Efficacy of the Gelstix nucleus augmentation device for the treatment of chronic discogenic low back pain: protocol for a randomised, sham-controlled, double-blind, multicentre trial

Eva Koetsier, Sander M J van Kuijk, Paolo Maino, Jasmina Dukanac, Luca Scascighini, Alessandro Cianfoni, Pietro Scarone, Dominique E Kuhlen, Markus W Hollman, Jan-Willem Kallewaard, Eva Koetsier, Sander M J van Kuijk, Paolo Maino, Jasmina Dukanac, Luca Scascighini, Alessandro Cianfoni, Pietro Scarone, Dominique E Kuhlen, Markus W Hollman, Jan-Willem Kallewaard

Abstract

Introduction: Discogenic pain is the cause of pain in 26%-40% of patients with for low back pain. Consensus about treatment of chronic discogenic low back pain is lacking and most treatment alternatives are supported by limited evidence. The percutaneous implantation of hydrogels into the nucleus pulposus represents a promising regenerative intradiscal therapy. The hydrogel 'GelStix' is composed primarily of hydrolyzed polyacrylonitrile and acts as a reservoir of hydration, producing increased pressure and improved pH balance, potentially leading to disc preservation. We hypothesise that treatment with GelStix will lead to greater reduction in pain intensity at 6 months post-treatment compared with patients receiving sham treatment.

Methods and analysis: This is a parallel group, randomised sham-controlled double-blind, multicentre trial to assess whether the GelStix device is superior to sham in reducing pain intensity in patients with chronic discogenic low back pain. The study will be conducted in two regional hospitals in Europe. Seventy-two participants will be randomised in a 1:1 ratio. The primary outcome will be the change in pain intensity between preoperative baseline and at 6 months postintervention. Secondary outcomes were disability, quality of life, the patient's global impression of change scale, the use of pain medication and the disc degeneration process assessed by means of MRI. For change in pain intensity, disability, health-related quality of life and disc height, mean values will be compared between groups using linear regression analysis, adjusted for treatment centre.

Ethics and dissemination: Ethics approval was obtained from the Ethics Committee of the Canton Ticino, Switzerland (CE2982) and by the Medical Ethical Committee Arnhem-Nijmegen, the Netherlands (2016-2944). All patients that agree to participate will be asked to sign an informed consent form. Results will be disseminated through international publications in peer-reviewed journals, in addition to international conference presentations.

Trial registration number: NCT02763956.

Protocol version: 7.1, 18 November 2020.

Keywords: Back pain; Musculoskeletal disorders; PAIN MANAGEMENT.

Conflict of interest statement

Competing interests: None declared.

© Author(s) (or their employer(s)) 2022. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.

Figures

Figure 1
Figure 1
1835S GelStix. From left to right: 18 Gauge Needle, GelStix: dry, after 15 min hydration, after 30 min hydration, after 45 min hydration.
Figure 2
Figure 2
Study flow chart. NRS, Numeric Rating Scale.
Figure 3
Figure 3
(A) Using fluoroscopic guidance, the needle is introduce using a standard posterolateral discography approach. (B) The protective cap is removed from the preloaded implant holder. (C) The implant holder is threaded onto the proximal end of the introducer needle. (D) The holder stylet is pushed so that the implant is driven completely into the introducer needle. (E) The implant holder is removed. The needle stylet is driven through the needle and bottomed out to deliver the GelStix completely into the nucleus, keeping the needle tip centred in the nucleus. (F) The needle tip will keep centred approximately in the nucleus and the procedure will be repeated to insert additional GelStix.

