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The role of regenerative medicine in chronic pain management

An overview of the developing uses and evidence for platelet-rich plasma in pain medicine

Within the speciality of pain management the use of regenerative medicine is a relatively new treatment option. Platelet-rich plasma therapy (PRP) in particular is attracting a lot of positive attention. PRP contains numerous growth factors and cytokines that potentially offer an alternative treatment modality to assist in the healing of multiple musculoskeletal issues. The use of PRP is expanding exponentially, creating new frontiers for the treatment of musculoskeletal and spinal pain.

The purpose of this overview is to highlight key aspects in the literature where PRP is being used to treat various ligament and tendon pathologies in keeping with the new guidelines from the American Society of Interventional Pain Physicians (2019).

History

The concept of using the body’s own inherent healing mechanism to assist in the repair, and to potentially replace or restore damaged tissue through the use of autologous or allogenic biologics, has always been considered a possibility. In the clinical setting, PRP began as early as the 1980s, when it was found to be effective in blood loss during cardiac surgery. Its effect on bone was then examined in the field of dentistry for its regenerative properties on bone maturation and formation. In time, its use in musculoskeletal medicine has grown, and a role in tendon and tissue healing has been heavily investigated. Over the last 10 years there has been an increase in the use of PRP among medical clinicians, especially for its potential in treating tendinopathy and degenerative cellular diseases. The clinical evidence now suggests the time has come to provide this as a treatment option for more individuals.

Why does PRP work?

In the early phase of any injury, the inflammatory phase predominates. Ice, rest, activity modification and anti-inflammatory medications are generally included in the current mode of management. Many injuries settle but, in some cases, local steroid injections are required. While steroids are the gold standard to reduce inflammation, they do little to directly promote the healing phase. Occasionally, even steroids fail to resolve the symptoms, leaving the individuals with a long uphill battle to recovery.

This is fundamentally where PRP therapy has an important role. PRP therapy can increase the rate of musculoskeletal healing by stimulating angiogenesis, cell proliferation, and chemotaxis. It has been demonstrated that PRP promotes healing in cases of tendinous and ligamentous injury and muscular strain and it has been utilised for the purpose of shortening the recovery period and it has helped improve the recovery time of athletes. PRP seeks to recruit and enhance the body’s own inherent healing mechanism to assist in the repair, and to potentially replace or restore, damaged tissue through the use of autologous or allogenic biologics.

How is PRP prepared?

Generally, the preparation of PRP involves obtaining autologous whole blood from the patient, followed by a centrifugation process to separate plasma from red blood cells and leukocytes. The method of isolation plays a role in the final concentration of platelets and leukocytes in the PRP preparation. What was once a complex ‘event’ has been simplified into a three-step process:

Withdraw a blood sample in a specific collecting tube.

Centrifuge the sample to separate the plasma, which is rich in several growth factors.

Reinject the product at the injury site. This is best undertaken using image guidance such as ultrasound or fluoroscopy to improve accuracy.

This preparation process, and the injection of the PRP, can be completed in a matter of minutes.

What does PRP contain?

Platelets, which are one of the main components in PRP, help mediate the release of several growth factors that are essential in the healing process. These include platelet-derived growth factor (PDGF), transforming growth factor (TGF-β), fibroblast growth factor (FGF), vascular endothelial growth factor (VEGF), epidermal growth factor (EGF), and insulin-like growth factor (IGF). These growth factors are essential for the three phases of healing: Inflammation, proliferation, and remodelling.

The proposed benefit of PRP is that it allows for the patient’s own blood to provide a high concentration of growth factors to promote healing at injury sites that have limited healing capacity due to blood supply. This matrix serves as a scaffold for sustained release of growth factors that drive chemotaxis and angiogenesis.

There are several basic science studies to support the use of PRP for tendon and ligament healing in the in vivo setting. PRP has been shown to:

a)   Induce tendon cell proliferation along with induction of angiogenic factors. 

b)   To have anabolic effects on tendon cells by increasing the total collagen synthesis in tenocytes. Collagen type I seems to be promoted by PRP and may help limit the development in fibrotic tissue. There is an important ratio between different types of collagen and a balance seems necessary to avoid increased fibrosis and reduced strength of a tendon.

What is the clinical evidence to support PRP?

