Prolotherapy in Musculoskeletal Disorders, Guideline for Orthopedic Application ()
1. Introduction
1.1. Background and Definition
Prolotherapy is defined as a nonsurgical regenerative injection technique that involves injecting sclerosing or proliferant substances into painful tendon insertion sites (entheses), ligaments, joints and adjacent joint spaces in single or several injection sessions to induce normal tissue growth in injured areas [1] [2] .
The term was first introduced by a general surgeon named George Hackett in 1956, who proposed that injecting sclerosing solutions could improve joint stability by tightening interarticular ligaments and joint capsules [1] [2] . The word “prolotherapy” consists of two following root words: The Latin “proles,” which means proliferation and offspring, and the English word “therapy” [1] . Dr. George Hackett initially formalized Prolotherapy injection protocols, discussing injecting small amounts of a solution into the affected site during several treatment sessions [4] .
1.2. Subtypes and Mechanism of Action
Prolotherapy has been considered an alternative treatment for a wide variety of painful musculoskeletal conditions that are usually refractory to standard therapies [4] . Protocol of injection varied from one condition to another, depending on several variables such as damage type and location, clinical severity, and practitioner preference [4] [5] . Prolotherapy is performed based on palpating tender points in affected sites [6] [7] , using anatomic landmarks [8] or under ultrasound or fluoroscopic guidance [5] [9] . There are multiple solutions used in prolotherapy, categorized into three major groups. Some agents are considered irritants (including phenol or Phenol-glycerin-glucose, guaiacol, and tannic acid), some are chemoattractants (sodium morrhuate), and others are known as osmotic agents (including hypertonic glucose, glycerin, and zinc sulphate) [10] . Even a mixture of these solutions can be used in treating musculoskeletal problems [7] . Chemoattractants act as vascular sclerosants and attract inflammatory mediators to the injury site [11] . Sodium morrhuate is the one and only member of this group [10] . Osmotic solutions create a hypertonic environment, leading to dehydration, cell rupture and osmotic shock, which in turn result in granulocytes and macrophages attraction and induce collagen deposition which ultimately stimulates tissue healing process. They also upregulate the expression of platelet-derived growth factor in injured areas [2] . Hypertonic dextrose (D-glucose) has been categorized as an osmotic agent. It is the most commonly used solution in practice that is water-soluble and considered one of the normal constituents of blood chemistry [1] . The third class, Irritants, directly attack cells and kill them by presenting their antigens at cellular surface through changing cell surface proteins [10] . In many of the earlier published studies, phenol-glycerin-glucose was included as an irritant substance, but it is no longer used today [11] . In vitro studies indicated that human fibroblasts and chondrocytes exposure to only 0.5% concentrations of dextrose have stimulated the production of several growth factors, which are essential to the functional and structural repair of tendinous and ligamentous tissues. These substances include platelet-derived growth factor, transforming growth factor β, epidermal growth factor, basic fibroblast growth factor, insulin-like growth factor, and connective tissue growth factor. In vitro studies demonstrate that the mentioned growth factors have promoted the expression of types 1 and 3 collagens which pertain to the growth of tendon, ligament, and cartilage. Growth factors production and cellular proliferation are the critical factors of tissue repair in prolotherapy injection. While using the concentrations of 0.5% dextrose prolotherapy showed promising results in experimental studies, dextrose concentrations higher than 10% are considered as inflammatory concentrations in clinics and be utilized as irritant agents in prolotherapy. Concentrations less than 10% are non-inflammatory [2] . Although the exact mechanism of action remains unclear, it is hypothesized that prolotherapy solutions may induce a local inflammatory response at the site of injection, which leads to fibroblast proliferation and subsequent collagen synthesis, resulting in stronger and tighter ligaments and tendons, reduction in pain and dysfunction and also improved joint stability and biomechanics [4] [5] .
The effect of prolotherapy in pain reduction is unclear, but investigations reported that dextrose could alleviate pain through blocking transient receptor potential vaniloid 1 (TRPV1) pain receptors and even modulate sensorineural pain receptors [1] .
In vitro studies demonstrated that in the environment of highly concentrated glucose, the expression of collagen type 1 and 3 genes are increased in fibroblasts, and the matrix protein aggrecan amounts is changed in chondrocytes, which could contribute to tissue regeneration in peri-articular structures. There is an increase in cellularity and fibrous components in the cartilage tissue in the hyperosmolar conditions [1] .
This review has especially focused on dextrose prolotherapy protocols, as it is the most common prolotherapy substance in practice [1] .
2. Technique and Protocol
Actual concentration of hyperosmolar dextrose may vary according to condition but the usual range is 12.5% to 25%. In intra articular injections, concentrations of 25% dextrose are most often used, and in peri-articular injections, 15% dextrose is usually the choice [1] . An anesthetic agent must be applied locally or as a co-injecting solution to minimize the patient’s discomfort during the procedure. Lidocaine is the most common, but procaine and pontocaine are also used [7] . The selection criteria for choosing between prolotherapy agents are not mentioned in none of studies that utilized prolotherapy as therapeutic procedure. Hyperosmolar D-glucose is the most usual agent and it also could be used in combination with sodium morrhuate. Procedure will be performed by an experienced, trained physician in several treatment sessions, dividing by weekly or monthly intervals [4] [12] . Usual injection intervals range from 2 to 6 weeks, and treatment sessions vary from 1 to 12 sessions or more [2] [4] [6] [7] . The procedure was accomplished by making multiple insertions within or adjacent to the damaged tissue, usually in one to three points to a maximum of 10 points, at each visit [2] [13] . Usual volume of injection is 0.5 to 1 ml. maximum total of injection volume is considered 5 ml at each session [6] . Target tissue characteristics determine the size of the needle, and usually, the smallest needle that can reach the target is selected [1] . Injection techniques in each indication is pragmatically defined and number of injection, injection volume, and needle size vary case by case in each category, regardingly, there is no particular unique protocol for prolotherapy injections that practitioners could benefit as a reference technique [1] . All injection steps must be performed under sterile conditions and by an expert physician [14] . Outcome assessment is usually performed months after treatment initiation to evaluate short-term and long-term effects of injection. Prolotherapy results in pain and stiffness reduction both at rest and activity levels, functional and range of motion (ROM) improvement, and size, strength, and laxity promotion in weakened ligaments and tendons [15] [16] [17] [18] [19] .
