reduction.

The authors stated that future studies, particularly prospective studies are needed to evaluate the frequency of intra-neural edema in various neuropathic pain syndromes, long-term efficacy of hydro-dissection in comparison to that of standard-volume anesthetic blocks, and use of injectates other than D5W, such as platelet-rich plasma, which may have a favorable effect on dysfunctional nerves by itself.  In addition, because the amount of compression necessary to create a chronic constriction effect appeared to be minimal, it is important to consider all possible points of constriction on these predominantly small-fiber sympathetic nerves between their peripheral origin and central process entry into the neural foramina, without restriction to the classic entrapment locations.  The potential importance of the analgesic effect of dextrose in the absence of anesthetic should not be overlooked in clinical applications and research.  Compared with a nerve block with anesthetic, injection of dextrose for diagnostic purposes may provide a more precise method for identifying which branch or portion of a peripheral nerve is the nociceptive source within the nerve tree because it does not depolarize the nerve.

Chen et al (2018) stated that perineural injection with dextrose could be a novel intervention for peripheral entrapment neuropathy.  However, this intervention has not been reported for treating radial nerve palsy (RNP).  These investigators presented a case with RNP having outstanding improvement after 2 sessions of US-guided perineural injection with D5W.  The subject was a 62-year old woman presented with difficulty and weakness in extension of her left wrist and fingers after she slept with the arm compressed against her body.  On the basis of the findings of electrophysiological study and ultrasonography, the RNP with axonal injury was diagnosed.  Initially, the patient received 2-month conservative treatments without any improvement; 2 sessions of ultrasound-guided perineural injection with total 15 cc D5W with an interval of 1 month were performed 2 months after symptom onset.  A noteworthy improvement in sensory and motor functions was observed after US-guided perineural injection with D5W.  The authors concluded that the findings of this case showed that US-guided perineural injection with D5W may be an effective and novel intervention for RNP.  Moreover, these researchers stated that spontaneous recovery of the RNP could also occur and 1 case report could not demonstrate the overall effect of this treatment; and studies with larger sample sizes are needed to further explore the present study results.

Wu et al (2018) stated that perineural injection with D5W is a novel strategy in the treatment of carpal tunnel syndrome (CTS).  In contrast, perineural injection with corticosteroid has been used for decades for treating CTS, but possible neurotoxicity has been a major concern.  No studies investigating the comparative effects have been published so far.  These researchers performed a prospective, randomized, double-blinded, head-to-head comparative trial to compare these 2 approaches for patients having mild-to-moderate CTS.  A total of 54 participants with mild-to-moderate CTS were randomly divided into dextrose and steroid groups.  The patients were administered 1 session of perineural injection with 5-ml D5W (dextrose group) or 3-ml triamcinolone acetonide mixed with 2-ml normal saline (steroid group), under US-guidance.  A visual analog scale (VAS) was assigned to assess the primary outcome; the secondary outcomes were assessed using the Boston Carpal Tunnel Syndrome Questionnaire, cross-sectional area of the median nerve, and electrophysiological studies.  The assessment was performed prior to injection and 1, 3, 4, and 6 months post-injection.  All patients (27 wrists per group) completed the study.  Compared with the steroid group, the dextrose group exhibited a significant reduction in pain and disability through the 4th to the 6th month (p < 0.01).  The authors concluded that the findings of this study demonstrated that perineural injection of D5W was more beneficial than that of corticosteroid in patients with mild-to-moderate CTS at 4 to 6 months post-injection.  This was a small study (total of 54 in 2 study groups) with short-term (6 months) follow-up; these findings need to be validated by well-designed studies.

