Rachel Turner, Brent Shaw, Catherine Kingry, MD, Jacques Courseault, MD, CAQSM, FAAPMR


Hypermobile Ehlers-Danlos syndrome (hEDS) is the most common subtype of Ehlers-Danlos syndromes, which manifests as the most common connective tissue disorder, affecting at least 1 in 500 patients. Dextrose prolotherapy is a promising treatment for upper extremity pain. The Tulane Hypermobility and Ehlers-Danlos Clinic has noticed a significant benefit in prolotherapy treatment in patients.


The objective is to demonstrate the documented uses of dextrose prolotherapy for treating various upper extremity musculoskeletal injuries in both hypermobile and non-hypermobile patients.

Literature Survey

Data sources include qualitative dextrose prolotherapy studies in upper extremity musculoskeletal conditions. Constraints include limited data on intervention, varying dextrose prolotherapy protocols, injection intervals, and follow-up times. No time parameters.


A comprehensive search was completed to identify studies addressing upper extremity musculoskeletal conditions using dextrose prolotherapy. Three 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.


This review includes 26 prolotherapy studies that utilized varying dextrose concentrations from 5% to 50% in cranial, rotator cuff, epicondylar, wrist, hand, and cervical injections. The 26 studies included 20 randomized control trials (RCTs) and 6 case series. At present, management of hEDS is a variable endeavor, commonly focusing on symptomatic relief of joint laxity and chronic pain. As an outpatient, non-invasive procedure that is more cost-effective than surgical alternatives, dextrose prolotherapy has demonstrated positive results as a treatment modality for many musculoskeletal conditions. However, there are no well-established protocols for administration and many insurances do not cover this treatment. Our hope is that dextrose prolotherapy will become a recognizable and readily covered treatment for hEDS management.


Currently, there is no literature that directly investigates the therapeutic benefit of dextrose prolotherapy on hEDS patients. This review provides evidence that dextrose prolotherapy alleviates symptoms in analogous upper extremity pathologies, each demonstrating the benefit of dextrose prolotherapy with Level 1, 2, 3 or 4 evidence.


Musculoskeletal Conditions, Myofascial disorders/pain, Sports Medicine, Connective Tissue Disorders


The Ehlers-Danlos syndromes (EDS) are a group of genetic, connective tissue disorders that affect the skin, bones, joints, and other organs of the body due to abnormal collagen structure or processing. There are currently thirteen identified subtypes of EDS, and all share some degree of joint laxity and skin/soft tissue manifestations. Hypermobile Ehlers-Danlos syndrome (hEDS) is the most common, representing 80-90% of cases of EDS.1 hEDS affects at least 1:500 according to most recent prevalence studies, but prevalence may be higher.2 Hypermobility may have a prevalence as high as 30% of the population.3

The Beighton score is a tool used to assess joint hypermobility. The tool is a 9-point yes-or-no checklist that grades a patient’s ability to perform four bilateral motions and one unilateral motion to demonstrate hypermobility. In Figure 1 the Beighton criteria include: (A) forward flexion of the trunk with the knees fully extended so that the palms of the hands rest flat on the floor, (B & C) hyperextension of the right and left elbows beyond 190 degrees, (D & E) hyperextension of the right and left knees beyond 190 degrees, (F & G) opposition of the right and left thumbs to the flexor surface of the forearms, and (H & I) hyperextension and dorsiflexion of the right and left fifth fingers beyond 90 degrees.4

Hypermobile Ehlers-Danlos Syndrome

Over time, patients begin to experience the potential negative consequences of joint hypermobility. Loose joints over time can lead to early fibrotic/arthritic joints, osteoarthritis (OA), and chronic joint and limb pain. In one survey, 28 out of 28 subjects with hEDS aged 20 and over reported struggling with some type of chronic pain, with 24 of them reporting it as a progressive problem.5 Eighty-eight percent of the total hEDS respondents reported taking pain medications, and 51% reported using some form of opioid. As hEDS patients progress from a “hypermobility” phase to a “pain” phase, and finally to a “stiffness” phase, their longtime history of discomfort compels many hEDS patients to explore numerous coping strategies, suggesting that no one approach is uniformly successful. Hence, the management of hEDS primarily focuses on relieving symptoms, improving quality of life, and preventing further complications.

