Prolotherapy and Sclerotherapy

Number: 0207

Table Of Contents

Policy
Applicable CPT / HCPCS / ICD-10 Codes
Background
References


Policy

Scope of Policy

This Clinical Policy Bulletin addresses prolotherapy and sclerotherapy.

  1. Medical Necessity

    Aetna considers sclerotherapy medically necessary for the following indications:

    1. Active esophageal variceal hemorrhage in persons who failed to adequately respond to or cannot undergo endovenous ligation (EVL)
    2. Aneurysmal bone cyst
    3. Benign cystic thyroid nodules
    4. Epistaxis due to hereditary hemorrhagic telangiectasia
    5. Morton's neuroma (intermetatarsal neuroma) when conservative treatments including orthotic use, and corticosteroid injections have failed
    6. Pediatric rectal prolapse
    7. Symptomatic hemorrhoids when conservative treatments have failed (e.g., anti-spasmodic agents such as 0.5 % nitroglycerin, topical analgesics, such as mixed lidocaine-hydrocortisone, and topical steroids, such as hydrocortisone cream or suppository)
    8. Symptomatic lymphatic malformations
    9. Symptomatic orbital varices
    10. Symptomatic (pain, hematuria, and/or hypertension) renal cysts that are 3 to 20 cm in size
    11. Symptomatic testicular hydrocele
    12. Symptomatic venous malformations
    13. Venous ulcerations.

    Aetna considers ultrasound-guided percutaneous cyst aspiration with sclerotherapy medically necessary for the treatment of symptomatic (e.g., abdominal pain that is attributed to the cyst), large (4 cm or larger), simple hepatic cysts. Note: Communication of the cyst with the biliary tree is an absolute contraindication to injection sclerotherapy.

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

  2. Experimental, Investigational, or Unproven

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

    1. Electro-sclerotherapy for capillary malformations;
    2. Neural prolotherapy (low dose dextrose) for neurogenic inflammatory pain and all other indications;
    3. Prolotherapy (also known as proliferant therapy, proliferation therapy, joint sclerotherapy, or reconstructive ligament therapy) for all indications, including the following (not an all-inclusive list):

      1. Achilles tendinosis
      2. Back pain
      3. Bladder pain syndrome / interstitial cystitis
      4. Buttock pain
      5. Chronic ankle instability
      6. Chronic ankle ligament injury
      7. Chronic supraspinatus tendinopathy
      8. Chronic tendinopathy of the foot
      9. Coccynodynia
      10. Core muscle injuries
      11. Epicondylitis (lateral epicondylopathy)
      12. Fasciopathies (including plantar fasciopathy)
      13. Hand osteoarthritis
      14. Iliotibial band syndrome
      15. Ischio-femoral impingement
      16. Knee ligament instability
      17. Knee osteoarthritis
      18. Ligament injuries
      19. Low back pain
      20. Metatarso-phalangeal joint instability
      21. Musculoskeletal pain
      22. Myofascial pain
      23. Neck pain
      24. Neuropathic pain
      25. Osgood-Schlatter disease
      26. Osteomyelitis pubis
      27. Plantar fasciitis
      28. Post-herpetic neuralgia
      29. Rotator cuff disease (including bursitis, glenohumeral osteoarthritis, and rotator cuff tendinopathy)
      30. Sacroiliac joint pain / instability
      31. Shoulder pain
      32. Temporomandibular joint syndrome / Temporomandibular joint hypermobility / Temporomandibular joint luxation
      33. Tendinopathies;
    4. Prolozone therapy for any diagnosis;
    5. Sarapin, an herbal extract that has been used as a sclerosant in prolotherapy, for all indications;
    6. Sclerotherapy for the following indications (not an all-inclusive list):

      1. Achilles tendinopathy
      2. Hepatic cysts
      3. Ovarian endometrioma
      4. Patellar tendinopathies
      5. Prophylaxis of esophageal variceal bleeding
      6. Seromas
      7. Use in high varix ligation.
  3. Related Policies


Table:

CPT Codes / HCPCS Codes / ICD-10 Codes

Code Code Description

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):

B02.22 Postherpetic trigeminal neuralgia
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
M25.371 - M25.373 Other instability, ankle [Chronic]
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]
M54.2 Cervicalgia
M54.50 - M54.59 Low back pain
M67.811 - M67.819 Other specified disorders of synovium and tendon, shoulder [Chronic supraspinatus tendinopathy]
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 [Chronic supraspinatus tendinopathy]
M75.50 – M75.52 Bursitis of shoulder [Rotator cuff bursitis]
M76.00 – M76.02 Gluteal tendinitis [Buttock pain]
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]
N30.10 - N30.11 Interstitial cystitis (chronic)
R39.82 Chronic bladder pain
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
S39.011A - S39.013S Strain of muscle, fascia and tendon of abdomen, lower back and pelvis [Core muscle injuries]
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, Ultrasound-guided percutaneous cyst aspiration with sclerotherapy- 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
43204 Esophagoscopy, flexible, transoral; with injection sclerosis of esophageal varices [not covered for prophylaxis of esophageal variceal bleeding]
43243 Esophagogastroduodenoscopy, flexible, transoral; with injection sclerosis of esophageal/gastric varices [not covered for prophylaxis of esophageal variceal bleeding]
45520 Perirectal injection of sclerosing solution for prolapse [pediatric rectal prolapse]
49185 Sclerotherapy of a fluid collection (eg, lymphocele, cyst, or seroma), percutaneous, including contrast injection(s), sclerosant injection(s), diagnostic study, imaging guidance (eg, ultrasound, fluoroscopy) and radiological supervision and interpretation when performed

CPT codes not covered for indications listed in the CPB:

Ultrasound-guided sclerotherapy for ovarian endometrioma – no specific code

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
I85.01 Esophageal varices with bleeding
I85.11 Secondary esophageal varices with bleeding
I87.311 – I87.319 Chronic venous hypertension (idiopathic) with ulcer
I87.331 – I87.339 Chronic venous hypertension (idiopathic) with ulcer and inflammation
I87.8 Other specified disorders of veins [venous ulceration]
K62.3 Rectal prolapse [pediatric rectal prolapse]
K64.0 - K64.9 Hemorrhoids and perianal venous thrombosis [Symptomatic hemorrhoids]
K76.89 Other specified diseases of liver [Symptomatic, large, simple hepatic cyst]
M85.50 - M85.59 Aneurysmal bone cyst
N28.1 Cyst of kidney, acquired
N43.0 - N43.3 Hydrocele and spermatocele [Symptomatic]
Q27.9 Congenital malformation of peripheral vascular system, unspecified [venous] [not covered for capillary malformations]
Q61.9 Cystic kidney disease, unspecified
Q89.9 Congenital malformation, unspecified [Symptomatic lymphatic malformation]

ICD-10 codes not covered for indications listed in the CPB:

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
N80.1 Endometriosis of ovary [ovarian endometrioma]
N83.291 – N83.299 Other ovarian cysts [ovarian endometrioma]
Q44.6 Cystic disease of liver
T79.2xxA – T79.2xxS Traumatic secondary and recurrent hemorrhage and seroma

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. Evaluations 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.

In a systematic review and meta-analysis, Fong et al (2023) examined the effectiveness of hypertonic DPT in plantar fasciopathy (PF) compared with other non-surgical treatments.  These investigators searched PubMed/Medline, Embase, Cochrane Central Register of Controlled Trials, Web of Science, Allied and Complementary Medicine Database, Global Health, Ovid Nursing Database, Dimensions, and WHO ICTRP from inception to April 30, 2022.  Two independent reviewers selected RCTs that examined the effectiveness of DPT in PF compared with non-surgical treatments.  Outcomes included pain intensity, foot and ankle function, as well as plantar fascia thickness.  They carried out data extraction.  Risk of bias (RoB) assessment was conducted using the Cochrane Risk of Bias 2 (RoB 2) tool, and certainty of evidence was assessed with Grading of Recommendation Assessment, Development, and Evaluation (GRADE) approach.  A total of 8 RCTs (n = 469) met the inclusion criteria.  Pooled results favored the use of DPT versus normal saline (NS) injections in reducing pain (weighted MD [WMD] -41.72; 95 % CI: -62.36 to -21.08; p < 0.01; low certainty evidence) and improving function [WMD -39.04; 95 % CI: -55.24 to -22.85; p < 0.01; low certainty evidence] in the medium-term.  Pooled results also showed corticosteroid (CS) injections was superior to DPT in reducing pain in the short-term [SMD 0.77; 95 % CI: 0.40 to 1.14; p < 0.01; moderate certainty evidence].  Overall RoB varied from "some concerns" to "high".  The overall certainty of evidence presented ranged from very low to moderate based on the assessment with the GRADE approach.  The authors concluded that low certainty evidence showed that DPT was superior to NS injections in reducing pain and improving function in the medium-term; however, moderate certainty evidence showed that it was inferior to CS in reducing pain in the short-term.  These researchers stated that further high-quality RCTs with standard protocol, longer-term follow-up, and adequate sample size are needed to confirm its role in clinical practice.

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.

Waluyo et al (2023) noted that current treatments for OA do not resolve the underlying cause; DPT is an alternative method that has been proposed for treatment of OA, due to its ability to aid tissue regeneration, improve clinical manifestations, and repair damaged tissue structures, which are pathological conditions in OA.  In a systematic review, these investigators examined the effectiveness of DPT compared with other interventions in the management of OA.  They searched electronic databases PubMed, Google Scholar, Cochrane, and BioMed Central from inception to October 2021.  Search terms included [(prolotherapy) OR (prolotherapies) OR (dextrose prolotherapy)] AND [(osteoarthritis) OR (osteoarthritides) OR (knee osteoarthritis) OR (hip osteoarthritis) OR (hand osteoarthritis) OR (shoulder osteoarthritis)].  RCTs that compared the use of DPT with other interventions (injection, placebo, therapy, or conservative treatment) in the treatment of OA were included.  Potential articles were screened for eligibility, and data were extracted by all authors.  Risk of bias was assessed using the Cochrane Risk of Bias tool.  Study population, methods, and results data were extracted and tabulated by 3 authors.  A total of 12 studies reported that DPT was as effective or even more effective in improving functional outcomes compared with other interventions while others found that hyaluronic acid (HA), PRP, erythropoietin (EP), and autologous conditioned serum (ACS) were more effective.  A total of 14 studies examined the effectiveness of DPT and 10of them reported that DPT was more effective in reducing pain compared with other interventions.  The authors concluded that DPT in OA conferred potential benefits for pain and functional outcomes; however, this systematic review found that the studies to-date are at high-risk of bias.  Moreover, these researchers stated that further high-quality RCTs are needed to establish the benefits of this intervention.  To improve study quality, future studies should include blinding of participants, outcome assessors, and better documentation of missing data and drop-outs.  These investigators stated that the drawbacks of this study were related to the limited number of RCTs regarding the effects of DPT on OA other than knee OA.  Furthermore, several data were unavailable from some included studies.