References

    1. Zhao L, Manchikanti L, Kaye AD, et al. . Treatment of discogenic low back pain: current treatment strategies and future Options-a literature review. Curr Pain Headache Rep 2019;23:86. 10.1007/s11916-019-0821-x
    1. Peng B-G, Pathophysiology PBG. Pathophysiology, diagnosis, and treatment of discogenic low back pain. World J Orthop 2013;4:42–52. 10.5312/wjo.v4.i2.42
    1. Kallewaard JW, Terheggen MAMB, Groen GJ, et al. . 15. discogenic low back pain. Pain Pract 2010;10:560–79. 10.1111/j.1533-2500.2010.00408.x
    1. Fujii K, Yamazaki M, Kang JD, et al. . Discogenic back pain: literature review of definition, diagnosis, and treatment. JBMR Plus 2019;3:e10180. 10.1002/jbm4.10180
    1. Cheung KMC, Karppinen J, Chan D, et al. . Prevalence and pattern of lumbar magnetic resonance imaging changes in a population study of one thousand forty-three individuals. Spine 2009;34:934–40. 10.1097/BRS.0b013e3181a01b3f
    1. Schwarzer AC, Aprill CN, Derby R, et al. . The relative contributions of the disc and zygapophyseal joint in chronic low back pain. Spine 1994;19:801–6. 10.1097/00007632-199404000-00013
    1. Verrills P, Nowesenitz G, Barnard A. Prevalence and characteristics of discogenic pain in tertiary practice: 223 consecutive cases utilizing lumbar Discography. Pain Med 2015;16:1490–9. 10.1111/pme.12809
    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;12:224–33. 10.1111/j.1526-4637.2010.01045.x
    1. Manchikanti L, Singh V, Pampati V, et al. . Evaluation of the relative contributions of various structures in chronic low back pain. Pain Physician 2001;4:308–16.
    1. Vo NV, Hartman RA, Patil PR, et al. . Molecular mechanisms of biological aging in intervertebral discs. J Orthop Res 2016;34:1289–306. 10.1002/jor.23195
    1. Singh K, Masuda K, Thonar EJ-MA, et al. . Age-Related changes in the extracellular matrix of nucleus pulposus and anulus fibrosus of human intervertebral disc. Spine 2009;34:10–16. 10.1097/BRS.0b013e31818e5ddd
    1. Patil P, Niedernhofer LJ, Robbins PD, et al. . Cellular senescence in intervertebral disc aging and degeneration. Curr Mol Biol Rep 2018;4:180–90. 10.1007/s40610-018-0108-8
    1. Kos N, Gradisnik L, Velnar T. A brief review of the degenerative intervertebral disc disease. Med Arch 2019;73:421–4. 10.5455/medarh.2019.73.421-424
    1. Bibby SRS, Jones DA, Ripley RM, et al. . Metabolism of the intervertebral disc: effects of low levels of oxygen, glucose, and pH on rates of energy metabolism of bovine nucleus pulposus cells. Spine 2005;30:487–96. 10.1097/01.brs.0000154619.38122.47
    1. Liang C-Z, Li H, Tao Y-Q, et al. . The relationship between low pH in intervertebral discs and low back pain: a systematic review. Arch Med Sci 2012;8:952–6. 10.5114/aoms.2012.32401
    1. Keshari KR, Lotz JC, Link TM, et al. . Lactic acid and proteoglycans as metabolic markers for discogenic back pain. Spine 2008;33:312–7. 10.1097/BRS.0b013e31816201c3
    1. Schwarzer AC, Aprill CN, Derby R, et al. . The prevalence and clinical features of internal disc disruption in patients with chronic low back pain. Spine 1995;20:1878–83. 10.1097/00007632-199509000-00007
    1. Brinjikji W, Luetmer PH, Comstock B, et al. . Systematic literature review of imaging features of spinal degeneration in asymptomatic populations. AJNR Am J Neuroradiol 2015;36:811–6. 10.3174/ajnr.A4173
    1. Manchikanti L, Benyamin RM, Singh V, et al. . An update of the systematic appraisal of the accuracy and utility of lumbar discography in chronic low back pain. Pain Physician 2013;16:SE55–95.
    1. Laslett M, Oberg B, Aprill CN, et al. . Centralization as a predictor of provocation discography results in chronic low back pain, and the influence of disability and distress on diagnostic power. Spine J 2005;5:370–80. 10.1016/j.spinee.2004.11.007
    1. Laslett M, Aprill CN, McDonald B, et al. . Clinical predictors of lumbar provocation discography: a study of clinical predictors of lumbar provocation discography. Eur Spine J 2006;15:1473–84. 10.1007/s00586-006-0062-7
    1. Wolfer LR, Derby R, Lee J-E, et al. . Systematic review of lumbar provocation discography in asymptomatic subjects with a meta-analysis of false-positive rates. Pain Physician 2008;11:513–38.
    1. McCormick ZL, DeFrancesch F, Loomba V, et al. . Diagnostic value, prognostic value, and safety of provocation Discography. Pain Med 2018;19:3–8. 10.1093/pm/pnx034