The lack of efficacy in many pain treatments is the inability to approach the problem at its source: the repair of the fragile connective tissue causing hypermobility.1 Dextrose prolotherapy is a favorable option as it aims to find equilibrium between tissue repair and breakdown. Dextrose prolotherapy has yielded positive results in clinical research involving many musculoskeletal conditions shown in Table 1. It is an outpatient procedure that is more cost-effective than surgery alternatives and can provide pain relief and joint stabilization fairly quickly.1 The objective is to demonstrate the documented uses of dextrose prolotherapy for treating various upper extremity musculoskeletal injuries in both hypermobile and non-hypermobile patients.

Dextrose Prolotherapy

Dextrose prolotherapy has been used since the time of Hippocrates to heal injuries. Dr. George Hackett, an orthopedic surgeon, was the first clinician to establish injection criteria for dextrose prolotherapy use in tendon and ligament pathology for different anatomical areas.6 Hypertonic dextrose is considered an osmotic irritant solution. When hypertonic dextrose is injected into damaged areas around muscle, tendon, ligament, joint, and cartilage, the body repairs injured tissue and stimulates the growth of healthy tissue.6 It is believed that the irritant stimulates the natural healing cascade by triggering an initial local inflammation that releases growth factors and cytokines involving bleeding and inflammation.7 In a few weeks there is tissue proliferation noted and remodeling that takes months.7 These mediator molecules cause chemomodulation, leading to proliferation and strengthening of new connective tissue, joint stability, and a reduction in pain and dysfunction.8 Dextrose prolotherapy is hypothesized to reverse the course of the disease by strengthening the integrity of supporting joint tissues to reduce hypermobility.



The aim of this study was to systematically review dextrose prolotherapy for treating various upper extremity musculoskeletal injuries in both hypermobile and non-hypermobile patients.

Data Sources and Selection Criteria

Electronic databases PubMed, Healthline, OmniMedicalSearch, Medscape, and EMBASE were searched from 1990 to November 2021. The search was performed to the specifications outlined by a dextrose prolotherapy review performed by Hauser in 2016. Keywords used for the search included prolotherapy, dextrose, regenerative injection therapy, and musculoskeletal pain. Inclusion criteria were the injection of human subjects, published in a peer-reviewed journal, and use of dextrose as the sole prolotherapy proliferant. Exclusion criteria included the use of treatment of lower extremity injuries, prolotherapy solutions containing P2G, pumice, PRP, bone marrow, lipoaspirate, stem cells, or sodium monrrhuate. There was no lower limit placed on sample size due to the small overall number of published trials. Non-English studies were considered if they met inclusion criteria, provided an abstract in English, and presented sufficient tabular/graphic data for data abstraction.


Studies that investigate the efficacy of injection-based therapies to treat musculoskeletal pain assess change in pain intensity from baseline with patient-reported ratings, usually with the visual analog scale (VAS) or numerical rating scale (NRS). Changes in pain scores sufficient for clinical relevance can be determined by applying the minimal clinically important change (MCID) criteria.9 A reduction of two points represents the MCID using NRS10 and a decrease of ≤1.5 points with VAS and NRS represents a clinically irrelevant change in pain self-rating.11,12 Study heterogeneity and limited RCTs prevented the aggregation of statistical data necessary to perform a meta-analysis.