3. Prolotherapy in Orthopedics
Prolotherapy is widely used as an alternative treatment for many orthopedic indications, which can be categorized into the following groups:
Chronic low back pain (specific and nonspecific causes), neck pain, groin pain, and fibromyalgia [2] [4] [10] [20] ;
Osteoarthritis (knee osteoarthritis, fingers, and thumb osteoarthritis) [17] [19] ;
Tendinopathies (lateral epicondylosis, rotator cuff tendinopathy, patellar tendinopathy, Achillestendinopathy, plantarfasciopathy, Osgood-Schlatter disease, hip adductor tendinopathy, temporomandibular joint dysfunction) [1] [2] .
4. Chronic Low Back Pain
Chronic low back pain (CLBP) is defined by prolonged pain and dysfunction, which remains resistant to therapies for at least three months. CLBP is one of the most common debilitating factors in the middle-aged population. The most frequent indication for prolotherapy in musculoskeletal disorders is low back pain. Injection therapies have received interest in recent years, addressing specific and nonspecific causes of back pain. Sacroiliac joint dysfunction, refractory coccygodynia, and moderate to severe degenerative disc disease, which can lead to radiculopathy, are specific causes of CLBP, and the remaining conditions are counted as nonspecific [11] . Protocols for injection vary extensively but mostly include three to eight sessions of intra-ligamentous, intra-articular, or peri-articular injections at weekly or fortnightly intervals [10] . There is no agreement on the total injection volume for prolotherapy agents, but in most cases, physicians inject at least 20 ml of solution at each treatment session. Some studies reported administering fewer amounts of solutions. Normal saline, lidocaine, and procaine injections are frequently used as control procedures [10] . Frequently measured outcomes are pain and disability. Prolotherapy is usually performed in association with other co-interventions. Supplementary interventions are performed prior to injections, during, or after the injections. Pre-injection procedures include triamcinolone injections into the tender points, injection of lidocaine, or spinal manipulation under intravenous sedation or analgesics application. Lumbar flexion and extension stretching exercises, spinal care guides, spine supporting braces, walking and commencing previously painful activities, paracetamol, zinc, manganese, and vitamin C can be prescribed during or after the prolotherapy session. It is hypothesized that a combination of prolotherapy with other routine treatment options can be more effective and enhances the outcomes [10] . As a result, when prolotherapy is used in combination with other treatments, reduction in pain and improvement in disability scores are more significant. However, the effectiveness of prolotherapy injection alone remains controversial, according to many studies [10] [13] . In addition to its role in treating CLBP, investigations showed that prolotherapy has more viable effects than corticosteroid injection on long-term outcomes of back pain(9). Transient increases in back pain and stiffness, diarrhea, and nausea are common side effects following injection that usually resolve in a few days. Post-injection headaches are reported only in a few cases and are considered a rare complication of therapy [10] (Table 1).
5. Osteoarthritis
Osteoarthritis (OA) is a chronic age-related degenerative condition affecting big weight-bearing joints [21] [22] . Knee is the most common joint affected by OA [23] . Knee Osteoarthritis (KOA) is the most frequent cause of knee pain [22] , which results in functional impairment and low quality of life [24] . Conservative treatments include lifestyle modifications, stretching exercises, nonsteroidal anti-inflammatory drugs, and new regenerative injection therapies [22] . Treatments are administered to reduce symptoms and improve joint ROM [25] . If conservative therapies fail to reach therapeutic goals, operative treatments are performed to help regain joint function [24] . Regenerative therapies include injecting corticosteroids, platelet-rich plasma, hyaluronic acid, ozone, botulinum toxin, and prolotherapy agent into the joint [25] . Guidelines of Osteoarthritis Research Society International (OARSI) and American College of Rheumatology/Arthritis Foundation have recommended the conditional use of prolotherapy for the management of knee-OA in 2019 [25] . Patients receive one to five doses of dextrose prolotherapy injection, with three as the most frequent [23] . Injection intervals vary between once weekly to once every two months, and the most common is once every month [23] . The concentration depends on the injection
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Table 1. Prolotherapy in chronic low back pain (Dechow, Davies et al., 1999, Yelland, Glasziou et al., 2004, Kim, Lee et al., 2010).
site, with a 10 to 25% range for intra-articular and 12.5 to 15% for extra-articular technique [23] [25] . Most commonly administered concentration is 25% in the intra-articular approach and 15% in extra-articular ones [23] . The recommended injection protocol is applying hyperosmolar dextrose in 2 - 6 sessions at monthly intervals to reach the maximum therapeutic effect [21] [25] . Comparator could be saline injection group, lidocaine, hyaluronic acid (HA), platelet-rich plasma, erythropoietin, autologous conditioned serum, botulinum neurotoxin A, radiofrequency waves, and physical therapy [26] [27] . Measured outcomes are pain through visual analogue score (VAS), functional status (Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) and Knee Injury and Osteoarthritis Outcome Score (KOOS) questionnaire), satisfaction assessment (36-item Short Form Health Survey (SF-36) questionnaire), and EuroQol-5D and Knee Pain Scale (KPS) questionnaire [27] . The most frequent outcomes used for assessment are WOMAC in the first place and VAS score in the second place, after WOMAC [27] . Prolotherapy has a significant impact on functional status and ROM improvement and pain reduction during different periods of follow-up [23] . Prolotherapy is associated with more significant results in comparison with control groups such as saline or lidocaine group [23] [27] . It has been shown that the effects of prolotherapy are long-term and could remain after 12 months or more after injection [22] [23] . Some studies reported sustained outcomes of prolotherapy even after 3.5 years [22] . Prolotherapy injection also has indicated promising results in management of OA complications in carpometacarpal joints in fingers. Long-term follow-up shows improvement in pain scoring scales and flexion ROM in the hand joints [17] [18] [19] [28] [29] [30] (Table 2).