Maniquis-Smigel et al (2018) noted that chronic low-back pain (CLBP) participants in a prior controlled study reported short-term pain relief after caudal epidural injection of D5W.  In a prospective, uncontrolled study,  these researchers examined if repeated caudal epidural injections of D5W resulted in serial short-term diminution of CLBP and progressive long-term decrease in pain and disability.; Participants were adults with CLBP with radiation to gluteal or leg areas.  They received caudal epidural injection of 10 ml of D5W (without anesthetic) every 2 weeks for 4 treatments and then as needed for 1 year.  Outcome measures included NRS score (0 to 10 points), Oswestry Disability Index (ODI, disability, %), and fraction of participants with greater than or equal to 50 % reduction in NRS score.  Analysis by intention-to-treat (ITT).  Participants (n = 32, 55 ± 9.8 years old, 9 women) had moderate-to-severe CLBP (6.5 ± 1.2 NRS points) for 11.1 ± 10.8 years.  They received 5.5 ± 2.9 caudal D5W injections through 12 months of follow-up.  The data capture rate for analysis was 94 % at 12 months for NRS and ODI outcome measures, with 6 % carried forward by ITT.  A consistent pattern of analgesia was demonstrated after D5W injection.  Compared with baseline status, NRS and ODI scores improved by 3.4 ± 2.3 (52 %) and 18.2 ± 16.4% (42 %) points, respectively.  The fraction of participants with 50 % reduction in NRS-based pain was 21/32 (66 %).  The authors concluded that epidural D5W injection, in the absence of anesthetic, resulted in consistent post-injection analgesia and clinically significant improvement in pain and disability through 12 months for most participants.  The consistent pattern post-injection analgesia suggested a potential sensorineural effect of dextrose on neurogenic pain.

The authors stated that the drawbacks of this study included a small sample size (n = 32) and lack of a control group.  In addition, control participants received epidural saline as part of the preceding RCT and then received epidural D5W without a wash-out period, potentially affecting the results, although the effect of epidural saline was minimal.  This study was not powered to detect rare events, but caudal epidural D5W injection appeared to be safe; no unexpected side effects or adverse effects were reported.  This was consistent with a lack of evidence of toxicity of dextrose in multiple previous studies, in which dextrose 5 to 10 % was included in anesthetic solutions injected in the subdural space to facilitate distribution of the injectate.  These investigators stated that further studies are needed to better evaluate the clinical indications and effects of epidural D5W compared both to control and active therapy.  While the safety of D5W is advantageous, future work should also consider other concentrations of dextrose, and be powered to detect rare procedure-related adverse events.

Sclerotherapy for Inter-Metatarsal Neuromas

Santos and colleagues (2018) noted that an inter-metatarsal neuroma is a plantar digital neuritis causing metatarsalgia of the affected inter-metatarsal space.  Currently, the evidence to support the management of the condition is poor with only some quality evidence supporting the short-term management of inter-metatarsal neuromas using steroid injections.  Some investigators have supported the use of alcohol sclerosing intra-lesional injections to treat inter-metatarsal neuromas.  Following a search of the evidence, a total of 11 articles were identified.  The systematic review found that alcohol injections appeared to be safe although some studies reported a short-term side effect of a flogistic reaction and there were variances in the alcohol concentration used and guiding verses not-guiding the injection using US imaging.  Some of the evidence may suggest a sclerosing histological effect of the nerve.  However, all the studies reviewed present a research design offering a low-level of evidence that is open to methodological biases and interpretation.  Thus, this review found insufficient high-quality research evidence to afford conclusions on the management of inter-metatarsal neuromas with alcohol sclerosing agent injections.

