1. Corticosteroid Injections

Corticosteroids (CS) are commonly used joint injections as a treatment for pain relief; the aim of the CS injections is to reduce inflammatory markers, this could last from days to months, however, this varies in people and pathology.5, 6. The Food and Drug Administration (FDA) had previously shared a warning in 2014 regarding the safety aspect of these injections; patients should be made aware of these risks, including neurological adverse effects when injected close to the spine and must be considered before use.7 Evidence has shown that steroid injections can improve patients suffering with sciatica and lower back pain through a faster pain relief especially within the first week when compared to a water-based solution.8 The findings of a high-quality randomised control trial demonstrated that epidural steroid injections combined with local aesthetic compared to local anaesthetics alone when being used for disc herniation pathologies did not differ largely in the short term. We are unable to effectively compare these short-term results with the long-term as a meta-analysis was not performed.9 Some research has suggested CS can be ineffective although they have shown to be beneficial in the short term when compared to water or placebo injections. In conclusion CS injections can be used as a faster symptom management to alter the mechanical properties and aid the motion at the segment; the solution also contains anti-inflammatory properties to reduce the irritants present.8

2. Platelet-Rich Plasma Injections

Platelet-Rich Plasma (PRP) injections use the platelets collected from the patient’s own blood to stimulate the tissues when they are injected back, for the endothelial growth factors. PRP has been used for a variety of conditions, however, many of these studies only involve small sample sizes and more clinical trials are needed for post-PRP injection rehabilitation and protocols.9 PRP contain growth factors and cytokines which are needed for soft tissue healing and bone mineralisation, assisting the body’s own healing process.10 A previous study focuses on the use of the injections and its effect in tendons, they only used participants with healthy tendons and it cannot be categorized to degenerative disorders. The small clinical studies gave the patients eccentric exercises to do alongside the PRP and placebo injections, both groups showed an increase of patient satisfactory and this had no statistical difference. This could be due to using an invasive procedure as it raises patient expectation as well as doing an exercise programme and not the injection alone.11 PRP is used as a more conservative management in treating tendon problems commonly at the knee and elbow, previous clinical data has reported better functional recovery and reduced pain scores.12 Chronic tendons as well as muscle injuries can also benefit from PRP injections, this is due to the tissue restoration, it can have the desired effect of many of the population including recreational and elite athletes.13 In summary PRP injection is a more recent treatment approach with many avenues of optimal amount of solution to be explored, a lot of research is promising in the aim of using a more conservative approach and regenerative medicine.

3. Stem Cell Injections Stem

Cell Injections are a more recent research area; with the first reported case in 1998 and a lot of research focussing on the knee joint.11 The reasoning behind this is for articular cartilage lesions are more common in the knee joint, with the aim using embryonic or reprogrammed tissue for regenerative medicine. The articular cartilage is not well vascularised and the aim of these injections is to repopulate the cells in this area and stop further degeneration.6 Further studies have also focussed on the use of stem cell injections for treating Osteoarthritis (OA) demonstrating a longer process and can often lead to insignificant results due to the poor regeneration of chondrocytes when in the late stage of OA. This is seen as a desirable treatment option when successful, it is imperative to calculate the correct dose-size to create the optimal results although this is still under review.13 A meta-analysis looking at 18 studies which included a follow up period of 3-24months; the results showed that the dose-responsiveness rather than the number of stem cells, with the most efficient time being at three months however this was still a continued improvement. It was also reiterated that an optimum dose is yet to be established due to conflicting studies demonstrating different results.14 A study using 18 participants with the average age of 54.6 years, looked at stem cells injected into an OA knee which showed a positive effect of reducing pain and improving functionality. The clinical procedure includes an arthroscopic procedure to remove some stem cells which could affect results short term. The study linked the positive outcome with the number of cells injected, after 2 years the results showed long term use was more effective for the patient.15, 16. In summary, stem cell injections are a recent area of research using regenerative medicine which has a promising outcome by reducing pain and improving function in early stages of OA.

4. Hyaluronic Acid

Hyaluronic Acid (HA) is a natural occurring product and is found in soft connective animal tissues. Due to the HA being found in connective tissue it can stimulate cell health and regulate the structure of the extra-cellular matrix, the molecular weight can vary between each injection. When injected into a large joint the HA interacts with the collagen by causing an anti-inflammatory response and enhancing cell proliferation.17 This can subsequently affect the tissues in the surrounding areas including ligament, cartilage, adipose tissue and osteochondral defects, which make the treatment effective for people suffering with OA and rheumatoid arthritis (RA). Despite this, there are factors such as location of pathology, age, genetics and social history which can impact the effectiveness of this treatment method for individuals suffering from OA and RA; the length of time the HA lasts within the joint can vary from days to months due to the anti-inflammatory and anti-nociceptive properties.18 A study by Derneck, a randomised placebo-controlled, used patients with early stage OA with an average age of 60 years old. The findings showed HA to be successful in treating OA in the early stages and with lower grades of OA, the success rate can have other variable factors including the molecular weight of the solution. This study followed up with participants at months one, three and six after having the injection, showing participants improved when compared to a placebo at each month. During this study participants were able to continue taking NSAIDs and other analgesics whilst also attending mandatory exercise groups which can have added other variable factors to the results.19 This can also show that during the use of this intraarticular injection patients are able to continue with their normal daily life. A meta-analysis, 10 studies looking only at human randomised clinical trials, studying the benefits of HA injections for OA knee pain over 6 months, it showed the peak effectiveness at 8 weeks then continued to have some effect over a 24-week period. This was calculated through the researchers using a multivariate longitudinal regression model to draw these conclusions.20 Another meta-analysis using 14 randomised control trials compared CS with HA injections. The results suggested that the analgesic effects can vary over time; the VAS score of CS was significantly lower in month one compared to HA. After three months no significant difference was found; after six months the VAS of the HA was significantly lower compared to CS. It is important to note that there was no placebo group to compare these results to. The meta-analysis also found that both intra-articular injections improved range of motion at months three and six. There has been some evidence showing that HA can lead to some adverse effects which can be linked to the higher injection frequency. 21 New research is suggesting that HA can be effective in the long term, especially for patients with mild OA, commonly aged over 50 years, although further studies inclusive of a larger sample group over an extended period of time are needed for conclusive evidence. This is vital information for making a clinical decision for the best outcome of the patient.