6. Tendinopathy
Tendinopathy is defined by a triad of pain, swelling, and articular dysfunction in the affected site [31] . It involves a large variety of disorders, including rotator
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Table 2. Prolotherapy in osteoarthritis (Reeves and Hassanein, 2000, Rabago, Patterson et al., 2013, Sert, Sen et al., 2020, Sit, Wu et al., 2020).
cuff tendinopathy, lateral epicondylitis, Achilles tendinopathy, plantar fasciitis, Osgood Schlatter, and hip adductor tendinopathy. Tendinopathies are now considered non-inflammatory conditions resulting from collagen destruction, connective tissue growth, and neovascularization [32] . The strongest data supporting prolotherapy injection’s efficacy in treating chronic musculoskeletal conditions is extracted from the overuse tendinopathy problem studies [2] . Injections are performed by inserting a needle directly into or alongside the damaged ligament and tendons [5] [6] . Pain reduction and functional improvement have been reported as major outcomes of prolotherapy in tendinopathies [15] (Table 3).
6.1. Rotator Cuff Tendinopathy
Rotator cuff tendinopathy is chronic overuse tendinopathy that is determined by pain and weakness during shoulder movements of external rotation and elevation Shoulder pain is categorized as the third common cause of musculoskeletal pain, and tendinopathy of rotator cuff is the most common generator of that pain [8] . There is no consensus on the optimal treatment utilized for rotator cuff tendinopathy. Many typical treatments have been proposed, including exercise therapies, oral anti-inflammatory drugs, interventional therapies, and surgical procedures [8] [33] . Exercise therapy is generally counted as the first treatment choice in patients with impingement symptoms [34] . However, these exercises are often supplemented by adjunct therapies such as injection of corticosteroids, platelet-rich plasma, prolotherapy solutions, and hyaluronic acid. Corticosteroid is the most common substance in injections, but its long-term application is not recommended regarding to the deleterious effects that it can has on tendon integrity and further surgical outcomes [34] . Corticosteroid adjuvant therapy can be replaced by other injection therapies, such as prolotherapy. During the past decades, there has been emerging evidence in the effectiveness of prolotherapy for treating rotator cuff tendinopathy. They include various injection protocols and techniques to strengthen rotator cuff tendons, improve shoulder function and reduce pain. Initially, a landmark-based approach was performed for injecting prolotherapy solution; however, as we move forward, more accurate injections have been performed using ultrasound as a guide [8] . Dextrose injection in Rotator cuff tendinous structures results in a short-term improvement of pain, functional status, and ROM and is associated with compelling long-term follow-up results [8] . In long-term evaluation, prolotherapy has more significant effects than placebo injection on pain reduction [34] . Although, investigations suggest prolotherapy as an effective treatment, especially when performed through multiple-site injection techniques and in higher concentrations [33] . Compared to arthroscopic surgery techniques, the rate of complications is lower in prolotherapy. The variable results in prolotherapy studies may be related to the heterogeneity of treatment protocols varying in dextrose concentration, volume of injection, number of injection sites and injection intervals for rotator cuff tendinopathy [8] [33] [34] [35] .
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Table 3. Prolotherapy in tendinopathies (Maxwell, Ryan et al., 2007, Topol, Podesta et al., 2011, Yelland, Sweeting et al., 2011, Kim and Lee, 2014, Seven, Ersen et al., 2017, Ersen, Koca et al., 2018, Ahadi, Esmaeili Jamkarani et al., 2019, Yelland, Rabago et al., 2019, Akcay, Gurel Kandemir et al., 2020, Mansiz-Kaplan, Nacir et al., 2020, Nakase, Oshima et al., 2020, Asheghan, Hashemi et al., 2021, Raissi, Arbabi et al., 2021, Wu, Tu et al., 2022).
6.2. Lateral Epicondylitis
Lateral epicondylitis (tennis elbow) is a painful enthesopathy at the common extensor tendon in the elbow [36] . The disorder usually develops due to repetitive and intensive use of hand extensor muscles [37] . It is commonly observed in industrial workers and tennis players [38] . The condition occurs when normal tendon repair process fails to be completed, which leads to tendon degenerative changes and micro tears. The effect of local inflammation in pathology is slight [36] . Although most cases are self-limited and resolved between 6 to 12 months, 20% of cases became chronic and resistant to usual care [38] . Treatment options include operative and non-operative therapies. Physiotherapy and exercise-based rehabilitation are the primary choices for treatment. Second-line interventions include corticosteroid injection, shock wave therapy, braces and analgesics, and biological treatments [38] . Prolotherapy is a biological therapy that has shown promising results in pain improvement and functional assessment in terms of lateral epicondylitis treatment. Prolotherapy is widely compared with saline injection as a control group. Injection for the control groups is performed using the same technique of prolotherapy injection. It is hypothesized that the control injection can have a therapeutic effect by triggering cellular rupture and local bleeding [39] . There is no consensus on the number of treatment sessions, frequencies, concentrations, and dosages of the solution, and the injection techniques. The prolotherapy solution comprises hypertonic dextrose alone or in a mixture with other irritant substances, including sodium morrhuate, glycerin, or phenol. The concentration ranges from 10% to 25%, with 20% as the most frequent concentration. Treatment sessions widely vary in number and frequency. In most cases, one or more therapeutic sessions, with a mode of three, are accomplished for each patient every three or four weeks. In some studies, practitioners used peppering techniques for injection, while in other studies, they didn’t. The injection can be appliedto the points of tenderness around the elbow or, more commonly, into the epicondyle region and adjacent areas such as supracondylar ridge, annular and radial collateral ligament, and insertion of the extensor carpal muscles [39] [40] . Frequently measured outcomes include pain (VAS score), functional status of the elbow measured through disabilities of the arm, shoulder and hand (DASH)and The Patient-Rated Tennis Elbow Evaluation (PRTEE) questionairres, and handgrip strength. Different studies indicated that prolotherapy injection could significantly improve all of the mentioned outcomes [32] [37] [39] . Some studies reported that in comparison with other interventions, prolotherapy had significant effects on pain reduction and functional improvement in medium and long-term follow-up, while in the short-term, it doesn’t accompany substantial results [40] .