Sclerotherapy for Rectal Prolapse

In a systematic review and meta-analysis, Hintz and colleagues (2019) evaluated the effectiveness and complications of various sclerosing agents in treating pediatric rectal prolapse.  After protocol registration (CRD-42018088980), multiple databases were searched.  Studies describing injection sclerotherapy for treatment of pediatric rectal prolapse were included, with screening and data abstraction duplicated.  The methodological quality of included papers was assessed using the Methodological Index for Non-Randomized Studies (MINORS) score.  A total of 19 studies were identified, published between 1970 and 2017.  Most studies were single-institution case-series, with median "N" 57 +/- 88.9 and mean MINORS score of 0.51 +/- 0.17 (perfect score = 1).  A total of 1,510 patients with a mean age of 4.5 years were accounted for: 36.2 % female, most without co-morbidities.  Mean follow-up duration was 30 months. The most common sclerosing agent described was ethanol (45 %), followed by phenol (33 %).  The mean number of treatments per patient was 1.1 +/ -0.34.  The overall success rate after a single sclerotherapy treatment was 76.9 % +/- 8.8 %.  The overall complication rate was 14.4 % +/- 2 %.  The authors concluded that injection sclerotherapy appeared effective and low-risk in the treatment of pediatric rectal prolapse and should be considered before more invasive surgical options.  Moreover, these researchers stated that the available evidence is of relatively poor quality, and prospective comparative investigations are needed.  Level of evidence = III.

Sclerotherapy for the Prophylaxis of Esophageal Variceal Bleeding

Gana and colleagues (2020) noted that portal hypertension commonly accompanies advanced liver disease and often gives rise to life-threatening complications, including hemorrhage from esophageal and gastro-intestinal (GI) varices.  Variceal hemorrhage commonly occurs in children with chronic liver disease or portal vein obstruction; thus, prevention is important.  In adults, numerous randomized clinical trials have demonstrated benefits of non-selective beta-blockers and endoscopic variceal ligation as primary prevention in decreasing the risk of variceal hemorrhage.  In children, band ligation, beta-blockers, and sclerotherapy have been proposed as alternatives for primary prophylaxis of esophageal variceal bleeding; however, primary prophylaxis is not the current standard of care in children because it is unclear if those treatments are of benefit or cause harm when used for primary prophylaxis of esophageal variceal bleeding in children and adolescents.  In a Cochrane review, these investigators examined the benefits and harms of band ligation versus sclerotherapy for primary prophylaxis of esophageal variceal bleeding in children and adolescents with chronic liver disease or portal vein thrombosis.  They searched the Cochrane Hepato-Biliary Group Controlled Trials Register, CENTRAL, PubMed, Embase, LILACS, and Science Citation Index Expanded (April 27, 2020).  These researchers scrutinized the reference lists of retrieved publications; and carried out a manual search from the main pediatric gastroenterology and hepatology conferences (NASPGHAN and ESPGHAN) abstract books from 2008 to 2019.  They searched ClinicalTrials.gov, FDA, EMA, and WHO for ongoing clinical trials.  There were no language or document type restrictions.  These investigators planned to include randomized clinical trials irrespective of blinding, language, or publication status for assessment of benefits and harms.  If the search for randomized clinical trials retrieved quasi-randomized and observational studies, then they read them through to extract information on harms.  These investigators planned to summarize data from randomized clinical trials by standard Cochrane methodologies.  They planned to evaluate risk of bias and use GRADE to examine the certainty of evidence per outcome.  The primary outcomes were all-cause mortality, serious AEs and liver-related morbidity, and quality of life (QOL).  The secondary outcomes were esophageal variceal bleeding and AEs not considered serious.  These investigators planned to analyze data with ITT; and planned to use Review Manager 5 to analyze the data.  They found no randomized clinical trials examining band ligation versus sclerotherapy for primary prophylaxis of esophageal variceal bleeding in children with chronic liver disease or portal vein thrombosis.  The authors concluded that randomized clinical trials evaluating the benefits or harms of band ligation versus sclerotherapy for primary prophylaxis of esophageal variceal bleeding in children with chronic liver disease or portal vein thrombosis are lacking; thus, trials with adequate power and proper design, examining the benefits and harms of band ligation versus sclerotherapy on patient-relevant clinical outcomes such as mortality, QOL, failure to control variceal bleeding, and AEs are needed.  These researchers stated that unless such trials are performed and the results become published, they could not make any conclusions regarding the benefits or harms of these 2 interventions.