Conclusively, the findings of all four injections has deduced that regenerative medicine is becoming more popular as a conservative treatment option. Until recently, CS injections have previously been used as a last resort option to reduce pain and inflammation with a lot of research to support this however other lubrication injections are being explored to relieve patient’s symptoms such as pain and functionality. HA is showing many benefits as a lubricant injection through stimulation of cell health and proliferation which has continued to show a progression in the long term.

References

1. Kawano, T. et al (2003) Mechanical effects of the intraarticular administration of high molecular weight hyaluronic acid plus phospholipid on synovial joint lubrication and prevention of articular cartilage degeneration in experimental osteoarthritis. Arthritis & Rheumatology. 48(7). 2. Singh, A. et al. (2014) Enhance Lubrication on Tissue and Biomaterial Surfaces through peptide-mediated Binding of Hyaluronic Acid. Nat Mater. 13(10): 988-995. 3. Berkoff, D. Miller, L. & Block, J. (2012) Clinical utility of ultrasound guidance for intra-articular knee injections: a review. Clinical Interventions in Aging. 7: 89-95. 4. Peterson, C & Hodler, J. (2010) Evidence-based radiology (part 2); Is there sufficient research to support the use of therapeutic injections into the peripheral joints? Skeletal Radiology. 39(1): 11-18. 5. Habib, G. (2009) Systemic effects of intra-articular corticosteroids. Clinical Rheumatology. 28(7): 749-756. 6. Orth, P. Rey-Rico, A. Venkatesan, J. Madry, H. & Cucchiarini, M. (2014) Chronic perspectives in stem cell research for knee cartilage repair. Stem Cells and Cloning. 7: 1-17 7. FDA Drug Safety Communication: FDA requires label changes to warn of rare but serious neurologic problems after epidural corticosteroid injections for pain. 8. Manchikanti, L. et al. (2015) Comparison of the efficiency of saline, local anaesthetics, and steroids in epidural and facet join injections for the management of spinal pain: A systematic review of randomized controlled trials. Surgical Neurology International. 6(4): S194-S235. 9. Sayegh, F. et al. (2009) Efficiency of Steroid and Nonsteroid Caudal Epidural Injections for Low Back Pain and Sciatica. Spine. 34(14). 10. Sampson, S. Gerhardt, M. & Mandelbaum, B. (2008) Platelet rich plasma injection grafts for musculoskeletal injuries: a review. Current Reviews in Musculoskeletal Medicine. 1(3-4): 165-174. 11. Vos, R. Weir, A. & Shie, H. (2010) Platelet-Rich Plasma Injection for Chronic Achilles Tendinopathy. JAMA. 303(2): 1440149. 12. Andia, I. Sanchez, M. & Maffulli, N. (2010) Tendon healing and platelet-rich plasma therapies. Expert Opinion.10(10). 13. Mishra, A. Woodall, J & Vierira, A. (2009) Treatment of Tendon and Muscle Using Platelet-Rich Plasma. Clinicals in Sports Medicine. 28(1). 14. Kristjánsson, B. & Honsawek, S. (2014) Current Perspectives in Mesenchymal Stem Cell Therapies for Osteoarthritis. Stem Cells International. 194318. 15. Dernek, B. et al. (2016) Efficacy of single-dose hyaluronic acid products with two different structures in patients with early-stage knee osteoarthritis. Journal of Physical Therapy Science. 28(11): 3036-3040. 16. Bannuru, R. et al. (2009) Therapeutic trajectory of hyaluronic acid versus corticosteroids in the treatment of knee osteoarthritis: A systematic review and meta-analysis. Arthritis Care & Research. 61(12). 17. Cui, G. Wang, Y. Li, C. Shi, C. Wang, W. (2016) Efficacy of mesenchymal stem cells in treating patients with osteoarthritis of the knee: A meta-analysis. Experimental and Therapeutic Medicine. 12(6). 18. Iannitti, T. Lodi, D. & Palmieri, B. (2011) Intra-Articular Injections for the Treatment of Osteoarthritis. Drugs in R&D. 11(1): 13-27. 19. Bannuru, R. Natov, N. Dasi, U. Schmid, C. & McAlindon, T. (2011) Therapeutic trajectory following intra-articular hyaluronic acid injection in knee osteoarthritis meta-analysis. Osteoarthritis and Cartilage. 19(6): 611-619. 20. Koh, Y. et al. (2013) Mesenchymal Stem Cell Injections Improve Symptoms of Knee Osteoarthritis. The Journal of Arthroscopic and Related Surgery. 29(4): 748-755. 21. He, W. et al. (2017) Efficacy and safety of intraarticular hyaluronic acid and corticosteroid for knee osteoarthritis: A meta-analysis. International Journal of Surgery. 39; 95-103.