Vomer et al (2023) stated that knee OA is a common chronic condition leading to pain and debility.  These investigators carried out a case-series study to examine the effect of prolotherapy on functional measures and QOL in patients with knee OA.  This trial included 15 patients (men and women aged 50- to 5 years of age) with a prior diagnosis of knee OA and moderate pain.  Subjects completed baseline WOMAC and EuroQol-5 Dimension (EQ5D) surveys and received an US-guided intra-articular prolotherapy injection.  They were then followed-up by Telehealth at 1-, 2-, and 3-month post-procedure.  Data points for 15 patients were recorded over the duration of the 3 months.  Results showed significantly improved functional scores from the baseline period (M = 0.60) to the 1-month (M = 0.43), 2-month (M = 0.48), and 3-month (M = 0.46), observed power = 0.99.  Participants reported significantly lower pain scores between the baseline period (M = 0.60) compared to the 1-month (M = 0.34), 2-month (M = 0.35) and 3-month (M = 0.39) periods.  There was no statistical significance across time in participants' EQ5D scores.  The repeated-measures analysis of variance (ANOVA) revealed no statistically significant differences in participants scores between the baseline (M = 64.4), 1-month (M = 68.93), 2-month (M = 68.47), or 3-month (M = 68.33), observed power = 0.31.  There were no statistically significant differences in participants WOMAC stiffness scores between the baseline (M = 0.67), 1-month (M = 0.46), 2-month (M = 0.57), or 3-month (M = 0.56) periods, observed power = 0.73.  The results revealed no significant change in participants' EQ5D and WOMAC stiffness scores.  The results supported a statistically significant improvement in patients' self-reported functioning and pain scores between the baseline and 1-month, 2-month, and 3-month periods.  The authors concluded that the significant improvement in function occurred between the baseline and 1-month time-periods and the pain reduction was sustained throughout the 2-month and 3-month periods.  These investigators stated that the findings of this study supported prolotherapy as an effective therapeutic option to improve pain and function in knee OA. Moreover, these researchers stated that this study could be repeated with a large sample size to further examine the effects of prolotherapy on QOL measures, and establish it as a safe and effective treatment for knee OA in the future.

The authors stated that this study had several drawbacks.  First, since this was a case-series study, there was no control group; thus, these investigators were unable to determine if these results were due to prolotherapy alone.  Second, this trial entailed a small sample size of 15 patients.  Third, knee OA is a chronic condition, and it is unclear what the effects of prolotherapy are in this cohort beyond the 3-month follow-up.

In a double-blind RCT, Martinez-Barro et al (2023) examined the effectiveness of prolotherapy in OA grade II to III in the functionality and muscular work of knee flexors and extensors.  This study included patients diagnosed with OA grades II to III.  The experimental group was infiltrated in both knees with 6-ml of 25 % glucose solution and 0.05 % lidocaine; control group with 0.45 % saline solution and 0.05 % lidocaine.  All patients received a comprehensive rehabilitation program.  The isokinetic work of the knee flexor and extensor muscles, pain and functionality were measured before infiltration and at 3-month follow-up.  To compare the difference in means, the Student's t-test was applied, considering p < 0.05 as significant.  A total of 37 patients were recruited, 17 in the prolotherapy group.  There were no inter-group differences in functionality, isokinetic knee flexor/extensor work, and pain at baseline, or during follow-up up to 12 weeks.  The authors concluded that both prolotherapy and saline infiltration increased functionality, strength, and decreased pain; however, no statistically significant difference was observed between the 2 groups.

Temporomandibular Joint Hypermobility

Comert Kilic and Gungormus (2016) performed a randomized clinical trial involving adult patients with bilateral TMJ hypermobility referred for treatmentt.  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 Preferred Reporting Items for Systematic Reviews and Meta-Analyses (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 (2021) 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 (2021) 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 (2021) 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 ratio (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 (2021) 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.

Prolotherapy for the Treatment of Bladder Pain Syndrome / Interstitial Cystitis

Chen and colleagues (2021) stated that interstitial cystitis/bladder pain syndrome (IC/BPS) is a painful recurrent condition characterized by the discomfort of the bladder, and current therapeutic options have limited effectiveness.  These investigators examined the effects of dextrose prolotherapy in a rat model of IC/BPS and patients with IC/BPS.  They used cyclophosphamide to induce IC/BPS in rats, and intra-vesical instillation of 10 % dextrose solution was carried out.  After 1 week, these researchers performed a urodynamic test, bladder staining, and ECM-related gene expression analysis to examine the treatment's effectiveness.  They found that dextrose treatment could recover the instability of the bladder, reduce frequent urination, and improve the glycosaminoglycan layer regeneration and the bladder wall thickness along with a significant intense expression of CD44 receptors.  Furthermore, these researchers enrolled 29 IC/BPS patients with previous hyaluronic acid [HA]/Botox treatment for more than 6 months with remained unchanged condition.  Subjects received intra-vesical injections of 10 % dextrose solution followed by assessments for up to 12 weeks.  Patient characteristics and a 3-day voiding diary before treatment were recorded.  Patient responses were examined using IC/BPS-related questionnaires.  Moreover, expressions of growth factors and cytokines were analyzed.  The results demonstrated that dextrose prolotherapy in patients with IC/BPS reduced the frequency of treatment over time, with the mean number of treatments being 3.03 ± 1.52, and significantly reduced the incidence of nocturia and questionnaire scores associated with symptoms.  Dextrose prolotherapy significantly enhanced EGF level and, in contrast, reduced the level of HGF, PIGF-1, and VEGF-D after several weeks following treatment.  The cytokine analysis showed that the expressions of IL-12p70 and IL-10 were significantly up-regulated after dextrose prolotherapy in IC/BPS patients.  The levels of most growth factors and cytokines in IC/BPS patients had no significant difference and showed a similar tendency as time progressed when compared to healthy controls.  Overall, the alteration of growth factors and cytokines exhibited safe treatment and potential stimulation of tissue remodeling.  The authors concluded that the findings of this study demonstrated that dextrose prolotherapy is a promising treatment strategy for IC/BPS disease management.  These researchers stated that further well-designed randomized trials are needed to confirm the effectiveness of dextrose prolotherapy for IC/BPS.

The authors stated that this study had several drawbacks.  These researchers enrolled a small number of patients (n = 29), which may have limited the collection of questionnaires, because subjects left the trial early due to restored bladder function or relief of pain and refusing back to the hospital following the rapid rising COVID-19 cases in Taiwan.  Another drawback was that this cohort study was designed to compare the difference in bladder function of IC/BPS patients before and after the dextrose treatment; there was no parallel placebo group.  Furthermore, these researchers did not collect biopsy from the bladder of IC/BPS patients to avoid further urothelium damage; thus, they have limited information on pathological regulation.

Sclerotherapy for the Treatment of Acute Esophageal Variceal Bleeding in Cirrhosis

In a meta-analysis, Su and colleagues (2021) examined the safety and effectiveness of endoscopic variceal ligation + endoscopic injection sclerotherapy (EVL+EIS) to control acute variceal bleeding (AVB).  Online databases, including Web of Science, PubMed, the Cochrane Library, Chinese National Knowledge Infrastructure (CNKI), China Biology Medicine (CBM) disc, VIP, and Wanfang, were searched to identify the studies comparing the differences between EVB+EIS and EVB, EIS from the inception of the databases up to December 30, 2020; STATA 13.0 was used for the meta-analysis.  A total of 8 studies involving 595 patients (317 patients in the EVL group and 278 patients in the EVL+EIS group) were included.  The results of the meta-analysis did not reveal any statistically significant differences in the effectiveness of acute bleeding control (p = 0.981), overall re-bleeding (p = 0.415), variceal eradication (p = 0.960), and overall mortality (p = 0.314); however, a significant difference was noted in the overall complications (p = 0.01).  the authors concluded that EVL was superior to the combination of EVL and EIS in safety, while no statistically significant differences were detected in effectiveness.  Moreover, these researchers stated that further RCTs should be designed with a large sample size, multiple centers to examine both clinical interventions.

The authors stated that this meta-analysis had several drawbacks.  First, the included studies were from different countries.  Second, the frequency of follow-up and the total duration of follow-up were also inconsistent.  Third, some disparities in medical technology and medical facilities were observed in the included literature.