In a Cochrane review, Gattini and associates (2020) examined the benefits and harms of sclerotherapy compared with sham or no intervention for primary prophylaxis of esophageal variceal bleeding in children with chronic liver disease or portal vein thrombosis.  These investigators searched the Cochrane Hepato-Biliary Group Controlled Trials Register, CENTRAL, PubMed, Embase Elsevier, and 2 other registers in February 2019.  They scrutinized the reference lists of the retrieved publications; and carried out a manual search of the main pediatric gastroenterology and hepatology conference (NASPGHAN and ESPGHAN) abstracts from January 2008 to December 2018.  They searched 4 registries for ongoing clinical trials; there were no language or document type restrictions.  These researchers included randomized clinical trials irrespective of blinding, language, or publication status examining sclerotherapy versus sham or no intervention for primary prophylaxis of esophageal variceal bleeding in children with chronic liver disease or portal vein thrombosis.  They used standard Cochrane methodology to carry out this systematic review; and used the ITT principle to analyze outcome data, and GRADE to evaluate the certainty of evidence per outcome.  These researchers found only 1 randomized clinical trial that fulfilled the inclusion criteria.  The trial was at high risk of bias.  The trial included 108 Brazilian children with median age of 4.3 years (range of 11 months to 13 years); 56 children were randomized to prophylactic sclerotherapy (ethanolamine oleate 2 %) and 52 children to no intervention (control).  Children were followed-up for a median of 4.5 years; 8 children (6 from the sclerotherapy group versus 2 from the control group) dropped out before the end of the trial.  The follow-up was from 18 months to 8 years.  Mortality was 16 % (9/56 children) in the sclerotherapy group versus 15 % (8/52 children) in the control group (risk ration (RR) 1.04, 95 % CI: 0.44 to 2.50; very low-certainty evidence).  Upper GI bleeding occurred in 21 % (12/56) of the children in the sclerotherapy group versus 46 % (24/52) in the control group (RR 0.46, 95 % CI: 0.26 to 0.83; very low-certainty evidence).  There were more children with congestive hypertensive gastropathy in the sclerotherapy group than in the control group (14 % (8/56) versus 6 % (3/52); RR 2.48, 95 % CI: 0.69 to 8.84; very low-certainty evidence).  The incidence of gastric varices was similar between the sclerotherapy group and the control group (11 % (6/56) versus 10 % (5/52); RR 1.11, 95 % CI: 0.36 to 3.43; very low-certainty evidence).  The incidence of bleeding from gastric varices was higher in the sclerotherapy group than in the control group (4 % (3/56) versus 0 % (0/52); RR 6.51, 95 % CI: 0.34 to 123.06; very low-certainty evidence).  The study did not examine health-related QOL.  Esophageal variceal bleeding occurred in 5% (3/56) of the children in the sclerotherapy group versus 40% (21/52) of the children in the control group (RR 0.13, 95% CI 0.04 to 0.42; very low-certainty evidence). The most prevalent complications (defined as non-serious) were pain and fever after the procedure, which promptly resolved with analgesics.  However, numerical data on the frequency of these AEs and their occurrences in the 2 groups were lacking.

The authors concluded that the evidence, obtained from one randomized clinical trial at high risk of bias, is very uncertain on whether sclerotherapy has an influence on mortality and if it may decrease first upper gastrointestinal or esophageal variceal bleeding in children. The evidence is very uncertain on whether sclerotherapy has an influence on congestive hypertensive gastropathy, incidence on gastric varices, and incidence of bleeding from gastric varices. Health-related quality of life was not measured. There were no serious events caused by sclerotherapy, and analysis of non-serious adverse events could not be performed due to lack of numerical data. The GRADE assessment of each outcome showed a very low-certainty evidence. The results of the trial need to be interpreted with caution. Larger randomized clinical trials, following the SPIRIT and CONSORT statements, assessing the benefits and harms of sclerotherapy compared with sham or no intervention for primary prophylaxis of esophageal variceal bleeding in children with chronic liver disease or portal vein thrombosis are needed. The trials should include important clinical outcomes such as death, failure to control bleeding, and adverse events.