6.3. Achilles Tendinopathy
Achilles tendinopathy is the most frequent Achilles-related disorder in athletes and the general population [41] . The condition involves increased tendon thickness, decreased vascularity, and chronic tendinitis. Patients present with local pain and swelling over a specific area of a thickened tendon. Foot range of motion may be affected by decreased plantar flexion. Mid-portion Achilles tendinopathy and insertional Achilles tendinopathy are two major types of the disorder [42] . Various therapeutic modalities for Achilles tendinopathy include immobilization with night splints, physical therapy and eccentric loading exercises, shockwave therapy, nitrate oxide, cryotherapy, physiotherapy, and injection therapy [41] . Eccentric loading exercise (ELE) is considered a standard conservative treatment with promising results [6] . Prolotherapy can be used alone or as an additive to ELE treatment. The injection is performed at each tender point, usually located in the anterolateral and anteromedial border of the tendon and on the most posterior aspect of the tendon 2 - 7 cm away from the insertion point [41] . Treatment duration will be until the pain relief is achieved. Studies demonstrated that prolotherapy injection has more significant effects than eccentric loading exercise on short-, intermediate-, and long-term pain. It is also indicated that a combination of prolotherapy and ELE resulted in earlier stiffness reduction and activity improvement [41] . Some studies denied the beneficial therapeutic effect of prolotherapy alone when that doesn’t accompany eccentric loading exercises. Improvement in Victorian Institute of Sports Assessment—Achilles score (VISA-A) score increased vascularity, and reduction in tendon thickening can be expected as a result of prolotherapy injections in Achilles tendinopathy [43] .
6.4. Plantar Fasciitis
Plantar fasciitis is one of the most common causes of heel pain, associated with a high burden of disability [44] . The condition affects approximately 10% of the population and is more prevalent among runners and middle-aged people [45] . Clinical manifestation involves pain alongside the calcaneal enthesis early in the morning and during the first steps after prolonged standing or sitting [46] . Ethiopatology is characterized by collagen degeneration at the fascia attachment point due to micro tears resulting from overuse tendinopathy [47] . Diagnosis of plantar fasciitis is based on history and clinical evaluation, although ultrasonography can be used as a further diagnostic instrument in challenging cases. Plantar fascia thickness greater than 4 mm and the presence of hypoechogenic areas are sonographic features supporting the diagnosis of plantar fasciitis [48] . Common conservative therapies, including nonsteroidal anti-inflammatory drugs, stretching exercises, arch supports, dorsiflexion night splints, extracorporeal shockwave therapy (ESWT), physical therapy, and injection therapies considered first-line treatment [48] . The recovery rate is 70% - 80% in conventional therapies but nearly 10% of patients remain recalcitrant to treatment [44] [49] . Recent complementary treatment options such as ESWT and injection therapies showed compelling results in treating chronic and resistant cases. Prolotherapy is administered to improve the patient’s condition. Prolotherapy could be performed in one or more sessions, frequently in three sessions. Patients receive prolotherapy agents in a regular weekly order, usually every three weeks [46] [47] [48] [50] [51] . Studies reported that repeated injections are associated with the most accurate and effective results [51] . A concentration of dextrose 15% or 20% is frequently used [48] [52] . Injection is performed under palpation guidance or ultrasound guidance. It is recommended to use the ultrasound method, regarding its functionally better outcomes. Although studies determine that the palpation method is associated with a higher rate of disease recurrence [51] . In the ultrasound method, an ultrasound probe is placed over the fascia to reveal the thickness and echogenicity of different parts. A needle is inserted medially, perpendicular to the long axis of the transducer, approaching the most thickened and hypoechogenic area under sonographicguidance [49] [51] . In the palpation method, the injection can be administered in various techniques, including needle insertion into the most tender point of the heel [47] or injection at five different points of the fascia, including the attachment point of plantar fascia at heel (medial and lateral), at metatarsal bones (top of the first and fifth metatarsus), and at the middle part of the fascia [48] Peppering technique is considered in many injections [48] [49] . Corticosteroid injection, normal saline injection, platelet-rich plasma (PRP) injection, ESWT, and stretching exercises are common control groups used to compare prolotherapy effects with other procedures. Measured outcomes are categorized into three different classes, including pain assessment during rest and activity through VAS score, and NRS (numeric rating scale), functional assessment (foot functional index (FFI), foot and ankle ability measure (FAAM), The American Orthopedic Foot and Ankle Score (AOFAS), and sonographic features (plantar fascia thickness, echogenicity). Studies indicate that dextrose prolotherapy is associated with significant improvement in pain (at rest and activity), FFI and FAAM scores, and plantar fascia thickness and hypoechogenicity in patients with plantar fasciitis [47] [48] . Compared with non-active treatments (normal saline injection and exercises), prolotherapy is significantly better at improving short-term pain [53] . Prolotherapy has been more effective than corticosteroid injection in long-term outcomes, while corticosteroid injection demonstrated more significant improvements in short-term evaluation [44] . Results didn’t significantly differ between ESWT groups and prolotherapy [52] . PRP injection is more effective than dextrose prolotherapy in FFI score improvement [49] .
6.5. Osgood-Schlatter
Osgood-Schlatter disease (OSD) is a common cause of chronic knee pain associated with disabilities in daily work and sport participation [54] . Nonsteroidal anti-inflammatory drugs, knee paddling, and physical and surgical therapies are usual conservative treatments for OSD. Most patients respond to conventional therapies; however, some remain resistant [55] . Only a few studies aimed to assess the effectiveness of prolotherapy on Osgood-Schlatter, making it difficult to reach a reliable conclusion. Injections performed under sonographic guidance or based on anatomical landmarks. Deep infrapatellar bursa, infrapatellar fat pad, and superficial infrapatellar bursa are frequent injection sites when ultrasound guidance is applied [55] . Monthly injections in a total period of three months are a usual method [55] [56] . Hyperosmolar dextrose prolotherapy can result in a rapid asymptomatic sport participation, greater pain reduction during activity, and significant improvement in functional status which is measured by Victorian Institute of Sports Assessment—Patellar Tendon (VISA-P) score [2] [54] [55] [56] .
7. Contraindication
Absolute contraindications are similar to any other type of injection, including the presence of Cellulitis, Septic arthritis, Local abscess, and any other sign or symptom of the skin or joint infections, suffering active rheumatologic disorders, taking immunosuppressive drugs, and being allergic to corn. Relative contraindications includeacute gouty arthritis, acute fracture, bleeding disorders, taking anticoagulants, and patients revealing any sign of infection. According the fact that injecting irritant substances could cause bleeding and hematomas at injected area, this is assumed that prolotherapy in patients who are taking anticoagulants could lead to major bleeding complcations and should be avoided, excessive additional studies will be needed to prove this hypothesis [1] [4] .
8. Post-Injection Precautions
Patients will be advised to use acetaminophen with or without codeine in order to relieve post-injection discomfort and flare (500 - 650 mg every 4 hours as needed) [4] [57] [58] .