Temporomandibular joint syndrome

hEDS patients are at increased risk for spontaneous dislocation of temporomandibular joints (TMJ), which can also be one of the primary symptoms reported in patients with hEDS.13 Weakness of the lateral ligament, sphenomandibular ligament, and stylomandibular ligament supporting the TMJ has a close association with its supplication.14 These patients usually turn to surgery to limit the range of motion of the condyle, however, dextrose prolotherapy may improve joint and peri-articular ligament integrity of the TMJ.15

In 2011, Refai et al performed the first study that investigated dextrose prolotherapy’s effect on TMJ dislocation.16 Twelve patients were randomly assigned to either a treatment group that received four 10% dextrose injections 6 weeks apart or to a placebo group. Dextrose prolotherapy provided decreased pain, improved functionality, and quality of life without significant side effects. In 2018, Mustafa et al investigated if the concentration of dextrose would have any effect on the benefit of TMJ treatment using dextrose prolotherapy.17 The three treatment groups of 10%, 20%, and 30% dextrose, all demonstrated improvement of clinical symptoms after treatment and compared to placebo. No concentration showed superior improvement over the others. In 2020, Zarate et al. performed a randomized control trial of 29 patients to determine if dextrose or lidocaine was superior in treating TMJ dysfunction.18 At 12 months the dextrose prolotherapy group had greater improvement in both jaw pain and dysfunction compared to the lidocaine group.18 In that same year, a randomized control trial was performed in 40 patients using dextrose trigger point injections to relieve symptoms of TMJ dysfunction and hypermobility.19 At 3-month follow-up the dextrose group outperformed the control group in terms of improvements in pain and pressure thresholds.19

In 2016, Cömert & Güngörmüş conducted a randomized control trial of 30 patients with TMJ hypermobility. These patients were injected with 3 monthly injections and at a 12-month follow-up, there were no differences between the treatment and saline group.20 The injection protocol was different from those trials that supported dextrose prolotherapy’s use in TMJ subluxation by patients only receiving 3 injections compared to four found in other trials.16,18,19 It would be advisable moving forward that patients receive 4 treatments spaced at six weeks apart to provide the best outcomes.

There have been three notable case series that investigated TMJ pathology, all of which showed noticeable improvement in TMJ subluxation compared to baseline.21-23

Summary Regarding TMJ Pathology

There are evidence-based randomized control trials to demonstrate dextrose prolotherapy’s benefit in treating TMJ dislocation. Additional trials performed exclusively on an hEDS population would be beneficial to investigate further.

Cervical Spine

Craniocervical instability is often present in hEDS. Craniocervical instability often results in laxity in the skull and cervical ligamentous connections.24 Cervical instability can lead to neuronal injury due to the stretching and deformation of cervical ligaments.24 Two studies investigated the potential for dextrose prolotherapy to improve cervical instability with encouraging results.25,26

Myofascial Pain Syndrome

Cervical myofascial pain syndrome (CMPS) is common amongst hEDS patients.27 In a study where 94 CMPS were surveyed, 18.5% displayed joint hypermobility syndrome.27 Trigger point injections with dextrose are a modality that is becoming more common.

Kim and colleagues administered three 5% dextrose trigger point injections to 64 patients.28 Compared to the saline and lidocaine groups, the dextrose group experienced a superior improvement in pain, suggesting a benefit to preferring dextrose for injection.28

Another randomized control trial compared  5% dextrose to saline in 40 patients with Myofascial Pain Syndrome.26 One series of trigger point injections were performed under ultrasound guidance with a one-month follow-up. At the conclusion of the study, the researchers found that dextrose provided a prolonged beneficial effect compared to saline.26

Lastly, a retrospective case series was performed in 2020 that tracked the progress of 45 MPS patients a month after treatment.29 The study found that 15% of dextrose prolotherapy injections were effective in reducing pain and symptom intensities.29


Summary Regarding Cervical Spine Pathology

Weak evidence supports dextrose prolotherapy’s benefit on cervical instability and Myofascial Pain Syndrome. Performing randomized control trials on treating cervical instability with dextrose prolotherapy would be a beneficial next step.