Sclerotherapy for the Treatment of Chronic Patellar Tendinopathies

Morath and colleagues (2020) noted that chronic patellar tendinopathy (CPT) is a frequent overuse disorder in athletes and active people.  Sclerotherapy (ST) and prolotherapy (PT) are, among a wide range of conservative therapeutic options, 2 promising therapies and have shown positive results in other tendinopathies.  Since the treatments' safety and efficacy are still undefined, this review sought to answer questions on recommendations for use in clinical utility, safety, and how to perform the injection in the most effective way.  An electronic database search was carried out following the PRISMA guidelines.  Inclusion criteria were set up according to the PICOS-scheme.  Included were athletes and non-athletes of all ages with diagnosed painful CPT.  Studies including patients suffering from patellar tendinopathy that can be originated to any systemic condition affecting the musculoskeletal system (e.g., disorders associated with rheumatism) and animal studies were excluded.  Methodological quality (modified Coleman Methodology Score) and risk of bias (Cochrane Risk of Bias Assessment Tool 2.0) were assessed by 2 independent reviewers, with disagreements resolved with a 3rd reviewer.  The search yielded a total of 416 entries.  After screening titles, abstracts, and full texts, a total of 10 articles were found for qualitative analysis . The mean Coleman Score was 64.57; 3 RCTs showed positive results with an increase in Victorian Institute of Sport Assessment -Patellar (VISA-P) score or a decrease in VAS or Nirschl Pain Phase Scale (NPPS), respectively.  The non-randomized studies confirmed the positive results as well.  Among all 10 studies no serious AEs were reported.  The authors concluded that based on this limited set of studies, there appeared to be some evidence that ST and PT may be effective therapeutic options to treat pain and to improve function in patients with CPT.  Moreover, these researchers stated that to strengthen this recommendation, more research is needed with larger volume studies and RCTs in a double-blinded design; and including direct head-to-head comparisons with long-term follow-up.  Level of Evidence = IV.

Sclerotherapy for the Treatment of Hepatic Cysts

Furumaya and colleagues (2020) noted that simple hepatic cysts (SHC) may cause pain and bloating and thus impair QOL.  Whereas current guidelines recommend laparoscopic cyst de-roofing, percutaneous aspiration and sclerotherapy (PAS) may be used as a less invasive alternative.  In a systematic review, these researchers examined the efficacy of PAS and surgical management in patients with symptomatic SHC.  They carried out a systematic search in PubMed and Embase according to PRISMA-guidelines.  Studies reporting symptoms were included.  Methodological quality was assessed by the MINORS-tool.  Primary outcomes were symptom relief, symptomatic recurrence and QOL, for which a meta-analysis of proportions was carried out.  A total of 736 patients from 34 studies were included of whom 265 (36 %) underwent PAS, 348 (47 %) laparoscopic cyst de-roofing, and 123 (17 %) open surgical management.  During follow-up of 26.1, 38.2 and 21.3 months, symptoms persisted in 3.5 %, 2.1 %, 4.2 %, for PAS, laparoscopic and open surgical management, respectively.  Major complication rates were 0.8 %, 1.7 %, and 2.4 % and cyst recurrence rates were 0.0 %, 5.6 %, and 7.7 %, respectively.  The authors concluded that outcomes of PAS for symptomatic SHC appeared to be excellent.  Moreover, these researchers stated that studies including a step-up approach that reserves laparoscopic cyst de-roofing for symptomatic recurrence after 1 or 2 PAS procedures are needed.

