Dextrose Prolotherapy for Upper-Extremity Musculoskeletal Pain in Hypermobile Ehlers-Danlos Syndrome: A Systematic Review

Abstract

01 · Introduction

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.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

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.

02 · Methods

Objective. 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 treatment of lower extremity injuries, prolotherapy solutions containing P2G, pumice, PRP, bone marrow, lipoaspirate, stem cells, or sodium morrhuate. 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.

Outcomes. 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.

03 · Results

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 subluxation.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.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 an RCT of 29 patients to determine if dextrose or lidocaine was superior in treating TMJ dysfunction.¹⁸ At 12 months the dextrose group had greater improvement in both jaw pain and dysfunction compared to the lidocaine group.¹⁸ That same year, an RCT in 40 patients used dextrose trigger point injections for TMJ dysfunction and hypermobility.¹⁹ At 3-month follow-up the dextrose group outperformed the control group in pain and pressure thresholds.¹⁹

In 2016, Cömert & Güngörmüş conducted an RCT of 30 patients with TMJ hypermobility; with 3 monthly injections and a 12-month follow-up, there were no differences between the treatment and saline group.²⁰ The protocol differed from trials that supported dextrose prolotherapy’s use in TMJ subluxation by using only 3 injections rather than four.^16,18,19 It would be advisable that patients receive 4 treatments spaced six weeks apart for best outcomes. Three notable case series investigating TMJ pathology all showed noticeable improvement in TMJ subluxation compared to baseline.^21–23

Cervical Spine

Craniocervical instability is often present in hEDS, resulting in laxity in the skull and cervical ligamentous connections.²⁴ Cervical instability can lead to neuronal injury due to 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 survey of 94 CMPS patients, 18.5% displayed joint hypermobility syndrome.²⁷ Kim and colleagues administered three 5% dextrose trigger point injections to 64 patients; compared to saline and lidocaine, the dextrose group experienced superior improvement in pain.²⁸ Another RCT compared 5% dextrose to saline in 40 patients with Myofascial Pain Syndrome under ultrasound guidance with a one-month follow-up; dextrose provided a prolonged beneficial effect compared to saline.²⁶ Lastly, a 2020 retrospective case series tracked 45 MPS patients a month after treatment.²⁹

Rotator Cuff

Shoulder instability, rotator cuff, and labral tears are prevalent in hypermobile patients.³¹ Patients respond well to physical therapy and may also benefit from supplemental dextrose prolotherapy.³¹ Bertrand and colleagues performed the first RCT for rotator cuff pathology.³² Seventy-three patients received three monthly injections of either 25% dextrose or saline with a physical therapy program; the dextrose group reported superior long-term pain improvement and satisfaction compared to placebo.³² Turkish researchers performed the largest RCT to date in 120 patients with chronic rotator cuff lesions; 92.9% of the treatment group reported excellent or good outcomes compared to 56.8% in the exercise control group.³³

Another study evaluated ultrasound-guided dextrose prolotherapy versus corticosteroids for supraspinatus tendinopathy in 36 patients; there were significant differences from baseline in each group at 6 months, but no inter-group differences.³⁴ A similar study in 31 patients using 20% dextrose found greater improvement in pain, function, and range of motion versus saline at 2 weeks, which did not sustain through 6 weeks.³⁵ Chang et al performed the most recent RCT in patients with rotator cuff disease and bursitis; 50 patients received three bursal injections of 15% dextrose or saline. Dextrose may increase tissue stiffness under elastography, but there were no intergroup differences in pain, function, or disability.³⁶

Lateral Epicondylitis

The laxity of the elbow joints in hEDS puts excessive strain on the forearm flexor and extensor tendons, resulting in medial and lateral epicondylitis.³⁷ In a pilot RCT, 24 patients received three injections of 50% dextrose or saline, with significant improvements in pain and quality of life and no adverse effects.³⁸ Carayannopoulos et al compared dextrose prolotherapy to steroids in 24 patients; both improved from baseline but there were no between-group differences.³⁹ Bayat and colleagues (2019) compared dextrose versus corticosteroid with a single injection plus physical therapy; at 3 months both improved, with dextrose showing slight benefit in pain and functionality.⁴⁰

In 2013, Rabago and colleagues conducted a 3-arm RCT of 26 patients (dextrose, dextrose-morrhuate, and “wait and see”); both dextrose groups showed superior improvements in the Patient-Rated Tennis Elbow Evaluation and grip strength at 16 weeks, with no MRI changes.⁴¹ Two 2020 studies compared 15% dextrose to saline and to HA respectively, and both found dextrose superior — further validating its use for lateral epicondylitis.^42,43

Wrist and Hand

Hypermobility of the proximal interphalangeal joints of the fingers is common in hEDS patients and 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 RCT for finger and thumb OA in 2000; 27 patients with 150 symptomatic OA joints received 15% dextrose or 0.075% xylocaine, and the dextrose group experienced superior benefit in active pain and increased flexion range of motion.⁴⁴ In 2014, Jahangiri and colleagues performed an RCT on 60 participants with first carpometacarpal joint OA; after 6 months, the dextrose group performed significantly better in pain and functionality than control.⁴⁵

Table 1

Evidence-level summary compiled from the studies reviewed; see the Results section and references for detail. No meta-analysis was performed due to protocol heterogeneity.

04 · Discussion

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 those looking for a minimally invasive alternative to surgery. Considering the many orthopedic benefits of dextrose prolotherapy, coverage of this non-operative treatment could significantly decrease the cost of care for many patients.

An important step in this process is to have a standard protocol for 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 reproducibility. Nevertheless, there is comparable flexibility in standardizing steroid injection therapies. Similarly, standardization of a dextrose prolotherapy protocol need not adhere to a single dictum, but rather be guided by 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 are fairly recent and there is a shift in research towards hypermobility. Some limitations of this review include publication bias, where manuscripts containing negative results were not published. Additionally, most studies had different dextrose prolotherapy protocols, injection intervals, and follow-up times, which leads to heterogeneity in summarizing results.

05 · Conclusion

The objective of this review was to bring awareness to hEDS and to 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 — of 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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This review is provided for education and professional reference and reflects the cited literature; it is not medical advice and does not create a physician–patient relationship. Dextrose prolotherapy protocols vary and are not universally insurance-covered. The Fascia Institute and Treatment Center® · 2520 Harvard Ave, Ste 2B, Metairie, LA 70001 · (504) 704-1254.