An UpToDate review on "Methods to achieve hemostasis in patients with acute variceal hemorrhage" (Bajaj, et al., 2022) explains: "Bleeding esophageal varices are typically managed with endoscopic therapy (algorithm 1). Endoscopic variceal ligation is generally preferred due to its high efficacy and low complication rate. Endoscopic sclerotherapy is an alternative that is also highly effective, but it is associated with higher complication rates than endoscopic variceal ligation."  The review states that cyanoacrylate can be used for gastric varices in centers where it is available  

Sclerotherapy for the Treatment of Renal Cysts

Choi and associates (2020) stated that percutaneous aspiration with sclerotherapy (PAS) and laparoscopic marsupialization (LM) are minimally invasive treatments for renal cysts (RCs).  These researchers compared the efficacy and cost-effectiveness of LM and PAS for the treatment of symptomatic simple RCs (SRCs).  Data were prospectively collected from 3 healthcare institutions in which 80 patients with symptomatic SRCs underwent a single session of PAS with 95 % ethanol (PAS group, n = 40) or underwent LM under general anesthesia (LM group, n = 40) between March 2012 and May 2016.  These investigators compared the patient profile, duration of procedure, hospital length of stay (LOS), radiological and symptomatic success rates, treatment costs, and incidence of complications between the 2 groups.  At the 6-month follow-up, the radiological success rate in the LM group was significantly greater than that in the PAS group (97.5 % versus 60 %; p < 0.001).  The symptomatic success rate was comparable in the 2 groups (95 % versus 90 %; p = 0.675).  The treatment failure rate did not significantly differ between the 2 groups (5.0 % versus 17.5 %, p = 0.154).  The mean total cost in the PAS and LM groups was 1,256 USD and 2,343 USD, respectively (p = 0.001).  No significant between-group difference was noted regarding the overall complication rate (p = 0.615).  the authors concluded that both LM and PAS were safe and effective procedures for the treatment of symptomatic SRCs.  A single session of PAS appeared to be a cost-effective method for the management of symptomatic SRCs.

In a meta-analysis, Zhang and co-workers (2020) compared the effectiveness between aspiration-sclerotherapy (AS) and laparoscopic de-roofing (LD) in the management of RCs.  These researchers carried out a comprehensive literature search was by PubMed, Medline, Ovid and Web of Science for relevant studies published up to January 2020.  The statistical analyses were performed with Review Manager 5.3.0 and Stata 15.1.  The sensitivity analysis was also carried out to confirm the reliability of this meta-analysis.  The searches of literature generated 6 studies (1,547 patients incorporated) comparing AS with LD in the impacts of RCs therapy.  Of these, 6 studies contained 1,106 and 441 patients who were treated with AS and LD, respectively.  The outcome of this meta-analysis indicated that LD group was superior in symptomatic successful rate [OR: 0.28; 95 % CI: 0.09 to 0.86; p = 0.03), radiological successful rate (OR: 0.06; 95 % CI: 0.02 to 0.15; p < 0.01) and recurrence rate (OR: 6.08; 95 % CI: 2.81 to 13.15; p < 0.01).  Nevertheless, AS group had shorter treatment time [MD: -51.10; 95 % CI: -73.01 to - 29.20; p < 0.01].  No statistically significant difference was showed in the rate of complications (OR: 3.19; 95 % CI: 0.39 to 25.88; p = 0.28).  The authors concluded that LD had higher symptomatic successful rate, radiological successful rate as well as lower recurrence rate than AS, while the treatment time was longer.

Cardenas-Vargas and colleagues (2020) examined the effectiveness of sclerotherapy using NBCA (Histoacryl Blue; B. Braun, Melgungen, Germany), with or without hydro-dissection, for the treatment of SRCs.  Patients who presented to an interventional radiology clinic for the diagnosis of symptomatic RCs that had previously been identified at an outpatient clinic were included in this trial.  A total of 28 patients were randomly divided into 2 groups, based on whether or not they underwent hydro-dissection along with US-guided NBCA-based sclerotherapy.  Sonography was carried out at 0, 7, and 180 days post-procedure to record the residual volume of the RCs and to determine the effectiveness of the procedure.  A total of 32 cysts in 28 patients were treated with sclerotherapy -- 18 (64 %) women and 10 (36 %) men; the average age of the patients was 61.8 years (range of 33 to 89 years).  The size (diameter) of the RCs ranged from 3 to greater than 11 cm.  All patients reported an improvement in symptoms associated with the existing RCs at 7 and 180 days post-procedure, and at 7 days post-procedure a statistically significant reduction in cyst volume was observed (all patients: 96.8 %; group A: 96 %; group B: 97.6 %).  The reduced cyst volume was still observed 180 days post-procedure (all patients: 98.6 %; group A: 98.2 %; group B: 98.9 %).  There was no significant difference between the 2 treatment groups.  The authors concluded that there was a significant and persistent reduction in the volume of RCs, in addition to an improvement of the associated symptoms, after treatment with NBCA-based sclerotherapy, with or without hydro-dissection.

Maugeri et al (2021) noted that there are currently several strategies for the treatment of symptomatic SRCs, such as PAS and LD; however, no clear indication exists for choosing between them.  In a systematic review and meta-analysis, these researchers examined studies that compared symptomatic and radiological success between AS and LD.  Results were reported as RR and 95 % CI using LD as control group.  The symptomatic and radiological successes were evaluated by 6 and 3 studies, respectively.  Notably, AS was associated with higher risk of failure than LD (RR = 2.82; 95 % CI: 1.84 to 4.31 for symptomatic failure; RR = 8.31; 95 % CI: 4.22 to 16.38 for radiological failure).  On the other hand, however, AS was associated with less frequent complications, shorter treatment duration and post-treatment hospital length of stay (LOS), and lower costs.  The authors concluded that this study underlined benefits and drawbacks of each intervention.

Brown et al (2021) noted that SRCs are common benign lesions of the kidney with up to 4 % of patients developing symptoms necessitating intervention including pain and hematuria.  In a systematic review, these investigators examined the safety and effectiveness of AS of symptomatic SRCs.  They carried out a systematic review using Cochrane guidelines on published literature from 1990 to 2020; RCTs, cohort studies and case series meeting the inclusion criteria were reviewed and cumulative analysis of outcomes was performed.  A total of 4,071 patients from 57 studies underwent aspiration ± sclerotherapy for their SRCs; 87.7 % of patients who had aspiration with sclerotherapy demonstrated “treatment success” with a greater than 50 % reduction in cyst size and complete resolution of symptoms; 453 minor, transient complications occurred (11.2 %) while a major complication rate of less than 0.1 % (4 patients) was reported.  Pooled analysis of all available current literature demonstrated that AS is a safe and effective 1st-line therapy for symptomatic SRCs.  Although these researchers were unable to compare those undergoing aspiration alone to AS, it was evident that the use of a sclerosing agent was integral to treatment success.  Moreover, cyst size should be considered when discussing therapeutic options.  The authors concluded that it was reasonable for AS to be used in the 1st instance in all cases of symptomatic SRCs.

Zhou et al (2022) compared the safety and effectiveness of percutaneous polidocanol sclerotherapy and LD in the management of pediatric symptomatic SRCs.  A total of 46 patients with symptomatic SRCs (cyst size greater than or equal to 4 cm) were treated either with polidocanol sclerotherapy (group A) or by LD (group B) between December 2009 and October 2019.  Subjects were re-evaluated at 1, 6, and 12 months and annually thereafter.  A total of 21 patients were treated with polidocanol sclerotherapy (group A) and 25 patients with LD (group B).  The mean follow-up period was 58.7 months (14 to 107) in group A, and 57.2 months (12 to 118) in group B.  Complete regression was observed in 19 (90.5 %) and 24 (96 %) patients in groups A and B, respectively (p < 0.05).  Partial regression was observed in 1 patient each in group A (4.8 %) and B (4 %).  In 1 group A patient, a LD was carried out due to sclerotherapy failure after 27 months.  The operation time, post-operative hospital LOS, and cost were significantly less in group A than in group B (36.3 ± 8.4 versus 96.9 ± 19.1, 19.7 ± 2.4 versus 56.0 ± 8.6, and ¥8,173 ± 1,343 versus ¥14,119 ± 2,021, respectively; p < 0.05).  The authors concluded that polidocanol sclerotherapy and LD were found to be equally effective interventions associated with minimal complications for pediatric symptomatic SRCs.  These investigators recommended polidocanol sclerotherapy as the 1st-line option for children with symptomatic SRCs and LD in cases of failed polidocanol sclerotherapy.

Furthermore, an UpToDate review on “Simple and complex kidney cysts in adults” (Kruskal and Richie, 2021) states that “Cyst sizes in patients who require intervention generally range from 5 to 20 cm”.  This UTD review cited 2 studies on the use of alcohol sclerotherapy for the treatment of SRCs.

Ultrasound-Guided Sclerotherapy for the Treatment of Ovarian Endometrioma

Aflatoonian and Tabibnejad (2020) noted that endometrioma is a common high-recurrence gynecological disease that affects infertility.  Surgical resection using laparotomy or laparoscopy is used as a standard treatment.  Moreover, sclerotherapy is reported to be effective as a non-invasive method for treating endometrioma.  In a retrospective, cross-sectional study, these researchers examined if the ethanol retention or aspiration after sclerotherapy would improve pregnancy outcome in infertile women with endometrioma.  Hospital records of 43 women with recurrent or bilateral endometrioma who had undergone transvaginal US-guided sclerotherapy were reviewed.  They were selected to receive either ethanol for 10 mins, ethanol injection, irrigation, and then aspiration or total retention without aspiration based on the surgeon's decision.  Subjects were followed-up for 3, 6 and 12 months for natural or artificial conception as well as for cyst recurrence.  Chemical pregnancy was positive in 52 % of the women in the aspiration group and 53.8 % in the retention group.  Ongoing pregnancy (44 % versus 46.2 %, p = 0.584) and live birth (40 % versus 46.2 %, p = 0.490) were reported marginally higher in the retention group compared with the aspiration group, and the differences were not statistically significant.  Moreover, the recurrence rates were found to be 48.1 % and 37.5 % in the aspiration and retention groups, respectively (p = 0.542).  The cysts size in the retention group was significantly correlated to the recurrence rate.  The authors concluded that both the aspiration and left in-situ of ethanol 95 % sclerotherapy had the similar impact on the treatment of ovarian endometrioma regarding pregnancy and recurrence rate; moreover, larger randomized studies with strict inclusion criteria are needed to examine the effect of endometrioma sclerotherapy on bilateral cyst and improvement of advanced reproductive technology (ART) outcome.