The authors stated that this review had several drawbacks.  First, selection bias may be present; centers may apply different protocols regarding patient and treatment selection. For example, in most centers open surgery is considered obsolete, reflected by the low number of patients in this treatment group.  Potential selection bias was reflected in the current data by a smaller mean cyst size before PAS (9.3 cm) than those treated through laparoscopic and open surgery (12.7 and 11.9 cm), and the higher rate of patients who underwent any treatment prior to surgical treatment (47/476, 9.9 %), compared to prior to PAS (1/294, 0.3 %).  Moreover, patients undergoing laparoscopic surgical treatment were older (62 years) than patients undergoing open surgery or PAS (58 years).  These factors could have negatively influenced treatment outcomes, in particular recurrence and cyst size were correlated in this study.  Second, validated QOL questionnaires were rarely used.  Comparison of the extent of symptom relief between studies may therefore be influenced by a varying interpretation of subjective signs.  Using a validated QOL questionnaire in all studies would make results more reliable and more comparable.  Third, recurrence necessitating further surgical treatment was only reported once after PAS in the dedicated studies.  In the surgical series though, there were 11 patients who had undergone previous PAS, which may suggest recurrence after PAS was under-reported.  The mean follow-up of the studies included in this review was approximately 2 years.  Whether this was a suitable amount of time to monitor recurrence is unknown, as prospective studies on time to recurrence are lacking.  The same mechanism may also apply to surgical management, although the follow-up period after laparoscopic treatment was longer, 38 months.  Fourth, results of the current review may not be extrapolated to patients with polycystic liver disease, as these patients were excluded.  Some evidence suggested that these patients are less likely to experience symptom relief.  As a consequence, a number of studies using mixed cohorts of polycystic liver disease and SHC patients were also excluded.