Ice massage for 5 - 10 min on the injection site is recommended after the procedure, the mechanism of effect is controversial [14] .
Participants must be discouraged from taking any nonsteroidal anti-inflammatory drugs (NSAIDs) after treatment sessions, it is hypothesized that NSAIDs interfere with beneficial effects of growth factors release by inhibiting prostaglandin pathway, further studies are needed to confirm this [57] .
Painful and weight-bearing activities must be avoided for 2 - 3 days after injection, and relative rest is recommended instead [59] .
9. Adverse Effects
Prolotherapy seems to be a safe procedure with limited side effects. However, some patients may experience a mild increase in pain and stiffness right after injection, as the most common side effect of prolotherapy. This could be explained by the prolotherapy mechanism of action, as stated before, the procedure can induce acute inflammation in the injured area which can lead to some undesirable effects including pain and discomfort. This mentioned inflammatory behavior does not raise concerns about whole nother serious adverse effects, as in vivo studies indicate a limited inflammatory response which regularly proceeds to reparatory responses instead of causing crippling problems. Headache, nausea and diarrhea are some of the other reported complications. A sense of fullness and occasional numbness, mild bleeding at the injection site, bruising, and developing post-injection flares within the first 72 hours after injection which usually subside in one or two days are other common adverse effects. Serious side effects are rare and include lightheadedness and spinal headaches, and nerve damage, allergic reactions, and infections. Neurologic impairment has been reported during perispinal injection with highly concentrated dextrose, which is linked with the methods that are no longer used in practice [1] [4] [11] [60] .
10. Conclusion
Prolotherapy is a regenerative therapeutic method which is consisted of injecting irritant solutions into the injured areas. Hyperosmolar dextrose is the most common agent. Administering proliferant substances can accelerate the tissue healing process by inducing cellular rupture and inflammatory response, leading to collagen deposition, cellular growth factor production, and regeneration. Although most of the chronic musculoskeletal conditions are considered non-inflammatory to date, resulting from collagen degeneration and connective tissue replacement. Regarding to the mentioned ethiopathology, prolotherapy has recently received notable attention in treating orthopedic musculoskeletal pain problems. There is no consensus on treatment protocol and various differences have been reported in substance dosage and concentration, injection intervals, needle size, site of injection and technique. Promising results have been shown in the term of pain and functional improvement when prolotherapy is administered for low back pain, osteoarthritis, and tendinopathies. The effectiveness is fully comparable with other treatment options. According to its reparative functions, this is suggested that dextrose prolotherapy can be utilized as an effective alternative therapy in treating chronic wounds. Although, more investigations are needed to confirm this hypothesis. In conclusion, prolotherapy is an effective, inexpensive, and available therapeutic option with limited side effects, which is associated with favorable results in different musculoskeletal conditions.
Author Contributions
All the authors have accepted responsibility for the entire content of this manuscript and approved submission.
Conflict of Interests
All the individuals who contributed to this manuscript are listed as authors. The authors have no competing interests to declare that are relevant to the content of this article.
References
- 1. Siadat, A.H. and Isseroff, R.R. (2019) Prolotherapy: Potential for the Treatment of Chronic Wounds? Advances in Wound Care, 8, 160-167. https://doi.org/10.1089/wound.2018.0866
- 2. Hauser, R.A., Lackner, J.B., Steilen-Matias, D. and Harris, D.K. (2016) A Systematic Review of Dextrose Prolotherapy for Chronic Musculoskeletal Pain. Clinical Medicine Insights: Arthritis and Musculoskeletal Disorders, 9, 139-159. https://doi.org/10.4137/CMAMD.S39160
- 3. Kim, S.R., Stitik, T.P., Foye, P.M., Greenwald, B.D. and Campagnolo, D.I. (2004) Critical Review of Prolotherapy for Osteoarthritis, Low Back Pain, and Other Musculoskeletal Conditions: A Physiatric Perspective. American Journal of Physical Medicine & Rehabilitation, 83, 379-389. https://doi.org/10.1097/01.PHM.0000124443.31707.74
- 4. Rabago, D., Slattengren, A. and Zgierska, A. (2010) Prolotherapy in Primary Care Practice. Primary Care, 37, 65-80. https://doi.org/10.1016/j.pop.2009.09.013
- 5. Ryan, M.B., Wong, A.D., Gillies, J.H., Wong, J. and Taunton, J.E. (2009) Sonographically Guided Intratendinous Injections of Hyperosmolar Dextrose/Lidocaine: A Pilot Study for the Treatment of Chronic Plantar Fasciitis. British Journal of Sports Medicine, 43, 303-306. https://doi.org/10.1136/bjsm.2008.050021
- 6. Yelland, M.J., Sweeting, K.R., Lyftogt, J.A., Ng, S.K., Scuffham, P.A. and Evans, K.A. (2011) Prolotherapy Injections and Eccentric Loading Exercises for Painful Achilles Tendinosis: A Randomised Trial. British Journal of Sports Medicine, 45, 421-428. https://doi.org/10.1136/bjsm.2009.057968
- 7. Dagenais, S., Haldeman, S. and Wooley, J.R. (2005) Intraligamentous Injection of Sclerosing Solutions (Prolotherapy) for Spinal Pain: A Critical Review of the Literature. The Spine Journal: Official Journal of the North American Spine Society, 5, 310-328. https://doi.org/10.1016/j.spinee.2004.09.011