In a systematic review and meta-analysis, Kim and colleagues (2022) examined the safety and effectiveness of US-guided sclerotherapy for the treatment of ovarian endometrioma.  Medline and Embase databases were searched for studies reporting outcomes in patients with endometrioma who were treated with US-guided sclerotherapy.  Meta-analyses of recurrence, pain resolution, pregnancy, technical success, and complication rates were analyzed.  Subgroup analyses were conducted regarding the indwelling time of sclerotherapy (less than or equal to 10 mins versus greater than 10 mins).  A total of 28 studies (1,301 patients) were included.  The pooled technical efficacy was 98.3 %.  The pooled estimates of recurrence, pain resolution, and pregnancy rate were 13.8 %, 85.9 %, and 37.6 %, respectively.  The pooled major complication rate was 1.7 %.  A sclerotherapy time of greater than 10 mins had a lower pooled recurrence rate than a time of less than or equal to 10 mins (11.2 % versus 20.9 %; p = 0.106).  Direct comparisons showed that the recurrence rate was significantly lower with sclerotherapy of greater than 10 mins than with sclerotherapy of less than or equal to 10 mins (odds ratio [OR], 0.2; p = 0.015).  Regarding pregnancy rates, sclerotherapy of greater than 10 mins showed no significant difference compared with sclerotherapy of less than or equal to 10 mins (35.9 % versus 38.8 %; p = 0.664).  Direct comparisons with surgery showed that sclerotherapy increased the pregnancy rate compared with surgery (OR, 2.0; p = 0.042).  There was no significant difference in anti-Mullerian hormone (AMH) level before and after sclerotherapy (p = 0.951).  There was no significant difference in major complication rates between sclerotherapy of greater than 10 mins and less than or equal to 10 mins (p = 0.837).  The authors concluded that US-guided sclerotherapy appeared to be a safe and effective therapeutic option regarding recurrence, pain resolution, and pregnancy for patients with ovarian endometrioma.  Moreover, these researchers stated that future RCTs are needed to compare the outcomes of US-guided sclerotherapy with surgery.

Prolotherapy for Buttock Pain

Sirh et al (2022) noted that LBP is a heterogeneous disease.  Myofascial pain and enthesopathy of the quadratus lumborum muscle are important causes of LBP and/or buttock pain.  However, a safe, and effective injection technique for the treatment of trigger points and enthesopathy in the quadratus lumborum muscle has not yet been developed.  In a retrospective, single-arm study, these investigators examined the importance of the quadratus lumborum muscle and introduced an effective landmark-based blind injection technique for the treatment of quadratus lumborum trigger points and enthesopathy.  Adult patients (n = 17) with LBP and/or buttock pain were placed in the lateral decubitus position.  These researchers palpated the quadratus lumborum muscle to accurately locate its lesions, including trigger points, taut bands, and tendon lesions, after 5 key landmarks had been identified.  A newly designed 60- to 90-mm, 28-G thin hypodermic needle was inserted at the tender points.  The needle was typically advanced until its tip touched the transverse process to treat myofascial trigger points and tendon lesions in the ilio-lumbar and lumbo-costal fibers, excluding superficial trigger points of the ilio-costal fibers.  Subsequently, lidocaine (0.5 %) or a mixture of lidocaine (0.5 %) and dextrose (12.5 % to 15 %) was injected.  The pre-treatment VAS score for all 17 patients decreased from 4 or higher to 8/10 (mean of 5.588) to 0 to 1/10 (mean of 0.294) after completion of all treatments.  The total number of treatments was 1 to 4 in acute and subacute cases and 2 to 8 in chronic cases.  The mean follow-up period was 73.5 days (treatment period: range of 4 to 43 days + at least 60 days of follow-up).  The authors concluded that the findings of this study suggested that a safer and more effective treatment could be provided via a repeated and integrated injection method using palpation-guided technique based on 5 landmarks with the newly designed needle and guide-tube, even without image guidance.  Moreover, these researchers stated that a prospective, larger, controlled study is needed to examine the effects of the trigger point injection and integrated injection technique in patients with combined problems of various structures and the quadratus lumborum.

The authors stated that this study had several drawbacks.  First, this trial did not include an adequate number of patients for statistical comparative analysis.  Second, the data were retrospectively reviewed.  Third, as most patients with quadratus lumborum muscle problems typically also exhibit myofascial pain in other lower back muscles, lumbar facet joint problems, and hip joint problems, these researchers did not enroll patients who were simultaneously receiving treatment for these issues.  Fourth, this trial was single-arm study without a control group and did not examine differences between acute, subacute, and chronic cases.  Fifth, this trial lacked long-term follow-up. 

Prolotherapy for Chronic Ankle Instability

Sit et al (2022) stated that lateral ankle sprain (LAS) is a common injury; and conservative care is not uniformly effective.  Chronic ankle instability (CAI) results in up to 70 % of patients with LAS in the physically active population.  LAS, together with subsequent osteochondral lesions and pain in many patients, results in the development of post-traumatic OA, resulting in a substantial direct and indirect personal and societal health burden.  Dextrose prolotherapy (DPT) is an injection-based therapy for many chronic musculoskeletal conditions but has not been tested for CAI.  This protocol describes a RCT to examine the effectiveness of DPT versus NS injections for CAI.  These researchers stated that a parallel-group, single-center RCT will be performed at a university-based primary care clinic in Hong Kong.  A total of 114 patients with CAI will be randomly allocated (1:1) to DPT and NS groups.  The primary outcome will be the Cumberland Ankle Instability Tool (CAIT) scores at 1 year.  The secondary outcomes will be the number of re-sprains in 1 year, the Star Excursion Balance Test (SEBT), the 5-level of EuroQol 5-dimension questionnaire, and the Foot and Ankle Ability Measure (FAAM).  All outcomes will be examined at baseline and at 16, 26, and 52 weeks using a linear mixed model.  The authors hypothesized the DPT is a safe, easily accessible, and effective treatment for patients with CAI.  This RCT study will inform whether DPT could be a primary non-surgical treatment for CAI.

Prolotherapy for Chronic Ankle Ligament Injury

In a n uncontrolled study, Mofrad et al (2022) examined the effectiveness of extra-articular, neuro-fascial dextrose prolotherapy for the treatment of chronic ankle ligament injury.  Patients with chronic ankle ligament injury entered this uncontrolled, before-after study based on eligibility criteria.  Subjects who consented to participate in the study filled out the prepared questionnaire containing demographic data, the CAIT, and the VAS.  The initial CAIT score of less than 25 indicated functional instability following an ankle sprain.  Patients underwent neuro-fascial prolotherapy with 12.5 % dextrose.  Two injections within 1 month were carried out.  The CAIT was completed 1, 3, and 6 months after the intervention.  A total of 25 patients with chronic ankle ligament injury were examined.  The mean CAIT score was 1.88 (± 2.35) before the intervention, which increased significantly over the study (p < 0.001).  The CAIT score reached 21.84 (± 6.04) in the 6th month after the intervention.  Moreover, the VAS score decreased significantly over the study from 6.12 (± 2.35) before the intervention to 1.24 (± 0.43) in the 6th month after the intervention (p < 0.001).  The authors concluded that the findings of this study revealed the therapeutic effectiveness of dextrose neuro-fascial prolotherapy in decreasing pain and functional instability in patients suffering chronic ankle pain due to ligamentous injury accompanied by CAI.  Moreover, these investigators stated that other studies with controlled interventions are needed to examine the effectiveness of neuro-fascial prolotherapy.

The authors stated that this study was limited by its uncontrolled design.  These researchers did not compare their intervention with a control group; thus, a possible source of bias.  The symptom severity in the subjects did not allow these researchers to use other non-surgical approaches.  Participants tried other non-invasive treatments without symptom improvement; however, neuro-fascial prolotherapy significantly reduced their pain and functional instability. 

Prolotherapy for Chronic Supraspinatus Tendinopathy

Lin et al (2022) noted that both corticosteroids and hypertonic dextrose injections are commonly used for the treatment of chronic supraspinatus tendinopathy.  In a cohort study, these investigators compared the supraspinatus echogenicity and clinical effects of echo-guided hypertonic dextrose versus corticosteroid injection for the treatment of chronic supraspinatus tendinopathy.  These researchers carried out a secondary data analysis of a previous clinical trial including patients who received NS versus hypertonic dextrose injection; patients who received corticosteroid injection were recruited between August 2017 and July 2021.  Baseline patient data were matched among these 3 groups at a 1:1:1 ratio.  At baseline and 2, 6, and 12 weeks after the intervention, these investigators compared morphological changes (supraspinatus thickness and echogenicity) and clinical parameters (VAS for pain, SPADI, and ROM).  Analysis of variance was used to compare mean changes from baseline among the groups.  A total of 75 patients (25 in each group) were included.  At 2-week follow-up, both the dextrose and the steroid groups exhibited improvement in VAS scores (MD from baseline: -2.0 in dextrose group; -3.3 in steroid group (p < 0.001)), SPADI scores (MD from baseline: -10.6 in dextrose group; -24.6 in steroid group (p < 0.001)), and flexion ROM (MD from baseline: 13.6° in dextrose group; 21.1° in steroid group) (p = 0.001).   6 weeks after injection, the hypertonic dextrose group exhibited more favorable echogenic improvement in supraspinatus tendon morphology compared with the other 2 groups (p < 0.001).  However, the steroid group showed significantly more improvement in clinical parameters compared with the other 2 groups at both week 6 (MD from baseline: VAS, -3.2; SPADI, -26.6; flexion ROM, 21.5°) and week 12 (MD from baseline: VAS, -2.5; SPADI, -20.4; flexion ROM, 15.2°) (p < 0.001 for all).  The authors concluded that hypertonic dextrose injection improved supraspinatus echogenicity after 6 weeks; but provided short-term symptomatic relief in the patients with chronic supraspinatus tendinopathy when compared with corticosteroid or saline injections.  Steroid injection exerted a more favorable clinical effect at weeks 6 and 12 but demonstrated a negative effect on the supraspinatus.  Level of Evidence = III.