    1. Carragee EJ, Don AS, Hurwitz EL, et al. . 2009 ISSLS Prize winner: does discography cause accelerated progression of degeneration changes in the lumbar disc: a ten-year matched cohort study. Spine 2009;34:2338–45. 10.1097/BRS.0b013e3181ab5432
    1. Cuellar JM, Stauff MP, Herzog RJ, et al. . Does provocative discography cause clinically important injury to the lumbar intervertebral disc? A 10-year matched cohort study. Spine J 2016;16:273–80. 10.1016/j.spinee.2015.06.051
    1. Koetsier E, Kallewaard JW, Maino P. Commentary on: does provocative discography cause clinically important injury to the lumbar intervertebral disc? A 10-year matched cohort study, by Cueller, et al. Spine J 2016. Spine J 2017;17:610–1.
    1. McCormick ZL, Lehman VT, Plastaras CT, et al. . Low-Pressure lumbar provocation Discography according to spine intervention Society/International association for the study of pain standards does not cause acceleration of disc degeneration in patients with symptomatic low back pain: a 7-year matched cohort study. Spine 2019;44:E1161–8. 10.1097/BRS.0000000000003085
    1. van Middelkoop M, Rubinstein SM, Kuijpers T, et al. . A systematic review on the effectiveness of physical and rehabilitation interventions for chronic non-specific low back pain. Eur Spine J 2011;20:19–39. 10.1007/s00586-010-1518-3
    1. Kallewaard JW, Wintraecken VM, Geurts JW, et al. . A multicenter randomized controlled trial on the efficacy of intradiscal methylene blue injection for chronic discogenic low back pain: the IMBI study. Pain 2019;160:945–53. 10.1097/j.pain.0000000000001475
    1. Helm S, Hayek SM, Benyamin RM, et al. . Systematic review of the effectiveness of thermal annular procedures in treating discogenic low back pain. Pain Physician 2009;12:207–32.
    1. Freeman BJC. IDET: a critical appraisal of the evidence. Eur Spine J 2006;15:448–57. 10.1007/s00586-006-0156-2
    1. Huygen F, Kallewaard JW, van Tulder M, et al. . "Evidence-Based Interventional Pain Medicine According to Clinical Diagnoses": Update 2018. Pain Pract 2019;19:664–75. 10.1111/papr.12786
    1. Pan A, Hai Y, Yang J, et al. . Adjacent segment degeneration after lumbar spinal fusion compared with motion-preservation procedures: a meta-analysis. Eur Spine J 2016;25:1522–32. 10.1007/s00586-016-4415-6
    1. Bydon M, De la Garza-Ramos R, Macki M, et al. . Lumbar fusion versus nonoperative management for treatment of discogenic low back pain: a systematic review and meta-analysis of randomized controlled trials. J Spinal Disord Tech 2014;27:297–304. 10.1097/BSD.0000000000000072
    1. Wang X, Wanyan P, Tian JH, et al. . Meta-Analysis of randomized trials comparing fusion surgery to non-surgical treatment for discogenic chronic low back pain. J Back Musculoskelet Rehabil 2015;28:621–7. 10.3233/BMR-140571
    1. Vallejo R, Gupta A, Cedeno DL, et al. . Clinical effectiveness and mechanism of action of spinal cord stimulation for treating chronic low back and lower extremity pain: a systematic review. Curr Pain Headache Rep 2020;24:70. 10.1007/s11916-020-00907-2
    1. Kallewaard JW, Edelbroek C, Terheggen M, et al. . A prospective study of dorsal root ganglion stimulation for non-operated discogenic low back pain. Neuromodulation 2020;23:196–202. 10.1111/ner.12937
    1. Desai MJ, Mansfield JT, Robinson DM, et al. . Regenerative medicine for axial and radicular Spine-Related pain: a narrative review. Pain Pract 2020;20:437–53. 10.1111/papr.12868
    1. Gullbrand SE, Schaer TP, Agarwal P, et al. . Translation of an injectable triple-interpenetrating-network hydrogel for intervertebral disc regeneration in a goat model. Acta Biomater 2017;60:201–9. 10.1016/j.actbio.2017.07.025
    1. Gan Y, Li P, Wang L, et al. . An interpenetrating network-strengthened and toughened hydrogel that supports cell-based nucleus pulposus regeneration. Biomaterials 2017;136:12–28. 10.1016/j.biomaterials.2017.05.017
    1. Yue JJ, Morgenstern R, Morgenstern C. Shape memory hydrogels - A novel material for treating age-related degenerative conditions of the Spine. Eur Musculoskelet Rev 2011;6:184–8.
    1. Sing SH. Lumbar intradiscal treatments: Early evaluation of patient satisfaction in disc repair by nucleus augmentation (GelStixTM). J Tissue Eng Regen Med 2012;6:45.