Rotator Cuff 

Shoulder instability, rotator cuff, and labral tears are prevalent in hypermobile patients with excessive joint range of motion.31 Patients respond well to physical therapy for these types of injuries and may also benefit from supplemental dextrose prolotherapy treatment.31

Bertrand and colleagues performed the first randomized control trial for patients with rotator pathology.32 Seventy-three patients were administered three monthly injections with either 25% dextrose or saline with a supplemental physical therapy program. The results demonstrated that patients who received the dextrose prolotherapy injections reported superior long-term pain improvement and satisfaction compared to placebo.32

Turkish researchers performed the largest RCT to date investigating dextrose prolotherapy’s benefit in 120 patients with chronic rotator cuff lesions.33 Differences in pain and functionality measures were found at final follow-up at one year after injection. Results demonstrated that 92.9% of patients in the treatment group reported excellent or good outcomes compared to only 56.8% in the control group who were treated with exercise.33

Another study evaluated the effect of ultrasound-guided dextrose prolotherapy injections versus corticosteroids for supraspinatus tendinopathy.34 Thirty-six patients were divided into two groups. In the first group, dextrose prolotherapy was injected under ultrasound into the supraspinatus tendon. In the second, corticosteroid was injected into the subacromial bursa. The results found that there were significant differences compared to baseline in each group at 6 months; however, there were no inter-group differences.34

A similar study investigated dextrose prolotherapy’s effect on supraspinatus pathology in 31 patients using 20% dextrose.35 The randomized control trial found that patients in the treatment group demonstrated greater improvement in pain, functionality, and range of motion compared to the control of 5 mL of saline at 2 weeks. Yet these effects did not sustain during the 6-week period.35

Chang et al have performed the most recent RCT investigating dextrose prolotherapy’s effect in patients with rotator cuff disease and bursitis.36 Fifty patients were divided into two groups which would receive three bursal injections of 15% dextrose or saline. The study found that the dextrose prolotherapy injection may increase tissue stiffness under elastography, but there were no intergroup differences with respect to pain, functionality, or disability assessment.36

Summary Regarding Rotator Cuff Pathology

A double-blind, randomized controlled trial comparing ultrasound evaluation healing between dextrose prolotherapy and placebo is needed. The study should evaluate pain score, function, and ultrasound imaging to determine the efficacy of treatments.

Lateral Epicondylitis

The laxity of the elbow joints in patients with hEDS puts excessive strain on the forearm flexor and extensor tendons resulting in medial and lateral epicondylitis.37 With the ability to strengthen weak ligaments and tendons via dextrose prolotherapy, physicians have hypothesized its benefit in treating lateral epicondylitis.

A randomized control trial investigating dextrose prolotherapy’s effect on lateral epicondylitis.38 In this pilot study, 24 patients were administered three injections of a 50% dextrose solution or saline and findings revealed significant improvements in pain and quality of life variables with no adverse effects.38

Carayannopoulos et al conducted a randomized control trial that compared the benefit of dextrose prolotherapy to that of steroids in patients with lateral epicondylitis.39 Twenty-four patients were given two injections of dextrose prolotherapy or steroid each a month apart. The results demonstrated that both groups showed improvements compared to baseline but there were no differences between the groups.39

Bayat and colleagues conducted another dextrose prolotherapy versus corticosteroid study for lateral epicondylitis was performed in 2019 with patients receiving only one injection in addition to physical therapy.40 At final follow-up at 3 months both groups showed significant differences compared to baseline, with dextrose prolotherapy showing slight benefit over steroid injection in pain and shoulder functionality variables.40

In 2013, Rabago and colleagues conducted a 3-arm randomized controlled trial of 26 patients with the groups being a dextrose group, a dextrose-morrhuate group, and a “wait and see” group.41 After three injections, the study concluded that both dextrose groups demonstrated superior improvements in the Patient-Rated Tennis Elbow Evaluation and grip strength tests at a 16-week follow-up. No MRI changes were found in any group.41

Lastly, there were two studies performed in 2020 that compared 15% dextrose use to saline and HA injections into the lateral epicondyle respectively.42,43 Both studies found that the dextrose injections were superior compared to HA and control, further validating its use to treat lateral epicondylitis.42,43


Summary Regarding Lateral Epicondylitis Pathology

There is considerable level 1 evidence to demonstrate that dextrose prolotherapy is a safe and effective modality in treating lateral epicondylitis. Additional research on medial epicondyle pathology would be beneficial; in addition to, research specific to the hEDS population.