The authors stated that this study had several drawbacks.  First, to examine the effect of hypertonic dextrose injection on the patients with chronic supraspinatus tendinopathy, these researchers gave a single injection specific to the supraspinatus tendon.  This method was different from the typical rotator cuff prolotherapy injection technique in which injections are administered at multiple sites in multiple sessions.  This may explain the difference in the effectiveness observed between this trial and previous studies reporting that prolotherapy was not inferior to steroid injection.  Second, this study lacked an objective functional assessment.  Although these investigators used the SPADI questionnaire, an objective assessment tool for shoulder strength and movement was not used.  Further investigation examining the strength or kinesiology of the shoulder following hypertonic dextrose injection is needed.  Third, although the authors tried to exclude concomitant shoulder problems such as fracture or arthroplasty, other kinds of shoulder diseases, such as arthritis, labral tears, acromial morphology problems, bursitis, and tendinopathy of other tendons, were difficult to totally exclude.  Fourth, the durations of the baseline variables of smoking and diabetes were not recorded.  The influence of these factors could not be evaluated in a short follow-up period.  In addition, the long-term clinical impact and structural changes on the supraspinatus tendon caused by tears could not be presented in this study.  Fifth, these researchers examined structural changes following injection by using US, not magnetic resonance imaging (MRI).  Although these investigators standardized the US examination protocol and quantitative evaluation, the bias introduced by the obtained image and data acquisition was inevitable.  Moreover, US could only present the gross structural changes and was limited to histological changes of the supraspinatus tendon.  Definite changes observed in the tenocyte and histology should be confirmed by means of MRI or a tendon biopsy study.

Prolotherapy for Core Muscle Injuries

Poor et al (2022) stated that core muscle injuries (CMI) are common in sports.  To minimize lost playing time, providers employ various non-surgical treatments, including PRP, corticosteroids, US-guided percutaneous tenotomy, and prolotherapy; however, limited data exist with regard to their effectiveness.  In a retrospective study, these investigators reviewed a cohort of consecutive professional and collegiate athletes who sustained CMI at various points within their seasons and underwent a combination of US-guided percutaneous needle "tenotomy" and corticosteroid injections to complete the remainder of their seasons.  A total of 25 consecutive collegiate or professional athletes with CMI involving the rectus abdominis-adductor aponeurotic plate were included in this trial.  Athletes with concomitant symptomatic hip femoro-acetabular impingement (FAI) were included in the study.  The primary outcome measure was whether athletes completed their seasons.  Secondary measures were weeks played after the procedures (delay until surgery), need for repeat procedures, and outcomes after eventual surgery.  Post-operative performance was examined through interviews at 6 weeks and 6 months post-operatively.  21 of 25 (84 %) athletes completed their seasons.  On average, athletes returned to play 3 days (range of 1 to 9 days) following the procedures.  Surgical repair was delayed a mean of 18 weeks (range of 2 to 44 weeks); 7 athletes had concomitant symptomatic FAI and 6 underwent combined hip arthroscopy and core muscle repairs.  Among 17 patients who eventually had core muscle surgery alone (no hip surgery), 82 % (14 of 17) reported performing at their pre-injury level at 6 weeks.  At 6 months, 96 % of post-operative athletes (22 of 23) reported performing at their pre-injury level.  The authors concluded that temporizing CMI with US-guided percutaneous tenotomy and corticosteroid injections was effective in allowing continued sport participation among high-level athletes and did not negatively affect post-operative outcomes.

Prolotherapy for Knee Osteoarthritis

In a systematic review, Cortez et al (2022) compared the effectiveness of DPT with other substances for pain relief in patients with primary knee OA.  The literature screening was carried out in January 2021 via Medline (PubMed), Embase, and database of the National Institute of Health (NIH) based on the following criteria: randomized clinical trials that subjected patients with primary knee OA who underwent treatment with DPT and other substances for pain relief.  Paired reviewers independently identified 3,381 articles and included 8 studies that met the eligibility criteria.  According to the findings of this review, subjects that underwent DPT showed improvements between baseline and posterior assessments and when compared to saline injections, but when compared to other substances, the results were unclear.  The authors concluded that although DPT is a useful treatment method by itself, it is still not possible to clearly affirm that it is superior or inferior to its counterparts.  These researchers stated that there is an urgent need for further studies to bring more evidence to the field.

Prolotherapy for Neck Pain

Williams et al (2021) stated that the increasing burden of musculoskeletal disorders combined with the high use of opiates and the relatively limited ability of traditional approaches to satisfactorily address many of these conditions has spurred an increased interest in alternative treatments such as regenerative medicine therapies.  Evidence is growing to support the use of regenerative injection treatments, including prolotherapy, PRP, platelet lysate (PL), and mesenchymal stromal cells.  These researchers offered a proof-of-concept via a case series of patients with neck pain treated using a functional spinal unit (FSU) model with combination prolotherapy, PRP, and PL injections.  A chart review identified patients with neck pain treated with a combination of cervical injections using concentrated platelets and prolotherapy.  A total of 14 patients met the inclusion criteria.  The average decrease in the numeric pain score (NPS) was 2.8 (p = 0.002).  The mean decrease in the functional rating index (FRI) was 27.3 (p = 0.004) at 24 months.  Two patients had mild adverse reactions.  The authors concluded that although these preliminary findings are encouraging, more comprehensive, RCTs including a larger number of patients and longer follow-up are needed to further validate these findings.  They noted that given the significant impact of neck pain on QOL for an aging population, an over-reliance on opioid medications for the management of chronic musculoskeletal pain by providers, and the significant societal costs, both directly and indirectly, a more comprehensive treatment approach from a biomechanical perspective that offers the possibility of disease modification rather than symptom management is needed.  This study further underscored the importance of continued research in this area to confirm the effectiveness of this approach and help shape medical policy such that more patients have access to care that may prove to be, in the end, safer and more effective than that offered in the current treatment model.

Prolotherapy for Plantar Fasciitis

In a systematic review and meta-analysis, Chutumstid et al (2023) examined the safety and effectiveness of DPT for the treatment of chronic plantar fasciitis.  Data sources included Embase, PubMed, Scopus, and Google Scholar (from inception to December 9, 2021).  These investigators carried out a comprehensive review of RCTs examining DPT for chronic plantar fasciitis.  Two investigators independently screened the titles, abstracts, and full texts and extracted data from eligible studies.  The changes in VAS pain score, foot function index (FFI), American Orthopedic Foot and Ankle Society (AOFAS) score, and plantar fascia thickness were analyzed.  Reports of complications of the procedure were collected.  A total of 8 RCTs were included in the meta-analysis, analyzing 444 patients in total.  The subgroup analysis showed that at short-term follow-up (less than 6 months) DPT was more effective in reducing VAS pain score compared to the non-active treatment control group including exercise and normal saline solution (NSS) injection.  However, there was no difference in the change of VAS pain score between DPT and active treatment control group, which included extracorporeal shock wave therapy (ESWT), steroid injection, and PRP injection.  Dextrose prolotherapy was more effective in reducing FFI, increasing AOFAS score, and reducing plantar fascia thickness at short-term (less than 6 months) follow-up compared to other comparators.  For long-term (6 months or longer) follow-up, there was no significant difference in the change in VAS pain score and FFI between the DPT group and other comparators.  No serious complication was reported.  The authors concluded that DPT was an effective treatment of chronic plantar fasciitis to reduce pain, improve foot functional score, and decrease plantar fascia thickness at short-term follow-up.  Moreover, these researchers stated that further investigation in larger populations are needed to identify the optimal treatment regimen including dextrose concentration, volume, injection site, injection technique, and the number of injections required.  The long-term effects of these treatments also need further examination.

In a systematic review and meta-analysis, Ahadi et al (2023) examined the effect of DPT versus placebo/other non-surgical treatments on pain in chronic plantar fasciitis.  These investigators searched seven electronic databases (PubMed/Medline, Web of Science, Embase, Scopus, ProQuest, CENTRAL, PEDro) from inception to December 31, 2021 with no language restriction for publications comparing the effect of DPT with placebo/other non-surgical treatments in patients with chronic plantar fasciitis.  The primary outcome was pain and the secondary outcomes were foot function and plantar fascia thickness.  The risk of bias was assessed using the Cochrane Collaboration's tool.  A total of 8 studies with a total of 449 patients were included in the meta-analysis.  All the included studies reported short-term pain.  A large effect size (dppc2 = -0.97, 95 % CI: -1.84 to -0.10) was observed favoring the use of DPT to reduce pain in patients with chronic plantar fasciitis in the short-term.  The results for foot function improvement (dppc2 = -1.28, 95 % CI: -2.49 to -0.07) and plantar fascia thickness reduction (dppc2 = -1.02, 95 % CI: -1.99 to -0.05) in the short-term were also in favor of DPT.  The authors concluded that since almost all the included studies had high risk of bias and multiple studies lacked long-term follow-ups, further high-quality research is needed to determine the long-term effects of DPT versus placebo/other non-surgical interventions.

Prolotherapy for Post-Herpetic Neuralgia

Kersschot and Karavani (2022) stated that post-herpetic neuralgia (PHN) is a painful condition that is difficult to manage, especially among the elderly.  These investigators described a clinical case of an 88-year-old patient with PHN who continued to suffer from pain for several months despite oral and transdermal pain treatment.  Multiple intra-dermal glucose 5 % injections allowed her to discontinue her pain medication regimen after 4 sessions.  The improvement was sustained at the 4-month follow-up after the last procedure.  A 5th session was carried out because of a flaring up of the pain.  The authors concluded that physicians may consider the use of intra-dermal glucose 5 % injections as an easy, safe, and inexpensive therapeutic option for PHN; however, no clinical trials are available yet.  These researchers stated that this article was written to invite the medical community to plan more research in this field.