    1. Ceylan A, İ A, Özgencil GE. Clinical results of intradiscal hydrogel administration (GelStix) in lumbar degenerative disc disease. Turkish J Med Sci 2019;49:1634–9.
    1. Pfirrmann CW, Metzdorf A, Zanetti M, et al. . Magnetic resonance classification of lumbar intervertebral disc degeneration. Spine 2001;26:1873–8. 10.1097/00007632-200109010-00011
    1. Adams MA, Dolan P, Hutton WC. The stages of disc degeneration as revealed by discograms. J Bone Joint Surg Br 1986;68:36–41. 10.1302/0301-620X.68B1.3941139
    1. Merskey H, Bogduk N, Seattle . Classification of Chronic Pain.. In: Descriptions of chronic pain syndromes and definitions of pain terms. 2. WA: IASP Press, 1994.
    1. Fukui S, Nitta K, Iwashita N, et al. . Percutaneous intradiscal high-pressure injection of saline and lidocaine in patients with lumbar intervertebral disc extrusion. J Anesth 2012;26:786–9. 10.1007/s00540-012-1419-1
    1. 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;11:100–6. 10.1016/j.spinee.2010.07.001
    1. Khot A, Bowditch M, Powell J, et al. . The use of intradiscal steroid therapy for lumbar spinal discogenic pain: a randomized controlled trial. Spine 2004;29:833–6. 10.1097/00007632-200404150-00002
    1. Dworkin RH, Turk DC, Farrar JT, et al. . Core outcome measures for chronic pain clinical trials: IMMPACT recommendations. Pain 2005;113:9–19. 10.1016/j.pain.2004.09.012
    1. Fairbank JC, Pynsent PB. The Oswestry disability index. Spine 2000;25:2940–53. 10.1097/00007632-200011150-00017
    1. EuroQol Group . EuroQol--a new facility for the measurement of health-related quality of life. Health Policy 1990;16:199–208. 10.1016/0168-8510(90)90421-9
    1. Cheung JPY, Luk KDK. The relevance of high-intensity zones in degenerative disc disease. Int Orthop 2019;43:861–7. 10.1007/s00264-018-4260-9
    1. Dudli S, Fields AJ, Samartzis D, et al. . Pathobiology of Modic changes. Eur Spine J 2016;25:3723–34. 10.1007/s00586-016-4459-7
    1. Kyere KA, Than KD, Wang AC, et al. . Schmorl’s nodes. Eur Spine J 2012;21:2115–21. 10.1007/s00586-012-2325-9
    1. Peters ML, Sommer M, Van Kleef M. Predictors of physical and emotional recovery 6 and 12 months after surgery. Br J Surg 2010;97:1518–27.
    1. Sullivan MJL, Bishop SR, Pivik J. The pain catastrophizing scale: development and validation. Psychol Assess 1995;7:524–32. 10.1037/1040-3590.7.4.524
    1. Zigmond AS, Snaith RP. The hospital anxiety and depression scale. Acta Psychiatr Scand 1983;67:361–70. 10.1111/j.1600-0447.1983.tb09716.x
    1. Nicholas MK. The pain self-efficacy questionnaire: taking pain into account. Eur J Pain 2007;11:153–63. 10.1016/j.ejpain.2005.12.008
    1. Reid MC, Williams CS, Gill TM. The relationship between psychological factors and disabling musculoskeletal pain in community-dwelling older persons. J Am Geriatr Soc 2003;51:1092–8. 10.1046/j.1532-5415.2003.51357.x
    1. Denison E, Åsenlöf P, Lindberg P. Self-Efficacy, fear avoidance, and pain intensity as predictors of disability in subacute and chronic musculoskeletal pain patients in primary health care. Pain 2004;111:245–52. 10.1016/j.pain.2004.07.001
    1. Kolahi J, Bang H, Park J. Towards a proposal for assessment of blinding success in clinical trials: up-to-date review. Community Dent Oral Epidemiol 2009;37:477–84. 10.1111/j.1600-0528.2009.00494.x
    1. Hróbjartsson A, Emanuelsson F, Skou Thomsen AS, Thomsen ASS, et al. . Bias due to lack of patient blinding in clinical trials. A systematic review of trials randomizing patients to blind and nonblind sub-studies. Int J Epidemiol 2014;43:1272–83. 10.1093/ije/dyu115
    1. Harris PA, Taylor R, Thielke R, et al. . Research electronic data capture (REDCap)--a metadata-driven methodology and workflow process for providing translational research informatics support. J Biomed Inform 2009;42:377–81. 10.1016/j.jbi.2008.08.010
    1. Kahan BC, Morris TP. Reporting and analysis of trials using stratified randomisation in leading medical journals: review and reanalysis. BMJ 2012;345:e5840. 10.1136/bmj.e5840
    1. Manchikanti L, Knezevic NN, Sanapati J, et al. . Is epidural injection of sodium chloride solution a true placebo or an active control agent? A systematic review and meta-analysis. Pain Physician 2021;24:41–59.

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