Wrist and Hand

Hypermobility of the proximal interphalangeal joints of the fingers is common in hEDS patients, which can be entirely asymptomatic.31 Thumb disabilities are almost universal in hEDS patients. A painful unstable non-arthritic first CMC joint can be stabilized surgically, with a good prognosis, however dextrose prolotherapy aims to be a less invasive alternative.31

Reeves & Hassanein performed the only randomized control trial for finger and thumb OA in 2000.44 Twenty-seven patients with 150 symptomatic OA joints were split into two groups and were administered 15% dextrose or 0.075% xylocaine to the medial and lateral aspects of each finger joint. The results demonstrated that patients experienced superior benefit in active pain and increased flexion range of motion compared to control.44

In 2014, Jahangiri and colleagues performed a randomized control trial on 60 participants with first carpometacarpal joint OA.45 After 6 months, the dextrose group performed significantly better in respect to pain and functionality compared to the control group.45


Summary Regarding Wrist and Hand Pathology

Based on the limited evidence, dextrose prolotherapy has shown promise in treating finger and thumb arthritis. Additional studies would need to be performed to validate these results, in addition to investigating wrist OA in patients with hEDS.


Dextrose prolotherapy should be considered as a treatment plan in the hEDS population and various musculoskeletal conditions because of the good potential benefits noted in small studies in the general population. Dextrose prolotherapy is safe, cheap, and can be used in many upper extremity musculoskeletal conditions. Presently, many insurances do not cover dextrose prolotherapy, which places a financial burden on looking for a minimally invasive alternative to surgery. Considering the many orthopedic benefits of dextrose prolotherapy, coverage of this non-operative treatment can significantly decrease the cost of care for many patients. Our hope is that dextrose prolotherapy will eventually become a non-surgical option for hEDS patients given their limited treatment options.

An important step in this process is to have a standard protocol in the concentration of dextrose in addition to the volume and variant of local anesthetic. This review included more than 25 dextrose prolotherapy studies that injected varying dextrose concentrations from 5% to 50% with varying degrees of success. In our practice, we have used 25% dextrose with great success in treating hEDS patients. It will be important to standardize a protocol with concentrations and volumes of dextrose prolotherapy and local anesthetic to promote reusability. Nevertheless, there is comparable flexibility in standardizing steroid injection therapies, where a wide array of steroids may be used or particularly chosen for more favorable side effect profiles. Similarly, standardization of dextrose prolotherapy protocol need not adhere to the dictum, but rather be guided based on its efficacy and appropriateness to the situation.  Much research needs to be done at the level of randomized controlled trials to determine safety and efficacy across the board.

To date, there are no randomized control trials or retrospective case series investigating dextrose prolotherapy’s effect in a population of solely hEDS patients. Research is lacking across the board in hEDS patients but the studies reviewed in this paper with dextrose prolotherapy are fairly recent and there is a shift in research towards hypermobility across the board.

Some limitations of this review include publication bias, where manuscripts containing negative results or results that did not benefit the authors were not published. Additionally, most studies had different dextrose prolotherapy protocols, injection intervals, and follow-up times which leads to heterogeneity in summarizing results.


The objective of this review was to bring awareness to hEDS as well as provide the framework to conduct pilot studies on hEDS populations. Currently, there is no literature to our knowledge that directly investigates the therapeutic benefit dextrose prolotherapy has on hEDS patients. In this review of 26 dextrose prolotherapy studies; in which 18 were RCTs, evidence is provided that dextrose prolotherapy alleviates symptoms in analogous upper extremity pathologies. These results should be considered with caution since hEDS patients heal differently than non-hEDS patients; however, there is enough evidence to warrant further investigation.


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