Sclerotherapy for Venous Malformation

Cao et al (2023) noted that sclerotherapy for venous malformation has been widely employed; however, no guidelines are available to assess the effectiveness of different sclerotherapy agents.  In a systematic review and network meta-analysis, these investigators examined the effectiveness of sclerotherapy agents for the treatment of venous malformations.  A total of 3 electronic databases were searched from their inception (1950) to April 29, 2021.  Studies comparing the effectiveness of different sclerotherapy agents were included.  The risk of bias within and across studies was assessed.  Pair-wise meta-analyses were carried out, followed by a network meta-analysis.  These researchers also examined inconsistency and publishing bias using various approaches.  A total of 7 studies with 547 patients in 6 arms were included in the present study.  These researchers defined the response and complete response as 2 separate outcomes.  Significant differences were observed in 4 comparisons with respect to the response (ethanol versus bleomycin, ethanol versus polidocanol, ethanol versus sodium tetradecyl sulfate, polidocanol versus sodium tetradecyl sulfate).  No statistically significant differences were observed in the other comparisons.  The evidence network revealed that for the response outcome, ethanol ranked 1st, followed by pingyangmycin, polidocanol, sodium morrhuate, bleomycin, and, finally, sodium tetradecyl sulfate.  For the complete response outcome, pingyangmycin had the best results, followed by sodium morrhuate, polidocanol, ethanol, bleomycin, and, finally, sodium tetradecyl sulfate.  Major complications, such as facial nerve palsy, serious local swelling, and necrosis, had occurred mostly in the ethanol group and rarely in the other groups.  Because of the limited data, no further analysis of major complications was performed; and the confidence in the comparisons and rankings was low.  These investigators found no verified inconsistency or publishing bias in the present study using the existing approaches.  The authors concluded that ethanol showed a significantly better response statistically compared with the other agents; however, ethanol had also resulted in the highest incidence of complications.  Pingyangmycin showed the 2nd-best response, best complete response, and a low rate of complications, respectively.  Overall, pingyangmycin achieved excellent performance and balance in terms of the different outcomes.  However, they could not be adequately recommended from the available data.  These researchers stated that more superior trials, especially RCTs, are needed in the future.

Sclerotherapy for Venous Ulceration

In a systematic review and meta-analysis, Joyce et al (2022) examined rates of ulcer healing following US-guided foam sclerotherapy (UGFS).  The Medline, CENTRAL and Embase databases were used to search for relevant studies using the terms “(sclerotherapy AND ulcer) OR (vein AND ulcer) OR (sclerotherapy AND vein)”.  Heterogeneity between studies was quantified using the I2 statistic.  A random effects model was used to calculate risk ratios where substantial heterogeneity was found.  The initial search yielded 8,266 articles. 8 studies were included in the qualitative synthesis and 3 in the meta-analysis.  Superior complete ulcer healing rates were noted in patients treated with foam sclerotherapy versus compression therapy alone (pooled OR 6.41, 95 % CI: 0.3 to 148.2, p = 0.246, random effects method).  A marked degree of heterogeneity was observed between studies (I2 = 81 %).  The authors concluded that a prospective, trial is needed to determine the true merits of UGFS in the setting of venous ulceration.

Sclerotherapy for the Treatment of Lymphatic Malformations

De Maria et al (2020) stated that percutaneous sclerotherapy is a commonly used modality for the treatment of lymphatic malformations (LMs) of the head, face, and neck.  The safety and effectiveness of sclerotherapy with various agents for diverse pathologic types of LMs have not been fully established.  In a systematic review and meta-analysis, these investigators examined the safety and effectiveness of percutaneous sclerotherapy for treatment of LMs of the head, face, and neck.  These investigators carried out a literature search using PubMed, Medline, and Embase from 2000 to 2018 for studies examining the safety and effectiveness of percutaneous sclerotherapy of head, face, and neck LMs.  Two independent reviewers selected studies and abstracted data.  The primary outcomes were complete and partial resolution of the LM.  Data were analyzed using random-effects meta-analysis.  A total of 25 studies reporting on 726 patients were included in the analysis.  The overall rate of complete cure of any pathologic type of LM after percutaneous sclerotherapy with any agent was 50.5 % (95 % CI: 36.6 %to 64.3 %).  Macro-cystic lesions had a cure rate of 53.1 % compared with cure rates of 35.1 % for micro-cystic lesions and 31.1 % for mixed lesions.  Regarding agents, doxycycline had the highest cure rate (62.4 %) compared with all other agents.  Overall permanent morbidity or mortality was 1.2 % (95 % CI: 0.4 % to 2.0 %) with no deaths; I2 values were greater than 50 % for most outcomes, indicating substantial heterogeneity.  The authors concluded that this systematic review and meta-analysis of 25 studies and more than 700 patients found that percutaneous sclerotherapy was a safe and effective modality for the treatment of LMs of the head, neck, and face.

Kalwani and Rockson (2021) noted that LMs are common congenital vascular lesions, most often diagnosed at birth.  They deform local anatomy and could be life-threatening if they compress the aero-digestive tract or other vital structures.  Significant progress has been made in the treatment of LMs in the past 2 decades.  In a systematic review, these investigators examined the available evidence on the management of LMs.  On September 21, 2020, these investigators searched PubMed/Medline for studies published from 2000 to 2020 reporting outcomes of invasive and pharmacologic treatment of LMs.  A total of 251 studies met the eligibility criteria.  Surgery has continued to be a mainstay in the management of LMs, especially in the treatment of micro-cystic and mixed lesions.  Sclerotherapy has emerged as a f1st-line treatment of macro-cystic LMs and as an adjunctive therapy used in combination with surgery for other lesions.  Sirolimus, a strong inhibitor of mTOR (mechanistic target of rapamycin), has shown tremendous promise in the treatment of LMs, as both an oral and a topical agent.  Recent investigations have shown the potential of targeted small molecule modulators of cellular pathways in the treatment of LMs.  The authors concluded that multiple invasive and pharmacologic therapies have been shown to be effective in the treatment of LMs.

In a retrospective study, Bouwman et al (2021) examined the outcomes of sclerotherapy in children with venous LMs who received sclerotherapy between 2011 and 2016 (n = 116 children, 234 procedures).  Complication severity was classified using the Society of Interventional Radiology classification.  Clinical response was rated on a scale of 0 (no change) to 3 (good improvement).  The sclerosants used were bleomycin (n = 132; 56 %), lauromacrogol (n = 42; 18 %), doxycycline (n = 15; 6 %), ethanol (n = 12; 5 %), or a combination (n = 33; 14 %); 4 major and 25 minor complications occurred without significant differences between the agents.  The median response rate per procedure was 2 -- some improvement -- for all sclerosants.  However, in pure LMs (67 %), bleomycin and a combination of agents resulted in the best clinical response.  On patient level, all had some or good clinical response.  Mixed macro-cystic and micro-cystic lesions showed a significantly lower clinical response (median 2 versus 3; p = 0.023 and p = 0.036, respectively) and required significantly more procedures (median of 2 versus 1; p = 0.043 and p = 0.044, respectively) compared with lesions with 1 component.  The authors concluded that sclerotherapy for venous LMs in children was safe and effective.  Bleomycin was the most frequently used agent in this clinic and appeared most effective for pure LMs.  Mixed macro-cystic and micro-cystic lesions are most difficult to treat effectively.

In a retrospective study, Wang et al (2022) compared the outcomes of sclerotherapy with bleomycin and lauromacrogol between LMs with and without intra-lesional hemorrhage and identified the factors affecting the outcomes of LMs with hemorrhage.  These researchers examined patients with LMs who underwent sclerotherapy with bleomycin and lauromacrogol between January 2019 and December 2021.  Regression models were used to analyze the factors associated with the outcomes of LMs with hemorrhage.  A total of 52 patients were included in the study, including 26 with intra-lesional hemorrhage.  Masses with bluish skin (p = 0.026) and pain (p = 0.001) were more common in LMs with hemorrhage.  With similar outcomes, the average number of sessions was 2.9 in LMs with hemorrhage and 2 in LMs without hemorrhage (p = 0.028).  The effectiveness of the macro-cystic and mixed types (93.3 % and 83.3 %, respectively) was higher than that of the micro-cystic type (40 %) (p = 0.036).  As the number of sessions increased, the relapse rate decreased (p = 0.018).  The authors concluded that sclerotherapy with bleomycin and lauromacrogol was safe and effective for LMs with hemorrhage.  An increased number of injections for patients with hemorrhage was associated with similar effectiveness for those without hemorrhage and similar relapse rates.

Leboulanger et al (2023) noted that cystic LMs are rare chronic conditions, with management differs according to the type (macro-cystic LMs, micro-cystic LMs, or both).  Studies are lacking due to rarity of the pathology.  These investigators attempted to establish a French National Diagnosis and Care Protocol (PNDS: Protocole National de Diagnostic et de Soins), to provide healthcare professionals with free open access synthesis on optimal management and care of patients with LMs ( https://www.has-sante.fr/upload/docs/application/pdf/2021-03/malformations_lymphatiques_kystiques_-_pnds.pdf ).  The process included a critical review of the literature and multi-disciplinary expert consensus.  LMs are congenital but are not always discovered at birth.  Nearly 75 % of them are located in the head and neck because of the highly dense lymphatic system in this region.  Physical examination (showing painless masses with normal skin color and depressible consistency, or cutaneous/mucosal lymphangiectasia) and color Doppler US, usually allow for diagnosis.  MRI (involving T2 sequences with fat saturation in at least 2 spatial planes) is the tool of choice for examining anatomical extension, characterizing lesions (micro-cystic and macro-cystic), and before considering therapeutic management.  A biopsy, coupled to a blood sample, can also be used for molecular biology analyses, to search for activating mutations of the PIK3CA gene, especially with LM integrating in a syndromic form (CLOVES or Klippel-Trenaunay syndrome) but also in certain isolated (or common) LMs.  The spontaneous evolution of LMs, in particular micro-cystic forms, is often toward progressive aggravation, with an increase in the number of vesicles, thickening, increased oozing and bleeding, while pure macro-cystic LMs may regress due to "natural sclerosis", i.e., fibrosis secondary to an inflammatory reorganization after common infantile infections.  In case of voluminous LMs or syndromic forms, functional and psychological repercussions can be major, deteriorating the patient's QOL.  LMs must be treated by physicians integrated in multi-disciplinary teams, and be personalized.  Management is a life-long process that entails one or several of the following approaches: conservative management, PT (compression), sclerotherapy, surgery, drugs such as mTOR inhibitors (sirolimus), that has shown effectiveness in decreasing the volume of LMs, and, more recently, PI3K-inhibitors in syndromic forms.

