Intradiscal Injections

Is There Evidence to Support It?

Intervertebral disc degeneration is one of the most common causes of chronic low back pain in adults. Compared to other sources of chronic low back pain, such as the sacroiliac joint or posterior facets, discogenic pain is more common in younger patients.[1] The pathomechanisms underlying discogenic back pain are incompletely understood, but they are thought to involve a complex interplay between inflammation, hypermobility, and nerve ingrowth and upregulation, all of which may be further modulated by psychosocial factors such as depression or the presence of work-related injury.[2] In the midst of such complexity, identifying a low-cost, minimally invasive treatment strategy such as intradiscal injection for the treatment of discogenic back pain would be of great clinical utility, but does the evidence support it?

Intradiscal Biologics

Among the different types of intradiscal injections, intradiscal biologics are currently perhaps the most popular. A 2022 systematic review examined several intradiscal biologic agents for the treatment of discogenic low back pain, including platelet rich plasma (PRP), autologous bone marrow aspirate concentrate (BMAC), autologous mesenchymal stroma cells (MSCs), and allograft disc chondrocytes.[3] Among the 2 randomized controlled trials and 10 observational cohort studies included in the review,[4-14] the aggregate rate of success (defined as pain reduction of ≥50% from baseline) for PRP and MSC injections at 6 months were 54.8% and 53.5%, respectively. However, the review ultimately concluded that the body of evidence supporting intradiscal MSCs and PRP was limited only to observational data that was “very low quality” for a variety of reasons, ranging from low sample size to insufficient blinding. Additionally, success rates in these studies often had lower end confidence intervals that overlapped with clinically important thresholds, suggesting the absence of clinical significance. Finally, the one randomized controlled trial that was included for PRP injection alone—comparing PRP versus sham 8 weeks after injection[13]—was also found to be “very low quality,” given the high risk of bias arising from inadequate randomization and missing outcome data in more than 20% of patients in that study.

Other reviews have also been performed, including one that focused solely on injection of BMAC and culture-expanded bone marrow MSCs.[15] In that review, 16 studies were identified, and it was generally concluded that intradiscal autologous or allogeneic BMAC and culture-expanded bone marrow-derived MSCs did improve pain compared to baseline. However, the quality of evidence among those studies was also found to be “very low” due to heterogeneity and limited generalizability.

Patient selection has also been studied. In a retrospective analysis of patients receiving intradiscal PRP injection with discogenic low back pain, Akeda et al found that patients who had more than 1 disc injected and patients with posteriorly located high intensity zones on magnetic resonance imaging (MRI) had relatively worse outcomes 12 months after the injection, as measured by changes in visual analog score and Oswestry Disability Index, respectively.[16] This study supports the notion that the presence of posterior high intensity zones on MRI and having multiple “target” discs may serve as negative prognostic indicators for patients undergoing PRP injection.

Nonbiologic Agents

Despite the current popularity of biologics, other agents historically have also been trialed as the key component in intradiscal injection formulations for the treatment of discogenic back pain.

One of the oldest among these are chemonucleolytic enzymes, first described by Dr. Lyman Smith in 1963, wherein intradiscal injection of the enzyme chymopapain caused dissolution of the nucleus pulposus having been first trialed in dogs and then humans.[17] Since then, the treatment was studied for many years but without resounding success, up until 2002 when commercial production of chymopapain was stopped due to reports of serious adverse events, including anaphylaxis and neurologic complications. However, over the past 2 decades, there has been renewed interest in a more specific and potentially less inflammatory chemonucleolytic enzyme: proteus vulgaris chondroitin sulfate ABC endolyase (condoliase). This enzyme, which is more specific to targeting the nucleus pulposus, is currently being studied as a new treatment option for discogenic back pain and has been approved by the drug regulatory authority in Japan following successful clinical phase II and phase III trials.[18,19]

Methylene blue—a substance that has been postulated to block nerve conduction and possess an anti-inflammatory effect[20,21]—has also been used for the treatment of discogenic back pain and was recently studied in a 2018 meta-analysis of 5 studies utilizing intradiscal injection. That review found a significant improvement in visual analog scores at 3 months after injection while also recognizing the need for larger sample sizes and better randomized controlled trials.[22]

Corticosteroids have also been widely used in orthopedics as a treatment to quell inflammation—even if temporarily—and the intervertebral disc is no exception. Cao et al performed a randomized controlled trial of intradiscal injection of corticosteroid versus saline among 120 patients with discogenic low back pain and end plate Modic changes who had undergone discography but did not wish to undergo surgery.[23] That study found a significant improvement in visual analog scale and Oswestry function scores at 3 and 6 months following corticosteroid injection compared to saline control. More recently, a systematic review including 8 studies of patients with chronic discogenic pain found a significant improvement in short-term pain scores at 1 month postinjection but no longer term improvement at 3, 6, or 12 months after injection.[24]

That review concluded that intradiscal steroid injection should only be used as a short-term bridge therapy, as it does not appear to provide long-term relief.

Conclusion

Despite the study of intradiscal injection for the treatment of discogenic back pain spanning more than 6 decades, there remains no clear consensus or strong evidence supporting intradiscal injection as a definitive treatment option. Additional large, thoughtfully crafted, randomized controlled trials are needed to determine whether any of the biologic or non-biologic intradiscal therapies previously described may serve as effective and durable therapies for the treatment of discogenic back pain.