- 8. Catapano, M., Zhang, K., Mittal, N., Sangha, H., Onishi, K. and de Sa, D. (2020) Effectiveness of Dextrose Prolotherapy for Rotator Cuff Tendinopathy: A Systematic Review. The Journal of Injury, Function, and Rehabilitation, 12, 288-300. https://doi.org/10.1002/pmrj.12268
- 9. Kim, W.M., Lee, H.G., Jeong, C.W., Kim, C.M. and Yoon, M.H. (2010) A Randomized Controlled Trial of Intra-Articular Prolotherapy versus Steroid Injection for Sacroiliac Joint Pain. Journal of Alternative and Complementary Medicine (New York), 16, 1285-1290. https://doi.org/10.1089/acm.2010.0031
- 10. Dagenais, S., Yelland, M.J., Del Mar, C. and Schoene, M.L. (2007) Prolotherapy Injections for Chronic Low-Back Pain. The Cochrane Database of Systematic Reviews, 2007, CD004059. https://doi.org/10.1002/14651858.CD004059.pub3
- 11. Distel, L.M. and Best, T.M. (2011) Prolotherapy: A Clinical Review of Its Role in Treating Chronic Musculoskeletal Pain. The Journal of Injury, Function, and Rehabilitation, 3, S78-S81. https://doi.org/10.1016/j.pmrj.2011.04.003
- 12. Dechow, E., Davies, R.K., Carr, A.J. and Thompson, P.W. (1999) A Randomized, Double-Blind, Placebo-Controlled Trial of Sclerosing Injections in Patients with Chronic Low Back Pain. Rheumatology (Oxford), 38, 1255-1259. https://doi.org/10.1093/rheumatology/38.12.1255
- 13. Yelland, M.J., Glasziou, P.P., Bogduk, N., Schluter, P.J. and McKernon, M. (2004) Prolotherapy Injections, Saline Injections, and Exercises for Chronic Low-Back Pain: A Randomized Trial. Spine, 29, 9-16. https://doi.org/10.1097/01.BRS.0000105529.07222.5B
- 14. Bayat, M., Raeissadat, S.A., Mortazavian Babaki, M. and Rahimi-Dehgolan, S. (2019) Is Dextrose Prolotherapy Superior to Corticosteroid Injection in Patients with Chronic Lateral Epicondylitis? A Randomized Clinical Trial. Orthopedic Research and Reviews, 11, 167-175. https://doi.org/10.2147/ORR.S218698
- 15. Chung, M.W., Hsu, C.Y., Chung, W.K. and Lin, Y.N. (2020) Effects of Dextrose Prolotherapy on Tendinopathy, Fasciopathy, and Ligament Injuries, Fact or Myth? A Systematic Review and Meta-Analysis. Medicine, 99, e23201. https://doi.org/10.1097/MD.0000000000023201
- 16. Scarpone, M., Rabago, D.P., Zgierska, A., Arbogast, G. and Snell, E. (2008) The Efficacy of Prolotherapy for Lateral Epicondylosis: A Pilot Study. Clinical Journal of Sport Medicine: Official Journal of the Canadian Academy of Sport Medicine, 18, 248-254. https://doi.org/10.1097/JSM.0b013e318170fc87
- 17. Reeves, K.D. and Hassanein, K. (2000) Randomized, Prospective, Placebo-Controlled Double-Blind Study of Dextrose Prolotherapy for Osteoarthritic Thumb and Finger (DIP, PIP, and Trapeziometacarpal) Joints: Evidence of Clinical Efficacy. Journal of Alternative and Complementary Medicine (New York), 6, 311-320. https://doi.org/10.1089/10755530050120673
- 18. Reeves, K.D. and Hassanein, K.M. (2003) Long-Term Effects of Dextrose Prolotherapy for Anterior Cruciate Ligament Laxity. Alternative Therapies in Health and Medicine, 9, 58-62.
- 19. Reeves, K.D. and Hassanein, K. (2000) Randomized Prospective Double-Blind Placebo-Controlled Study of Dextrose Prolotherapy for Knee Osteoarthritis with or without ACL Laxity. Alternative Therapies in Health and Medicine, 6, 68-74, 77-80.
- 20. Topol, G.A., Reeves, K.D. and Hassanein, K.M. (2005) Efficacy of Dextrose Prolotherapy in Elite Male Kicking-Sport Athletes with Chronic Groin Pain. Archives of Physical Medicine and Rehabilitation, 86, 697-702. https://doi.org/10.1016/j.apmr.2004.10.007
- 21. Wang, J., Liang, J., Yao, J., Song, H.X., Yang, X.T., Wu, F.C., et al. (2022) Meta-Analysis of Clinical Trials Focusing on Hypertonic Dextrose Prolotherapy (HDP) for Knee Osteoarthritis. Aging Clinical and Experimental Research, 34, 715-724. https://doi.org/10.1007/s40520-021-01963-3
- 22. Hassan, F., Murrell, W.D., Refalo, A. and Maffulli, N. (2018) Alternatives to Biologics in Management of Knee Osteoarthritis: A Systematic Review. Sports Medicine and Arthroscopy Review, 26, 79-85. https://doi.org/10.1097/JSA.0000000000000190
- 23. Arias-Vázquez, P.I., Tovilla-Zárate, C.A., Legorreta-Ramírez, B.G., Burad Fonz, W., Magaña-Ricardez, D., González-Castro, T.B., et al. (2019) Prolotherapy for Knee Osteoarthritis Using Hypertonic Dextrose vs Other Interventional Treatments: Systematic Review of Clinical Trials. Advances in Rheumatology (London), 59, Article No. 39. https://doi.org/10.1186/s42358-019-0083-7
- 24. Hassan, F., Trebinjac, S., Murrell, W.D. and Maffulli, N. (2017) The Effectiveness of Prolotherapy in Treating Knee Osteoarthritis in Adults: A Systematic Review. British Medical Bulletin, 122, 91-108. https://doi.org/10.1093/bmb/ldx006
- 25. Wee, T.C., Neo, E.J.R. and Tan, Y.L. (2021) Dextrose Prolotherapy in Knee Osteoarthritis: A Systematic Review and Meta-Analysis. Journal of Clinical Orthopaedics and Trauma, 19, 108-117. https://doi.org/10.1016/j.jcot.2021.05.015
- 26. Krstičević, M., Jerić, M., Došenović, S., Jeličić Kadić, A. and Puljak, L. (2017) Proliferative Injection Therapy for Osteoarthritis: A Systematic Review. International Orthopaedics, 41, 671-679. https://doi.org/10.1007/s00264-017-3422-5
- 27. Cortez, V.S., Moraes, W.A., Taba, J.V., Condi, A., Suzuki, M.O., Nascimento, F.S.D., et al. (2022) Comparing Dextrose Prolotherapy with Other Substances in Knee Osteoarthritis Pain Relief: A Systematic Review. Clinics, 77, Article ID: 100037. https://doi.org/10.1016/j.clinsp.2022.100037