Sun et al (2023) noted that bleomycin has been widely used in the treatment of LMs.  In a meta-analysis, these investigators examined the effectiveness and influencing factors of bleomycin in the treatment of LMs.  They carried out a systematic review and meta-analysis to clarify the relationship between bleomycin and LMs.  PubMed, ISI Web of Science and Medline were searched.  A total of 21 studies (including 428 cases) on bleomycin sclerotherapy for LMs were included in the current meta-analyses.  These researchers calculated pooled effective rate and 95 % CI using random effects model to evaluate the relations between bleomycin and LMs.  The results suggested that the effective rate of bleomycin was 84.0 % (95 % CI: 0.81 to 0.87) and ranged from 39 % (95 % CI 0.22 to 0.56) to 94 % (95 % CI: 0.87 to 1.02).  The heterogeneity among the studies was substantial (I2 = 61.7 %, p = 0.000).  In subgroup analyses, it was observed that among retrospective study and prospective study, the estimated effective rate was 80.0 % (95 % CI: 0.76 to 0.84) and 91.0 % (95 % CI: 0.85 to 0.97), respectively.  In terms of the dosage, the combined effective rates of weight-based group and fixed-dose group were 86 % (95 % CI: 0.83 to 0.90) and 74.0 % (95 % CI: 0.66 to 0.82), respectively.  There was no significant publication bias in Egger's test (p = 0.059, 95 % CI: -3.81 to 0.082), but Begg's test did (p = 0.023), and the funnel plot was asymmetric.  The authors concluded that the findings of this study suggested that bleomycin was safe and effective in the treatment of LMs and was primarily dose-dependent.

Ultrasound-Guided Percutaneous Aspiration with Sclerotherapy for the Treatment of Hepatic Cysts

Wijnands et al (2017) stated that aspiration sclerotherapy is a percutaneous procedure indicated for the treatment of symptomatic simple hepatic cysts (SHCs).  The safety and effectiveness of this procedure have been sources of debate and disagreement for years.  In a systematic review, these investigators examined the long-term safety and effectiveness of aspiration sclerotherapy.  They carried out a literature search using PubMed Medline, Embase, Web of Science, and the Cochrane Library (until August 2015).  Studies of proportional volume or diameter reduction following aspiration sclerotherapy of SHCs were included for full-text evaluation; case reports and case series were excluded.  Risk of bias was assessed by means of the Newcastle-Ottawa scale.  From a total of 9,357 citations, 100 were selected for full-text assessment.  These researchers included 16 studies, entailing 526 patients with a total of 588 treated cysts.  Overall, risk of bias was high, with 12 of 16 studies having a score of poor.  Proportional cyst volume reduction ranged between 76 % and 100 % after a median follow-up period of 1 to 54 months.  Change in symptoms was evaluated in 10 studies: 72 % to 100 % of patients reported symptom reduction, and 56 % to 100 % reported disappearance.  Post-procedural pain occurred most frequently, at a rate of 5 % to 90 % among studies.  Ethanol intoxication occurred in up to 93 % of cases and was reported more frequently in studies with either high ethanol volumes (133.7 to 138.3 ml) or long sclerotherapy duration (120 to 180 mins).  The authors found excellent results with respect to long-term safety and effectiveness following aspiration sclerotherapy of SHCs.

Furumaya et al (2021) noted that SHCs may cause pain and bloating; therefore, 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 investigators examined the effectiveness of PAS and surgical management in patients with symptomatic SHC.  They carried out a literature search in PubMed and Embase according to Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement.  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 weighted mean 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.  Studies including a step-up approach that reserves laparoscopic cyst de-roofing for symptomatic recurrence after 1 or 2 PAS procedures are needed.

Du et al (2022) stated that hepatic cysts in infants are uncommon.  With modern diagnostic imaging, clinicians can achieve an early diagnosis of congenital hepatic cysts.  In a retrospective, case-series study, these investigators examined the clinical features, surgical treatment methods and prognosis of infants with congenital hepatic cysts.  A total of 11 infants with hepatic cysts were analyzed; 10 had SHCs, and a girl with a large hepatic mass was diagnosed with a solitary intra-hepatic biliary cyst accompanied by a choledochal cyst.  Among the 10 SHCs, 8 were solitary and 2 were multiple.  A total of 87.5 % (7 of 8) of infants with solitary hepatic cysts were detected before delivery, and 86 % (6 of 7) of those cysts were located in the right lobe of the liver.  Surgical intervention was required for symptomatic hepatic cysts.  Cyst resection or un-roofing with fulguration of the cyst bed was employed.  No recurrence of cysts was observed in these infants.  The authors concluded that congenital hepatic cyst is a condition with a narrow differential diagnosis.  Accurate diagnosis is critical for appropriate management; and un-roofing is the favored treatment in infants with symptomatic cysts.  Most infants with congenital hepatic cysts have a good prognosis.  Moreover, these investigators stated that US-guided percutaneous aspiration may serve as a diagnostic tool.  To achieve permanent ablation, instillation of a sclerosant, such as ethanol, tetracycline, minocycline or pantopaque, is performed.  The sclerosing agent induces an obvious inflammatory reaction that potentially produces obliteration of the cyst space.  Communication of the cyst with the biliary tree is an absolute contraindication to injection sclerotherapy.

Furthermore, an UpToDate review on “Diagnosis and management of cystic lesions of the liver” (Regev and Reddy, 2023) states that “In one report, hemorrhage was associated with the appearance of septa in 2 of 57 patients (3.5 %) with large simple cysts (≥ 4 cm).  Hemorrhage is much less frequent in smaller cysts … For patients with symptomatic, large simple cysts, the choice of intervention is individualized and informed by cyst location and size, patient history and comorbidities, local expertise, and patient preferences.  For patients who are candidates for surgery, cyst deroofing with a laparoscopic or open surgical approach is usually curative.  For patients who cannot or do not wish to have surgical intervention, percutaneous aspiration with sclerotherapy is a reasonable alternative”.

Sclerotherapy for the Treatment of Hemorrhoid

Hachiro et al (2011) noted that aluminum potassium sulfate and tannic acid (ALTA) induce non-invasive sclerosis and the involution of hemorrhoids by initiating an inflammatory reaction.  These investigators examined the mid-term outcome after ALTA sclerotherapy for symptomatic hemorrhoids.  Between May 2006 and July 2009, a total of 1,210 patients with grade-III or grade-IV hemorrhoids underwent surgery at Kunimoto Hospital.  The treatment strategy for internal hemorrhoids was first establishing whether ALTA therapy was possible for the type of hemorrhoid, and then performing either ALTA therapy or alternatively, ligation and excision (LE) for those types unsuitable for ALTA therapy.  A total of 448 patients were treated with ALTA therapy alone (Group A), 706 patients were treated with a combination of ALTA and LE therapy (Group B), and 56 patients were treated with LE alone (Group C).  The overall recurrence rates were 3.6 % (16/448) and 0.3 % (2/706) in Groups A and B, respectively.  There was no recurrence in Group C.  Rectal ulcers developed at the injection site in 4 (0.9 %) patients from Group A; however, they healed within a few months with conservative therapy.  The authors concluded that ALTA sclerotherapy was a simple and safe treatment for symptomatic hemorrhoids, with few complications.

In a retrospective, multi-center study, Miyamoto et al (2016) examined the effectiveness of ALTA sclerotherapy in the treatment of grade-II and grade-III hemorrhoids.  This study included 604 patients with hemorrhoids who underwent ALTA sclerotherapy between January 2009 and February 2015.  Pre-operative and post-operative symptoms, complications, and success rate were assessed.  Follow-up consisted of a simple questionnaire, physical examination and an anoscopy.  Patients were followed-up at 1 day, 1 week, 2 weeks, 1 month, 1 year, 2 years, 3 years, 4 years, and 5 years after the ALTA sclerotherapy.  A total of 169 patients were diagnosed with grade-II hemorrhoids and 435 patients were diagnosed with grade-III hemorrhoids.  The 1-year, 3-year, and 5-year cumulative success rates of ALTA sclerotherapy for grades-II and grade-III hemorrhoids were 95.9 % and 93.1 %; 89.3 % and 83.7 %; and 89.3 % and 78.2 %, respectively.  No significant differences were observed in the cumulative success rates after ALTA sclerotherapy between grade-II and grade- III hemorrhoids (p = 0.09).  There were 47 post-operative complications (low-grade fever; anal pain; urinary retention; rectal ulcer; and others).  No serious or life-threatening complications occurred and all cases improved through conservative treatment.  At univariate analysis there were no predictive factors of failure.  The authors concluded that ALTA sclerotherapy exhibited a high success rate for grade-II and grade-III hemorrhoids during 5 years of post-operative treatment.

In a retrospective study, Tomiki et al (2019) compared the effects of endoscopic ALTA therapy and standard ALTA therapy.  These investigators examined patients who underwent treatment for internal hemorrhoids at their institution between 2014 and 2016.  They were divided into a standard ALTA group (n = 33, treated using proctoscopy) and an endoscopic ALTA group (n = 48).  They compared the clinical findings between the 2 groups.  There were no inter-group differences in background factors.  The mean ALTA dose was 21.9 ± 7.2 ml and 17.8 ± 3.4 ml in the standard and endoscopic ALTA groups, respectively (p < 0.01); AEs occurred in 4 patients (12.1 %) from the standard ALTA group, and 6 patients (12.5 %) from the endoscopic ALTA group.  In both groups, subjects reported good satisfaction with the therapeutic effect at 1 month after the procedure.  Hemorrhoids recurred in 2 patients (6.3 %) from the standard ALTA group, and 4 patients (8.3 %) from the endoscopic ALTA group.  The authors concluded that endoscopic ALTA sclerotherapy was equivalent to standard ALTA therapy in terms of effectiveness, AEs, and recurrence; thus, it was a useful non-surgical option for patients with internal hemorrhoids who preferred a less invasive treatment.