References

1. DePalma MJ, Ketchum JM, Saullo T. What is the source of chronic low back pain and does age play a role? Pain Med. 2011;12(2):224-233.

2. Ohtori S, Inoue G, Miyagi M, Takahashi K. Pathomechanisms of discogenic low back pain in humans and animal models. Spine J. 2015;15(6):1347-1355.

3. Schneider BJ, Hunt C, Conger A, et al. The effectiveness of intradiscal biologic treatments for discogenic low back pain: a systematic review. Spine J. 2022;22(2):226-237.

4. Akeda K, Ohishi K, Masuda K, et al. Intradiscal injection of autologous platelet-rich plasma releasate to treat discogenic low back pain: a preliminary clinical trial. Asian Spine J. 2017;11(3):380-389.

5. Comella K, Silbert R, Parlo M. Effects of the intradiscal implantation of stromal vascular fraction plus platelet rich plasma in patients with degenerative disc disease. J Transl Med. 2017;15(1):12.

6. Coric D, Pettine K, Sumich A, Boltes MO. Prospective study of disc repair with allogeneic chondrocytes presented at the 2012 Joint Spine Section Meeting. J Neurosurg Spine. 2013;18(1):85-95.

7. Kumar H, Ha DH, Lee EJ, et al. Safety and tolerability of intradiscal implantation of combined autologous adipose-derived mesenchymal stem cells and hyaluronic acid in patients with chronic discogenic low back pain: 1-year follow-up of a phase I study. Stem Cell Res Ther. 2017;8(1):262.

8. Levi D, Horn S, Tyszko S, Levin J, Hecht-Leavitt C, Walko E. Intradiscal platelet-rich plasma injection for chronic discogenic low back pain: preliminary results from a prospective trial. Pain Med. 2016;17(6):1010-1022.

9. Navani A, Hames A. Platelet-rich plasma injections for lumbar discogenic pain: a preliminary assessment of structural and functional changes. Tech Reg Anesth Pain Manage. 2015;19(1-2):38-44.

10. Noriega DC, Ardura F, Hernandez-Ramajo R, et al. Intervertebral disc repair by allogeneic mesenchymal bone marrow cells: a randomized controlled trial. Transplantation. 2017;101(8):1945-1951.

11. Orozco L, Soler R, Morera C, Alberca M, Sanchez A, Garcia-Sancho J. Intervertebral disc repair by autologous mesenchymal bone marrow cells: a pilot study. Transplantation. 2011;92(7):822-828.

12. Pettine KA, Suzuki RK, Sand TT, Murphy MB. Autologous bone marrow concentrate intradiscal injection for the treatment of degenerative disc disease with three-year follow-up. Int Orthop. 2017;41(10):2097-2103.

13. Tuakli-Wosornu YA, Terry A, Boachie-Adjei K, et al. Lumbar intradiskal platelet-rich plasma (PRP) injections: a prospective, double-blind, randomized controlled study. PM R. 2016;8(1):1-10; quiz 10.

14. Wolff M, Shillington JM, Rathbone C, Piasecki SK, Barnes B. Injections of concentrated bone marrow aspirate as treatment for discogenic pain: a retrospective analysis. BMC Musculoskelet Disord. 2020;21(1):135.

15. Her YF, Kubrova E, Martinez Alvarez GA, D’Souza RS. The analgesic efficacy of intradiscal injection of bone marrow aspirate concentrate and culture-expanded bone marrow mesenchymal stromal cells in discogenic pain: a systematic review. J Pain Res. 2022;15:3299-3318.

16. Akeda K, Fujiwara T, Takegami N, Yamada J, Sudo A. Retrospective analysis of factors associated with the treatment outcomes of intradiscal platelet-rich plasma-releasate injection therapy for patients with discogenic low back pain. Medicina (Kaunas). 2023;59(4):640.

17. Smith L. Enzyme Dissolution of the nucleus pulposus in humans. JAMA. 1964;187:137-140.

18. Ishibashi K, Iwai H, Koga H. Chemonucleolysis with chondroitin sulfate ABC endolyase as a novel minimally invasive treatment for patients with lumbar intervertebral disc herniation. J Spine Surg. 2019;5(Suppl 1):S115-S121.

19. Zhang F, Wang S, Li B, Tian W, Zhou Z, Liu S. Intradiscal injection for the management of low back pain. JOR Spine. 2022;5(1):e1186.

20. Alda M. Methylene blue in the treatment of neuropsychiatric disorders. CNS Drugs. 2019;33(8):719-725.

21. Li JW, Wang RL, Xu J, et al. Methylene blue prevents osteoarthritis progression and relieves pain in rats via upregulation of Nrf2/PRDX1. Acta Pharmacol Sin. 2022;43(2):417-428.

22. Guo X, Ding W, Liu L, Yang S. Intradiscal Methylene blue injection for discogenic low back pain: a meta-analysis. Pain Pract. 2019;19(1):118-129.

23. Cao P, Jiang L, Zhuang C, et al. Intradiscal injection therapy for degenerative chronic discogenic low back pain with end plate Modic changes. Spine J. 2011;11(2):100-106.

24. Mishra P, Goyal S, Makker R. Intradiscal steroid therapy in chronic discogenic pain: a systematic review of literature. Palliat Med Pract. 2023;17(3):152-163.

Authors: George W. Fryhofer, MD, MSc, and Gregory Lopez, MD

From Midwest Orthopaedic at Rush, Rush University Medical Center, in Chicago, Illinois.