- 28. Sit, R.W.S., Wu, R.W.K., Rabago, D., Reeves, K.D., Chan, D.C.C., et al. (2020) Efficacy of Intra-Articular Hypertonic Dextrose (Prolotherapy) for Knee Osteoarthritis: A Randomized Controlled Trial. Annals of Family Medicine, 18, 235-242. https://doi.org/10.1370/afm.2520
- 29. Rabago, D., Patterson, J.J., Mundt, M., Kijowski, R., Grettie, J., Segal, N.A., et al. (2013) Dextrose Prolotherapy for Knee Osteoarthritis: A Randomized Controlled Trial. Annals of Family Medicine, 11, 229-237. https://doi.org/10.1370/afm.1504
- 30. Sert, A.T., Sen, E.I., Esmaeilzadeh, S. and Ozcan, E. (2020) The Effects of Dextrose Prolotherapy in Symptomatic Knee Osteoarthritis: A Randomized Controlled Study. Journal of Alternative and Complementary Medicine, 26, 409-417. https://doi.org/10.1089/acm.2019.0335
- 31. Morath, O., Kubosch, E.J., Taeymans, J., Zwingmann, J., Konstantinidis, L., et al. (2018) The Effect of Sclerotherapy and Prolotherapy on Chronic Painful Achilles Tendinopathy—A Systematic Review Including Meta-Analysis. Scandinavian Journal of Medicine & Science in Sports, 28, 4-15. https://doi.org/10.1111/sms.12898
- 32. Apaydin, H., Bazancir, Z. and Altay, Z. (2020) Injection Therapy in Patients with Lateral Epicondylalgia: Hyaluronic Acid or Dextrose Prolotherapy? A Single-Blind, Randomized Clinical Trial. Journal of Alternative and Complementary Medicine (New York), 26, 1169-1175. https://doi.org/10.1089/acm.2020.0188
- 33. Robinson, D.M., Eng, C., Makovitch, S., Rothenberg, J.B., DeLuca, S., Douglas, S., et al. (2021) Non-Operative Orthobiologic Use for Rotator Cuff Disorders and Glenohumeral Osteoarthritis: A Systematic Review. Journal of Back and Musculoskeletal Rehabilitation, 34, 17-32. https://doi.org/10.3233/BMR-201844
- 34. Lin, M.T., Chiang, C.F., Wu, C.H., Huang, Y.T., Tu, Y.K. and Wang, T.G. (2019) Comparative Effectiveness of Injection Therapies in Rotator Cuff Tendinopathy: A Systematic Review, Pairwise and Network Meta-Analysis of Randomized Controlled Trials. Archives of Physical Medicine and Rehabilitation, 100, 336-49.E15. https://doi.org/10.1016/j.apmr.2018.06.028
- 35. Seven, M.M., Ersen, O., Akpancar, S., Ozkan, H., Turkkan, S., Yıldız, Y., et al. (2017) Effectiveness of Prolotherapy in the Treatment of Chronic Rotator Cuff Lesions. Orthopaedics & Traumatology: Surgery & Research, 103, 427-433. https://doi.org/10.1016/j.otsr.2017.01.003
- 36. Yelland, M., Rabago, D., Ryan, M., Ng, S.K., Vithanachchi, D., et al. (2019) Prolotherapy Injections and Physiotherapy Used Singly and in Combination for Lateral Epicondylalgia: A Single-Blinded Randomised Clinical Trial. BMC Musculoskeletal Disorders, 20, Article No. 509. https://doi.org/10.1186/s12891-019-2905-5
- 37. Ahadi, T., Esmaeili Jamkarani, M., Raissi, G.R., Mansoori, K., Emami Razavi, S.Z. and Sajadi, S. (2019) Prolotherapy vs Radial Extracorporeal Shock Wave Therapy in the Short-Term Treatment of Lateral Epicondylosis: A Randomized Clinical Trial. Painmedicine (Malden), 20, 1745-1749. https://doi.org/10.1093/pm/pny303
- 38. Zhu, M., Rabago, D., Chung, V.C., Reeves, K.D., Wong, S.Y. and Sit, R.W. (2022) Effects of Hypertonic Dextrose Injection (Prolotherapy) in Lateral Elbow Tendinosis: A Systematic Review and Meta-Analysis. Archives of Physical Medicine and Rehabilitation, 103, 2209-2218. https://doi.org/10.1016/j.apmr.2022.01.166
- 39. Akcay, S., Gurel Kandemir, N., Kaya, T., Dogan, N. and Eren, M. (2020) Dextrose Prolotherapy versus Normal Saline Injection for the Treatment of Lateral Epicondylopathy: A Randomized Controlled Trial. Journal of Alternative and Complementary Medicine (New York), 26, 1159-1168. https://doi.org/10.1089/acm.2020.0286
- 40. Arias-Vázquez, P.I., Castillo-Avila, R.G., Tovilla-Zárate, C.A., Quezada-González, H.R., Arcila-Novelo, R. and Loeza-Magaña, P. (2022) Efficacy of Prolotherapy in Pain Control and Function Improvement in Individuals with Lateral Epicondylitis: A Systematic Review and Meta-Analysis. ARP Rheumatology, 1, 152-167.
- 41. Sanderson, L.M. and Bryant, A. (2015) Effectiveness and Safety of Prolotherapy Injections for Management of Lower Limb Tendinopathy and Fasciopathy: A Systematic Review. Journal of Foot and Ankle Research, 8, Article No. 57. https://doi.org/10.1186/s13047-015-0114-5
- 42. Gross, C.E., Hsu, A.R., Chahal, J. and Holmes Jr, G.B. (2013) Injectable Treatments for Noninsertional Achilles Tendinosis: A Systematic Review. Foot & Ankle International, 34, 619-628. https://doi.org/10.1177/1071100713475353
- 43. Notarnicola, A., Tamma, R., Moretti, L., Panella, A., Dell’Endice, S., Zallone, A., et al. (2011) Effect of Shock Wave Treatment on Platelet-Rich Plasma Added to Osteoblast Cultures. Ultrasound in Medicine & Biology, 37, 160-168. https://doi.org/10.1016/j.ultrasmedbio.2010.10.016
- 44. Lai, W.F., Yoon, C.H., Chiang, M.T., Hong, Y.H., Chen, H.C., Song, W., et al. (2021) The Effectiveness of Dextrose Prolotherapy in Plantar Fasciitis: A Systemic Review and Meta-Analysis. Medicine, 100, e28216. https://doi.org/10.1097/MD.0000000000028216
- 45. Urits, I., Smoots, D., Franscioni, H., Patel, A., Fackler, N., Wiley, S., et al. (2020) Injection Techniques for Common Chronic Pain Conditionsof the Foot: A Comprehensive Review. Pain and Therapy, 9, 145-160. https://doi.org/10.1007/s40122-020-00157-5
- 46. Costantino, C., Vulpiani, M.C., Romiti, D., Vetrano, M. and Saraceni, V.M. (2014) Cryoultrasound Therapy in the Treatment of Chronic Plantar Fasciitis with Heel Spurs. A Randomized Controlled Clinical Study. European Journal of Physical and Rehabilitation Medicine, 50, 39-47.