Miyamoto (2023) stated that hemorrhoids, the most common anorectal disease, give rise to symptoms such as bleeding, prolapse, and pruritus.  The treatment for advanced hemorrhoids (Grade III or IV) is gradually shifting toward minimally invasive procedures.  These procedures focus on reduction of blood flow in hemorrhoids.  Conventional hemorrhoidectomy (CH), also known as Milligan-Morgan or Ferguson hemorrhoidectomy, is considered as the standard treatment for grade-III and grade-IV hemorrhoids because it achieves the lowest recurrence rate.  Over the years, alternative minimally invasive techniques such as stapled hemorrhoidopexy and trans-anal hemorrhoidal de-arterialization (THD) have been developed.  A new, effective sclerosant, ALTA, has been developed in Japan and has been used for all grades of hemorrhoids; however, its effectiveness declines over time.  Other minimally invasive, non-surgical procedures, including rubber band ligation, endoscopic injection sclerotherapy, and infra-red coagulation, have also been performed for grade-III hemorrhoids. Those minimally invasive treatments improve bleeding and prolapse and are highly recommended for patients who are unfit for CH.  THD with mucopexy or ALTA sclerotherapy has also been performed for grade-IV hemorrhoids; however, the recurrence rate after ALTA sclerotherapy for grade-IV hemorrhoids was higher than that for grade-III lesions in their case study.  The author concluded that minimally invasive treatments are a valid alternative for patients with advanced hemorrhoids after clear explanation of recurrence rates and possible complications.

He and Chen (2023) noted that injection sclerotherapy for all grades of internal hemorrhoids in various situations and co-morbidities has become a popular method of treatment.  Several types of surgical operations both conventional and stapled hemorrhoidectomy has many and serious described side effects.  On the contrary, proctoscopic injection sclerotherapy using some of the modern sclerosants and thin bore needle injections is an office-based method of treatment of internal hemorrhoids; it is low-cost, devoid of any major complications, and it is quite successful as reported.  Its safety and effectiveness has been established in studies published in recent years.  The authors stated that this manuscript was a result of thorough systemic review using PRISMA guidelines on various sclerosing agents, their merits and demerits, methods of administration, and outcome in internal hemorrhoids.

In a systematic review and meta-analysis, Gallo et al (2024) examined the safety and effectiveness of sclerotherapy for the treatment of hemorrhoidal disease (HD) over the last 4 decades.  This review followed the 2020 PRISMA guidelines.  These investigators carried out a comprehensive literature search, including studies reporting the use of sclerotherapy in patients with HD.  Study eligibility criteria were defined, and data were extracted independently by the authors.  Random-effects meta-analyses were performed to assess outcomes of interest.  Out of 1,965 records identified, 44 studies met the inclusion criteria, entailing 9,729 patients.  The majority of studies were conducted in Japan, followed by the U.K., Italy, and Portugal.  The median age of subjects was 52 years, and the majority were men.  The Goligher grade distribution indicated varying degrees of HD severity.  Sclerotherapy was predominantly administered via anoscopy, with polidocanol being the most commonly used agent.  The procedure was generally performed without pre-injection analgesia.  The meta-analysis of 14 RCTs showed that sclerotherapy was not inferior to control interventions in terms of success rate (RR 1.00, 95 % CI: 0.71 to 1.41) and recurrence rate (RR 1.11, 95 % CI: 0.69 to 1.77), while resulting in fewer complications (RR 0.46, 95 % CI: 0.23 to 0.92).  The authors concluded that this systematic review highlighted the safety and effectiveness of sclerotherapy for the treatment of HD, which yielded similar success rates and fewer complications compared to other conservative or surgical approaches.

Furthermore, an UpToDate review on “Home and office treatment of symptomatic hemorrhoids” (Bleday and Breen, 2024) provided the following information:

  • The initial treatment approach to most patients with new-onset symptomatic hemorrhoids is conservative, consisting of dietary/lifestyle modification and topical or oral medications to relieve symptoms (e.g., dibucaine 1 % rectal ointment; pramoxine 1 % rectal foam, zinc oxide topical paste, hydrocortisone rectal cream 1 to 2.5 %,  hydrocortisone rectal suppository 25 to 30 mg, nitroglycerin (glyceryl trinitrate) 0.2 to 0.5 % ointment, phenylephrine 0.25 % rectal ointment or suppository (e.g., Preparation-H), lidocaine and hydrocortisone cream (e.g., lidocaine-hydrocortisone 2 %-2%, 3 %-0.5 %, and 3 %-1 %), and lidocaine and hydrocortisone gel (e.g., lidocaine-hydrocortisone 2.8 %-0.55 % and 3 %-2.5 %)
  • Commonly performed office-based procedures include rubber band ligation, sclerotherapy, infrared coagulation of internal hemorrhoids, and excision of thrombosed external hemorrhoids. The choice first depends on local availability.
  • For patients who are on anti-coagulant or anti-platelet drugs, are immunocompromised, or have portal hypertension, we suggest sclerotherapy rather than another procedure.
  • This approach can be used to treat grade I and II bleeding internal hemorrhoids with reported success rates of 75 to 89 %, which has more recurrences than rubber band ligation.  In a meta-analysis of 5 trials, sclerotherapy resolved 90 to 100 % of grade II hemorrhoids; 36 to 49 % of patients reported post-procedural pain.  Bleeding is rare after sclerotherapy.
  • Hemorrhoidal bleeding in patients with portal hypertension is first treated conservatively.  Patients who fail conservative management are usually treated with sclerotherapy.

Sclerotherapy for the Treatment of Testicular Hydroceles

In a systematic review and meta-analysis, Shakiba et al (2023) compare hydrocelectomy versus aspiration and sclerotherapy for the treatment of primary hydrocele.  This review included RCTs and quasi-RCTs that compared aspiration and sclerotherapy with any type of sclerosants versus hydrocelectomy for primary hydrocele.  Studies were identified via a systematic search of the Cochrane Central Register of Controlled Trials, Medline, Embase, and ClinicalTrials.gov.  Citation tracking of related articles was conducted.  Data extraction and quality assessment were carried out independently by 2 authors.  The primary and secondary outcome measures were compared and analyzed using the Review Manager 5.3.5 software.  A total of 5 small RCTs were included in the present study.  These 5 RCTs included 335 patients with 342 hydroceles, randomized to aspiration and sclerotherapy (185 patients; 189 hydroceles) and surgery (150 patients; 153 hydroceles).  There was no significant difference in clinical cure between sclerotherapy and hydrocelectomy (RR 0.45, 95 % CI: 0.18 to 1.10).  Meta-analysis showed a significant increase in recurrence in the sclerotherapy group compared with the surgical group (RR 9.43, 95 % CI: 1.82 to 48.77).  There were no significant differences between the 2 groups in assessing fever, infection, and hematoma.  The authors concluded that aspiration and sclerotherapy was an efficient technique with a higher recurrent rate; thus, these investigators recommended aspiration and sclerotherapy for patients at high-risk for surgery or avoiding surgery.  Furthermore, included RCTs had low methodological quality, low sample size, and invalidated instruments for outcome assessment.  Moreover, these researchers stated that there is a great need for further methodologically rigorous RCTs with the registered protocol.

Prolotherapy for the Treatment of Chronic Tendinopathy of the Foot

Chowdhary et al (2023) reported on the case of a 65-year-old female recreational skier and avid walker who presented with a several-month history of right ankle and foot pain.  The patient's pain began without inciting event and was described as a constant aching pain aggravated by downhill walking and alleviated with rest.  She was diagnosed with right distal tibialis anterior tendinopathy with partial thickness tear noted on MRI and musculoskeletal US.  Given symptoms recalcitrant to conservative measures, the patient opted to pursue an US-guided prolotherapy injection and a course of PT; unfortunately, she did not have any improvement in symptoms.  The patient subsequently underwent US-guided percutaneous ultrasonic tenotomy and debridement of the distal tibialis anterior tendon, followed by a post-procedure rehabilitation protocol of PT with transition to home exercise program with complete resolution of her pain.  The authors concluded that prolotherapy, and percutaneous ultrasonic tenotomy and debridement are 2 therapeutic modalities that showed promise in the treatment of painful, chronic tendinopathy.

Prolotherapy for the Treatment of Low Back Pain

Pires et al (2023) stated that chronic LBP is defined as pain lasting longer than 3 months and is one of the conditions with the most significant social impact.  Treatment is complex and includes proliferative agents used in prolotherapy.  The mechanism of prolotherapy is unclear; however, osmotic agents (hypertonic solutions of dextrose or glucose) cause cellular rupture and an inflammatory response that releases cytokines and growth factors that results in scarring and re-innervation.  Subjects were patients with chronic LBP (greater than 12 weeks) who were non-traumatic and unresponsive to at least 1 month of PT.   All subjects were followed-up at a return visit at 1, 3, and 6 months for pain assessment using validated pain questionnaires and scales.  A total of 19 patients were included in the conservative group and 19 in the glucose group, with the majority being women (57.9 %).  Subjects were between 47 and 59 years of age (39.5 %), mixed race (76.33 %), married or in a committed relationship (73.7 %), and had completed the study for 5.2 years.  Overall mean body mass index (BMI) was 27.3 ± 4.4 kg/m2 and was higher in the conservative group (28.0 ± 4.7 kg/m2 ).  The groups showed differences in VAS scores, with median and amplitude values close to each other between the time-points evaluated and increasing values in the glucose group, which had significantly higher values for this scale at the 3rd evaluation (p = 0.031).  When comparing the Rolland-Morris scale scores between the groups, there was a significant difference only in the 3-m assessment ( p = 0.021).  In the follow-up assessment, both groups showed significant improvement between T0 and the other assessment time-points (p < 0.05) in all evaluations.  The authors concluded that both groups significantly improved on the evaluated scales during follow-up.  Overall, no effects were attributable to the glucose components or the prolotherapy protocol.  Moreover, these researchers stated that further clinical trials and meta-analyses are needed to verify which protocol is more effective in prolotherapy for the treatment of LBP.

The authors stated that drawbacks of this study included the lack of standardization of the most effective dose, and these values were not always available in other studies.  Furthermore, the duration and frequency of follow-up may result in under-reporting of pain scores, and effective treatment may be complex without a multi-modal and multi-disciplinary approach.


References

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