Table: CPT Codes / HCPCS Codes / ICD-10 Codes

Code	Code Description
Information in the [brackets] below has been added for clarification purposes.   Codes requiring a 7th character are represented by "+":
Prolotherapy:
Other CPT codes related to the CPB:
20550	Injection(s); single tendon sheath, or ligament, aponeurosis (e.g., plantar "fascia")
20600 - 20611	Arthrocentesis, aspiration and/or injection
HCPCS codes not covered for indications listed in the CPB:
M0076	Prolotherapy [joint sclerotherapy and reconstructive ligament therapy]
ICD-10 codes not covered for indications listed in the CPB (not all-inclusive):
M17.0 - M17.9	Osteoarthritis of knee
M18.0 - M18.9	Osteoarthritis of first carpometacarpal joint
M19.011 – M19.019	Primary osteoarthritis, shoulder [glenohumeral osteoarthritis]
M19.041 - M19.049	Primary osteoarthritis, hand
M19.141 - M19.149	Post-traumatic osteoarthritis, hand
M19.241 - M19.249	Secondary osteoarthritis, hand
M24.00 - M24.176 M24.30 - M24.9	Other specific joint derangements
M25.374 - M25.376	Other instability, foot [metatarso-phalangeal joint instability]
M25.50 - M25.59	Pain in joint
M25.851 - M25.859	Other specified joint disorders, hip. [ischio-femoral impingement]
M25.51 - M25.519	Pain in shoulder
M26.601 - M26.69	Temporomandibular joint disorders
M53.2X8	Spinal instabilities, sacral and sacrococcygeal region [sacroiliac joint instability]
M53.3	Sacrococcygeal disorders, not elsewhere classified [coccygodynia] [pain]
M54.5	Low back pain
M67.90 - M67.99	Unspecified disorder of synovium and tendon
M72.0 – M72.9	Fibroblastic disorders [fasciopathies]
M75.100 - M75.122	Rotator cuff tear or rupture, not specified as traumatic
M75.50 – M75.52	Bursitis of shoulder [Rotator cuff bursitis]
M76.30 - M76.32	Iliotibial band syndrome
M76.60 - M76.62	Achilles tendinitis
M77.00 - M77.12	Epicondylitis of elbow
M79.10 - M79.18	Myalgia
M79.2	Neuralgia and neuritis, unspecified
M86.18, M86.68	Other acute or chronic osteomyelitis [osteomyelitis pubis]
M92.50 - M92.52	Juvenile osteochondrosis of tibia and fibula [Osgood-Schlatter disease]
S03.00x+ - S03.02x+	Dislocation of jaw
S03.40XA - S03.9XXS	Sprain of jaw/joints and ligaments of other/unspecified parts of head
S13.4XXA - S13.9XXS	Sprain of ligaments of cervical spine/thyroid region/joints and ligaments of other/unspecified parts of neck
S23.3XXA - S23.9XXS	Sprain of ligaments of thoracic spine/ribs and sternum/other specified/unspecified parts of thorax
S33.5xx+ - S33.9xx+	Sprain of lumbar/sacral spine/joint/ligament
S43.401A - S43.92XS	Sprain of shoulder joint/acromioclavicular joint/sternoclavicular joint/other specified/unspecified parts of shoulder girdle
S46.001+ - S46.099+	Injury of muscle(s) and tendon(s) of the rotator cuff of shoulder
S53.401A - S53.499S	Sprain of elbow
S63.501A - S63.699S	Other and unspecified sprain of wrist/finger(s)
S63.8X1A - S63.92XS	Sprain of other part/unspecified part of wrist and hand
S73.101A - S73.199S	Sprain of hip
S83.401A - S83.529S	Sprain of collateral ligament/cruciate ligament of knee
S83.60XA - S83.62XS	Sprain of the superior tibiofibular joint and ligament
S83.8X1A - S83.92XS	Sprain of other specified/unspecified site of knee
S93.401A - S93.699S	Sprain of ankle/toe/foot
Neural Prolotherapy – no specific code:
ICD-10 codes not covered for indications listed in the CPB (not all-inclusive):
M79.2	Neuralgia and neuritis, unspecified
Sclerotherapy:
CPT codes covered if selection criteria are met:
Sclerotherapy aneurysmal bone cysts, benign cystic thyroid nodules, and symptomatic orbital varices - no specific code:
36465	Injection of non-compounded foam sclerosant with ultrasound compression maneuvers to guide dispersion of the injectate, inclusive of all imaging guidance and monitoring; single incompetent extremity truncal vein (eg, great saphenous vein, accessory saphenous vein)
36466	Injection of non-compounded foam sclerosant with ultrasound compression maneuvers to guide dispersion of the injectate, inclusive of all imaging guidance and monitoring; multiple incompetent truncal veins (eg, great saphenous vein, accessory saphenous vein), same leg.
36468	Injection(s) of sclerosant for spider veins (telangiectasia), limb or trunk
36470	Injection of sclerosant; single incompetent vein (other than telangiectasia)
36471	Injection of sclerosant; multiple incompetent veins (other than telangiectasia), same leg
45520	Perirectal injection of sclerosing solution for prolapse [pediatric rectal prolapse]
ICD-10 codes covered if selection criteria are met:
E04.1 - E04.2	Nontoxic single thyroid nodule or nontoxic multinodular goiter
G57.60 - G57.63	Lesion of plantar nerve
I78.0	Hereditary hemorrhagic telangiectasia
K62.3	Rectal prolapse [pediatric rectal prolapse]
M85.50 - M85.59	Aneurysmal bone cyst
ICD-10 codes not covered for indications listed in the CPB:
I85.01	Esophageal varices with bleeding
I85.11	Secondary esophageal varices with bleeding
L76.33 - L76.34	Postprocedural hematoma and seroma of skin and subcutaneous tissue following a procedure
M76.50 – M76.52	Patellar tendinitis [Patellar tendinopathies]
M76.60 - M76.62	Achilles tendinitis
Q27.9	Congenital malformation of peripheral vascular system, unspecified [capillary malformations]
Q44.6	Cystic disease of liver
T79.2xxA – T79.2xxS	Traumatic secondary and recurrent hemorrhage and seroma

The above policy is based on the following references: