By Dr. Kieran O’Sullivan, University of Limerick, Ireland
And Prof. Peter O’Sullivan, Curtin University, Australia
The 14-time Grand Slam winner, Rafael Nadal’s recent struggles to participate at the highest level due to ongoing low back pain (LBP) once again brings the issue of novel therapies offering tantalizing cures to the fore; he is undergoing stem cell therapy (SCT). So it is timely to explore: i) what this therapy potentially offers, ii) the quality of the supporting evidence, iii) its comparison to other needle-based therapies, and iv) what the use of several novel needle-based therapies in the last decade (e.g. stem cell therapy, platelet-rich plasma, dry needling) reveal about attitudes to management of pain in sporting populations.
What is stem cell therapy and why consider it?
Stem cell therapy (SCT) has opened up exciting avenues in health research across many disciplines. Focusing on the role of SCT in LBP, its proposed mechanism of action is regeneration of local spinal structures which are degenerative and/or presumed to be damaged.[1-3] There are several different methods of using SCT. This piece focuses on mesenchymal stem cells (MSCs) as they have been the most promising candidate cells for relief of pain, showing good differentiation potential towards cartilage, tendon and bone cells.[4, 5] Typically MSCs are extracted from the patient’s bone marrow and inserted into the affected region as undifferentiated MSCs, or a short while later as differentiated cells. Hopes for its potential in clinical practice were raised when it became clear that changes in cell structure could be observed in the host tissue very quickly (weeks) after only one treatment.[6, 7]
How good is the evidence of effectiveness?
A body of basic science (animal) data suggests that in closely controlled environments, MSCs can increase the expression and production of type II collagen and the extracellular matrix in intervertebral discs with a view to enhancing nutrition and consequent regeneration.[2, 8-10] However, not all animal studies have demonstrated a benefit. Interestingly, in those studies using larger animal models which more closely replicate the human intervertebral disc, there was no benefit from the use of MSCs. Furthermore, the evidence from small human studies is less than convincing.[12, 13] There is currently a notable lack of adequately powered, blinded randomised controlled trials (RCTs) examining the effectiveness of MSCs in LBP. This is somewhat surprising given the fact that such therapies are easier to study in RCTs than more complex behavioural interventions.
The use of MSCs in knee cartilage defects and knee osteoarthiritis has been examined over a longer period of time. Once again, animal studies are encouraging and uncontrolled human studies show promise. However, there does not appear to be a clear clinical benefit in humans based on their reported knee pain experience in RCTs, even if the cartilage appears to have benefitted through an increase in volume.
In conclusion, based on current evidence, while MSCs appear to be capable of regenerating tissue in animal models, changes in tissue structure (i) are not always replicated in human studies and (ii) do not appear to lead to reductions in pain and disability.
How does this evidence compare to other needle-based therapies?
Needle-based therapies usually aim to aid tissue repair (e.g. MSCs, prolotherapy, platelet-rich plasma) and/or provide direct pain relief (e.g. epidural and facet joint injections). The evidence for most needle-based therapies is underwhelming, whether they are focussed on tissue repair, pain relief or used to deliver medication . For example, epidural injections for LBP and/or leg pain have at best a short-term effect on pain.[19-21] The size of this effect is of marginal clinical significance, with a number needed to treat of 11.4, and the benefit is lost at medium- and long-term follow-up.[19, 20] The evidence is remarkably similar for facet joint injections, prolotherapy, dry needling,[18, 25] acupuncture[18, 26] and platelet-rich plasma.[27, 28] This is not to say that these interventions are never of assistance. Nevertheless, it does highlight that despite ongoing developments in such interventions, there is a consistent pattern in the limited effectiveness of such interventions. The need for accurate blinding and control arms in studies is of critical importance, as the benefits are almost entirely absent in very well conducted placebo controlled RCTs.[21, 26]
What does this tell us?
While the story of SCT seems tantalising as a new cure for LBP – the clinical data does not currently support this enthusiasm. The story of SCT and other needle-based therapies for LBP again highlights the limitation of reducing the understanding of a person’s pain experience and associated disability down to a single structural cause. We know that almost half of asymptomatic people under the age of 30 years have degenerate discs on MRI imaging [29, 30] and that the association between disc degeneration and pain or disability is weak to moderate at best.[29, 31] Furthermore prospective studies have failed to demonstrate that these findings are predictive of pain and disability. Many asymptomatic athletic populations have also demonstrated such findings on imaging and these are poorly correlated with previous, current and future LBP experiences.[33-35] Therefore the presumption that an MRI finding of disc degeneration is the cause of a person’s LBP, which then becomes the target for SCT or other needle-based therapies, may represent flawed logic in many situations.
Furthermore if the disc degeneration is symptomatic, it is likely to be infleunced by various other biopsychosocial risk factors such as movement control strategies, conditioning, training loads, technical factors linked to individual sports, lifestyle factors, tissue sensitivity, immune system function, a person’s beliefs and their psychological status. Therefore simply applying SCT or other needle-based therapies to a degenerate disc without addressing other important risk factors for pain and disability may result in the therapy failing. In the same way that ‘disc replacements’ and ‘fusions’ for LBP have not demonstrated long term superior effects for LBP over conservative care,[37, 38] the isolated use of SCT and other needle-based therapies will likely follow the same path as other reductionist approaches in the management of complex disorders like LBP.
Is there a role for SCT and other needle-based therapies for LBP in sport?
The implementation, and indeed removal, of novel therapies in clinical practice should be done in line with the available evidence. It appears clear however that SCT, like other popular therapies of our time such as platelet-rich plasma and dry needling, has managed to gain appeal in the absence of strong evidence that it enhances recovery over and above existing rehabilitation options. Clearly, more research is required to determine whether an athlete with LBP associated with a clear tissue injury and impaired repair processes, could benefit from this therapy while controlling for the other risk factors linked to the disorder. However a silver bullet seems unlikely for complex disorders like LBP. Many would suggest that the ability of some needle-based therapies to provide short-term pain relief justifies their role as a “window of opportunity” for rehabilitation and recovery. We accept that selecting those who require some pain control to help them overcome their pain, for example in some acute pain situations may be beneficial. However, the aforementioned blinded RCTs currently suggest the effect on pain is usually absent or very small, with large numbers of patients needing to be treated with such therapies for a single patient to demonstrate a clinically significant benefit.
There may be a role for integrated management approaches that target biopsychosocial risk factors in conjunction with novel therapies such as SCT and other needle-based therapies for the management of LBP – however currently the jury is out on this. While the risks for many needle-based therapies are relatively small, as these risks increase  it becomes harder to justify their use considering the very small benefits observed. It appears that both athletes and healthcare professionals are almost innately drawn to novel therapies and treatments which focus on local “issues in the tissues”, and the current use of SCT appears to reflect a pattern where adopting novel therapies in clinical practice runs ahead of the evidence.
Instead, we advocate an approach where the unique contributing factors for each athlete are considered, and where treatment options offered to each athlete are based on the best available evidence. In the event that local tissue sensitivity is seen as a significant barrier to rehabilitation and recovery, local therapies which provide at least some pain relief may have a role. However, the existing range of needle-based therapies to date have not demonstrated such an effect is clinically worthwhile, especially in terms of long-term management of chronic pain conditions like LBP.
- Zhou Y, Warycha B, Vu H. Stem Cell Therapy: Future of Pain Medicine. British Journal of Medical Practitioners 2014;7(3):a728-30
- Mwale F, Wang H, Roughly P, Antoniou J, Haglund L. Link N and MSCs can induce regeneration of the early degenerate intervertebral disc. Tissue Engineering Part A 2014;20(21-22):2942-49
- Kelly F, Porucznik M. Cell-based therapies in Sports Medicine. AAOS Now, 2014:1-10.
- Schmitt A, van Griensven M, Imhoff A, Buchmann S. Application of Stem Cells in Orthopedics. Stem Cells International 2012:Article ID 394962
- Drazin D, Rosner J, Avalos P, Acosta F. Stem Cell Therapy for Degenerative Disc Disease. Advances in Orthopedics 2012:Article ID 961052, 8 pages
- Sakai D, Mochida J, Yamamoto Y, al e. Transplantation of mesenchymal stem cells embedded in Atelocollagen gel to the intervertebral disc: a potential therapeutic model for disc degeneration. Biomaterials 2003;24(20):3531-41
- Wei A, Tao H, Chung S, Brisby H, Ma D, Diwan A. The fate of transplanted xenogeneic bone marrow derived stem cells in rat intervertebral discs. Journal of Orthopaedic Research 2009;27(3):374-79
- Chun H, Kim Y, Kim B, et al. Transplantation of human adipose-derived stem cells in a rabbit model of traumatic degeneration of lumbar discs. World Neurosurgery 2012;78(3-4):364-71
- Henriksson HB, Svanvik T, Jonsson M, et al. Transplantation of human mesenchymal stems cells into intervertebral discs in a xenogeneic porcine model. Spine 2009;34(2):141-48
- Hiyama A, Mochida J, Iwashina T, et al. Transplantation of mesenchymal stem cells in a canine disc degeneration model. Journal of Orthopaedic Research 2008;26(5):589-600
- Acosta Jr FL, Metz L, Adkisson IV HD, et al. Porcine intervertebral disc repair using allogeneic juvenile articular chondrocytes or mesenchymal stem cells. Tissue Engineering Part A 2011;17(23-24):3045-55
- Haufe S, Mork A. Intradiscal injection of hematopoietic stem cells in an attempt to rejuvenate the intervertebral discs. Stem Cells and Development 2006;15:136-37
- Orozco L, Soler R, Morera C, Alberca M, Sánchez A, García-Sancho J. Intervertebral disc repair by autologous mesenchymal bone marrow cells: a pilot study. Transplantation 2011;92:822-8. 2011:822-28
- Black LL, Gaynor J, Gahring D, et al. Effect of adipose-derived mesenchymal stem and regenerative cells on lameness in dogs with chronic osteoarthritis of the coxofemoral joints: a randomized, double-blinded, multicenter controlled trial. Veterinary Therapeutics 2007;8(4):272
- Haleem AM, El Singergy AA, Sabry D, et al. The Clinical Use of Human Culture–Expanded Autologous Bone Marrow Mesenchymal Stem Cells Transplanted on Platelet-Rich Fibrin Glue in the Treatment of Articular Cartilage Defects A Pilot Study and Preliminary Results. Cartilage 2010;1(4):253-61
- Wakitani S, Imoto K, Yamamoto T, Saito M, Murata N, Yoneda M. Human autologous culture expanded bone marrow mesenchymal cell transplantation for repair of cartilage defects in osteoarthritic knees. Osteoarthritis and Cartilage 2002;10(3):199-206
- Staal J, De Bie R, De Vet H, Hildebrandt J, Nelemans P. Injection therapy for subacute and chronic low-back pain. Cochrane Database Syst Rev 2008:CD001824
- Furlan AD, van Tulder M, Cherkin D, et al. Acupuncture and dry-needling for low back pain: an updated systematic review within the framework of the cochrane collaboration. Spine 2005;30(8):944-63
- Benoist M, Boulu P, Hayem G. Epidural steroid injections in the management of low-back pain with radiculopathy: an update of their efficacy and safety. Eur Spine J 2012;21(2):204-13
- Pinto RZ, Maher CG, Ferreira ML, et al. Epidural Corticosteroid Injections in the Management of SciaticaA Systematic Review and Meta-analysis. Ann Intern Med 2012;157(12):865-77
- Iversen T, Solberg TK, Romner B, et al. Effect of caudal epidural steroid or saline injection in chronic lumbar radiculopathy: multicentre, blinded, randomised controlled trial. Bmj 2011;343
- Arden N, Price C, Reading I, et al. A multicentre randomized controlled trial of epidural corticosteroid injections for sciatica: the WEST study. Rheumatol 2005;44(11):1399-406
- Boswell M, Colson J, Sehgal N, Dunbar E, Epter R. A systematic review of therapeutic facet joint interventions in chronic spinal pain. Pain Physician 2007;10:229-53
- Dagenais S, Yelland M, Del Mar C, Schoene M. Prolotherapy injections for chronic low-back pain. Cochrane Database of Systematic Reviews 2009
- Tough EA, White AR, Cummings TM, Richards SH, Campbell JL. Acupuncture and dry needling in the management of myofascial trigger point pain: a systematic review and meta-analysis of randomised controlled trials. Eur J Pain 2009;13(1):3-10
- Cherkin DC, Sherman KJ, Avins AL, et al. A randomized trial comparing acupuncture, simulated acupuncture, and usual care for chronic low back pain. Archives of internal medicine 2009;169(9):858-66
- Moraes VY, Lenza M, Tamaoki MJ, Faloppa F, Belloti JC. Platelet-rich therapies for musculoskeletal soft tissue injuries. Cochrane Database of Systematic Reviews 2014
- Sheth U, Simunovic N, Klein G, et al. Efficacy of autologous platelet-rich plasma use for orthopaedic indications: a meta-analysis. The Journal of Bone & Joint Surgery 2012;94(4):298-307
- Teraguchi M, Yoshimura N, Hashizume H, et al. Prevalence and distribution of intervertebral disc degeneration over the entire spine in a population-based cohort: the Wakayama Spine Study. Osteoarthritis and Cartilage 2014;22(1):104-10
- Brinjikji W, Luetmer P, Comstock B, et al. Systematic Literature Review of Imaging Features of Spinal Degeneration in Asymptomatic Populations. American Journal of Neuroradiology 2015:In press
- Chou R, Qaseem A, Owens DK, Shekelle P. Diagnostic imaging for low back pain: Advice for high-value health care from the American College of Physicians. Ann Intern Med 2011;154(3):181-89
- Steffens D, Hancock M, Maher C, Williams C, Jensen T, Latimer J. Does magnetic resonance imaging predict future low back pain? A systematic review. Eur J Pain 2014;18(6):755-65
- Baranto A, Hellström M, Cederlund C-G, Nyman R, Swärd L. Back pain and MRI changes in the thoraco-lumbar spine of top athletes in four different sports: a 15-year follow-up study. Knee Surgery, Sports Traumatology, Arthroscopy 2009;17(9):1125-34
- Kraft CN, Pennekamp PH, Becker U, et al. Magnetic Resonance Imaging Findings of the Lumbar Spine in Elite Horseback Riders Correlations With Back Pain, Body Mass Index, Trunk/Leg-Length Coefficient, and Riding Discipline. The American Journal of Sports Medicine 2009;37(11):2205-13
- Kaneoka K, Shimizu K, Hangai M, et al. Lumbar Intervertebral Disk Degeneration in Elite Competitive Swimmers A Case Control Study. The American Journal of Sports Medicine 2007;35(8):1341-45
- O’Sullivan P. It’s time for change with the management of non-specific chronic low back pain. British Journal of Sports Medicine 2012;46(4):224-27
- Mirza SK, Deyo RA. Systematic review of randomized trials comparing lumbar fusion surgery to nonoperative care for treatment of chronic back pain. Spine 2007;32(7):816-23
- Freeman BJ, Davenport J. Total disc replacement in the lumbar spine: a systematic review of the literature. Eur Spine J 2006;15(3):439-47
- Bø K, Herbert RD. When and how should new therapies become routine clinical practice? Physiotherapy 2009;95(1):51-57
- Pak J, Chang J-J, Lee JH, Lee SH. Safety reporting on implantation of autologous adipose tissue-derived stem cells with platelet-rich plasma into human articular joints. BMC Musculoskelet Disord 2013;14(1):337
- Epstein N. The risks of epidural and transforaminal steroid injections in the spine: Commentary and a comprehensive review of the literature. Surgical Neurology International 2013;4(S2):S74–S93