The evidence in the literature reflects the greater use of the technique globally. Table 1 highlights regions in the body where there has been a significant (>50%) and sustained improvement (>six months) in pain and function.

a) Lateral epicondylitis

Also known as tennis elbow, PRP has shown very favourable results compared to traditional steroid injection. In a meta-analysis of randomised, controlled trials examining the use of PRP, it was reported that PRP was significantly more effective at reducing pain intensity compared to various controls in both short-term (<6.5 months) and long-term (>one year) follow-up periods. In 2017, a study was undertaken to compare outcomes between a single PRP injection and surgery for patients suffering from lateral elbow tendinopathy. It appears that both can give at least similar pain relief in the first 12 months but after two years, arthroscopy was superior to PRP in long-term pain and functional outcomes. Nevertheless, for some individuals a 15-minute bedside procedure annually may be the preferred option.

b) Rotator cuff tendinopathy

The use of PRP in rotator cuff pathology has come with mixed results in the literature. Early studies on augmenting rotator cuff repair with PRP have been inconsistent with regard to clinical outcomes. A more recent meta-analysis by Hurley et al (2018) examined 18 randomised, controlled studies comparing PRP to arthroscopic repair alone. Their study included over 1,147 patients and found that PRP had significantly decreased rates of incomplete tendon healing for small-medium and medium-complete tears. They also found a significant decrease in visual analog scores (VAS pain score) at 30 days and final follow-up compared to the control group.

c)  Patellar tendinopathy

Patellar tendinopathy, otherwise known as ‘Jumper’s knee’, is characterised by chronic pain as a result of overuse. The clinical evidence suggests PRP can improve pain and function, with up to 22-to-81 per cent of patients able to return to their pre-symptom level of activity.

The number of PRP injections has also been shown to have an effect on the outcome of the treatment, with two injections found to improve outcomes significantly more than a singular injection.

d) Achilles tendinopathy

The Achilles tendon is a conjoined structure composed of the tendinous regions of the superficial posterior compartment musculature. The tendon resists forces up to 12 times’ body weight during exercise and is among the strongest in the body. Despite its robust structure, it is also among the most frequently ruptured tendons in the lower extremity and accounts for 20 per cent of major tendon injuries. Due to its relative non-invasiveness and minimal risk, PRP injections are being investigated with hopes of improving tendinopathy outcomes. Unfortunately, the initial results are not very encouraging.

e)  Ulnar collateral ligament injury

Injury to the medial ulnar collateral ligament (MUCL) occurs as a result of extraneous valgus loads and is common in overhead-throwing athletes. A fully torn ligament or one that has not responded favourably to conservative treatment will be treated surgically; however, success rates have varied from 83 to 90 per cent for a return to the sports field by nine-to-12 months’ post-surgery. A case study by Hoffman et al detailed the outcome of an MUCL reconstruction in a 25-year-old professional baseball pitcher that was augmented with a dermal allograft reconstituted in PRP and mesenchymal stem cells. The authors found that their patient was able to return to pitching by four months’ post-op.

Despite various case reports, there are no available randomised, controlled trials examining the effectiveness of PRP on MUCL and it is still unclear whether PRP expedites return to play in the conservative management of UCL injuries.

f)  Anterior cruciate ligament (ACL)

The ACL is vital to the stability of the knee and its rupture requires surgical intervention to restore this functionality. A systematic review by Figueroa et al regarding ACL repair with the aid of PRP showed variable results in terms of clinical outcomes, bone tunnel healing/widening, and graft maturation.

The use of PRP may show more promise in partial tears. A systematic review by Di Matteo et al included two studies of PRP used for partial ACL tears, which showed that between 70 and 84 per cent of patients return to their previous level of activity without surgery. Initial research regarding the use of PRP to treat ACL injuries shows promise in terms of its ability to help induce cell growth for various grafts; however, there is not sufficient research to conclude the best composition of PRP injections to induce the maximal amount of healing.

g)  Other options

With the ease of preparation, improved ultrasound accessibility and a growing awareness in the medical community, the probability is that different tendons and ligaments are going to be injected with PRP. For refractory cases such as gluteal tendonitis, ankle ligament and hand injury, the therapy will continue to open-up simple treatment options for more individuals. The initial feedback is very encouraging, both in terms of pain reduction and improved functional capacity. Capturing this data in a form that can be shared to advance the treatment is an important challenge.

While regenerative PRP management can be provided independently, it should be provided in conjunction with other modalities of treatment, including a structured exercise programme, physical therapy and behavioural therapy, along with the appropriate conventional medical therapy as necessary. Appropriate precautions should be taken into consideration and followed prior to performing biologic therapy.

With greater experience and understanding, the use of regenerative medicine will continue to grow and advance new frontiers for the treatment of musculoskeletal and spinal pain. 

References on request

Disclosure

Dr Dominic Hegarty, (BSc, BMedSc, MB, MSc (Pain Management), PhD, FCARSCI, FFPMCAI, FIPP) is a Consultant
in Pain Management at the Mater Private Hospital, Cork.
Dr Hegarty does not receive reimbursement from any specific company to use or promote the technique or products mentioned in this article.

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