- 47. Uğurlar, M., Sönmez, M.M., Uğurlar, Ö.Y., Adıyeke, L., Yıldırım, H. and Eren, O.T. (2018) Effectiveness of Four Different Treatment Modalities in the Treatment of Chronic Plantar Fasciitis during a 36-Month Follow-Up Period: A Randomized Controlled Trial. The Journal of Foot and Ankle Surgery: Official Publication of the American College of Foot and Ankle Surgeons, 57, 913-918. https://doi.org/10.1053/j.jfas.2018.03.017
- 48. Mansiz-Kaplan, B., Nacir, B., Pervane-Vural, S., Duyur-Cakit, B. and Genc, H. (2020) Effect of Dextrose Prolotherapy on Pain Intensity, Disability, and Plantar Fascia Thickness in Unilateral Plantar Fasciitis: A Randomized, Controlled, Double-Blind Study. American Journal of Physical Medicine & Rehabilitation, 99, 318-324. https://doi.org/10.1097/PHM.0000000000001330
- 49. Kim, E. and Lee, J.H. (2014) Autologous Platelet-Rich Plasma versus Dextrose Prolotherapy for the Treatment of Chronic Recalcitrant Plantar Fasciitis. The Journal of Injury, Function, and Rehabilitation, 6, 152-158. https://doi.org/10.1016/j.pmrj.2013.07.003
- 50. Raissi, G., Arbabi, A., Rafiei, M., Forogh, B., Babaei-Ghazani, A., Khalifeh Soltani, S., et al. (2021) Ultrasound-Guided Injection of Dextrose versus Corticosteroid in Chronic Plantar Fasciitis Management: A Randomized, Double-Blind Clinical Trial. Foot & Ankle Specialist, 16, 9-19. https://doi.org/10.1177/1938640020980924
- 51. Ersen, Ö., Koca, K., Akpancar, S., Seven, M.M., Akyıldız, F., Yıldız, Y., et al. (2018) A Randomized-Controlled Trial of Prolotherapy Injections in the Treatment of Plantar Fasciitis. Turkish Journal of Physical Medicine and Rehabilitation, 64, 59-65. https://doi.org/10.5606/tftrd.2018.944
- 52. Asheghan, M., Hashemi, S.E., Hollisaz, M.T., Roumizade, P., Hosseini, S.M. and Ghanjal, A. (2021) Dextrose Prolotherapy versus Radial Extracorporeal Shock Wave Therapy in the Treatment of Chronic Plantar Fasciitis: A Randomized, Controlled Clinical Trial. Foot and Ankle Surgery, 27, 643-649. https://doi.org/10.1016/j.fas.2020.08.008
- 53. Chutumstid, T., Susantitaphong, P. and Koonalinthip, N. (2022) Effectiveness of Dextrose Prolotherapy for the Treatment of Chronic Plantar Fasciitis: A Systematic Review and Meta-Analysisof Randomized Controlled Trials. The Journal of Injury, Function, and Rehabilitation, 15, 380-391. https://doi.org/10.1002/pmrj.12807
- 54. Wu, Z., Tu, X. and Tu, Z. (2022) Hyperosmolar Dextrose Injection for Osgood-Schlatter Disease: A Double-Blind, Randomized Controlled Trial. Archives of Orthopaedic and Trauma Surgery, 142, 2279-2285. https://doi.org/10.1007/s00402-021-04223-1
- 55. Nakase, J., Oshima, T., Takata, Y., Shimozaki, K., Asai, K. and Tsuchiya, H. (2020) No Superiority of Dextrose Injections over Placebo Injections for Osgood-Schlatter Disease: A Prospective Randomized Double-Blind Study. Archives of Orthopaedic and Trauma Surgery, 140, 197-202. https://doi.org/10.1007/s00402-019-03297-2
- 56. Topol, G.A., Podesta, L.A., Reeves, K.D., Raya, M.F., Fullerton, B.D. and Yeh, H.W. (2011) Hyperosmolar Dextrose Injection for Recalcitrant Osgood-Schlatter Disease. Pediatrics, 128, e1121-e1128. https://doi.org/10.1542/peds.2010-1931
- 57. Bertrand, H., Reeves, K.D., Bennett, C.J., Bicknell, S. and Cheng, A.L. (2016) Dextrose Prolotherapy versus Control Injections in Painful Rotator Cuff Tendinopathy. Archives of Physical Medicine and Rehabilitation, 97, 17-25. https://doi.org/10.1016/j.apmr.2015.08.412
- 58. Maxwell, N.J., Ryan, M.B., Taunton, J.E., Gillies, J.H. and Wong, A.D. (2007) Sonographically Guided Intratendinous Injection of Hyperosmolar Dextrose to Treat Chronic Tendinosis of the Achilles Tendon: A Pilot Study. American Journal of Roentgenology, 189, W215-W220. https://doi.org/10.2214/AJR.06.1158
- 59. Rabago, D., Mundt, M., Zgierska, A. and Grettie, J. (2015) Hypertonic Dextrose Injection (Prolotherapy) for Knee Osteoarthritis: Long Term Outcomes. Complementary Therapies in Medicine, 23, 388-395. https://doi.org/10.1016/j.ctim.2015.04.003
- 60. Dagenais, S., Ogunseitan, O., Haldeman, S., Wooley, J.R. and Newcomb, R.L. (2006) Side Effects and Adverse Events Related to Intraligamentous Injection of Sclerosing Solutions (Prolotherapy) for Back and Neck Pain: A Survey of Practitioners. Archives of Physical Medicine and Rehabilitation, 87, 909-913. https://doi.org/10.1016/j.apmr.2006.03.017