Discogenic Pain

Chapter 6 Discogenic Pain

Intradiscal Therapeutic Injections and Use of Intradiscal Biologic Agents

Chapter Synopsis: Discogenic pain is a complex process with multiple components. After an annular tear of the intervertebral disc, nociceptors and blood vessels invade new areas of the disc that are normally noninnervated and avascular. Cytokine alterations promote nociception, both directly and indirectly, while altered anabolic-catabolic balance compromises the disc’s hydraulic load-bearing function, also effecting changes in the intervertebral joints. This chapter assesses the nonsurgical therapies available to combat each of these components of lumbar discogenic pain. Growth factors in the bone morphogenetic protein family show promise in repairing metabolic and even structural disc abnormalities, but nonspecific anabolic effects of any growth factor must be considered. Although this treatment has potential, it is still in development. Intradiscal injection of fibrin sealants has been shown to improve cell proliferation and matrix production. Although still in an early stage, this therapy seems to address all the components of discogenic pain and disease. Many in the field are excited about the potential for stem cell therapy for discogenic disease. Mesenchymal stem cells transform into chondrocytes, which produce collagen and aggrecan to maintain the disc’s structural integrity. Several currently available therapies are also considered, including pharmaceutical interventions and therapies to ablate nociceptive structures.

Important Points:

Intradiscal ablative agents ethanol and methylene blue seem to be effective treatments for discogenic pain, requiring careful use to avoid potential epidural spread, but are readily available for use today.

Intradiscal fibrin sealants may represent a useful interim step for addressing discogenic pain; studies are underway.

Use of mesenchymal stem cells could be an emerging restorative agent but requires further research.

Clinical Pearls: Understanding the anatomy and pathophysiology of discogenic pain allows thoughtful consideration of emerging paradigms and techniques for treatment. The specific mechanism of delivery and confinement of any drug or biological modality to an anatomic disc target is critical to the success and safety of any of these techniques.

Clinical Pitfalls: Many published studies report on treatments for degenerated discs, radicular pain, or sciatica and overbroadly refer to these conditions as “discogenic pain.” Many techniques applicable for radicular pain have not proven useful for discogenic pain originating from a painful posterior annular tear. Imprecision in nomenclature is frequent, even in contemporary surgical literature. Novel techniques require confirmation of safety and efficacy in human trials before widespread use.

In lumbar discogenic pain the injured intervertebral disc produces pain not only as a primary nociceptive structure but also as a result of reduced disco-vertebral mechanical load-bearing capacity and subsequently altered spinal biomechanics, including increased zygapophyseal joint loading. As a consequence, therapeutic strategies for discogenic pain are directed toward three general objectives: (1) resolution of primary nociception resulting from post-injury neoinnervation and neovascularization of the posterior annular tear; (2) restoring or mitigating the pro-nociceptive anabolic-catabolic imbalance, including restoration of normalized cytokine immunochemistry within the nucleoannular biochemical and cellular milieu; and (3) restoring lost mechanical and hydraulic function, including the loss of intervertebral hydrostatic pressure, intervertebral disc height, and annular integrity. Therapeutic approaches may rely on direct molecular effects, gene induction or suppression, or cellular replacement. This chapter discusses present and emerging clinical intradiscal therapies for discogenic pain within this triad of therapeutic objectives.

The adult lower lumbar intervertebral discs are the largest structures within the human body that have no dedicated primary arteriovenous vascular supply, except a small marginal circulation to the outermost annulus, since the vascular buds in the vertebral endplates have typically regressed by 10 years of age. As a consequence, delivery of oxygen and glucose, as well as removal of metabolic waste products, is dependent on diffusion of these substances through the vertebral body endplates, producing a nuclear milieu marked by low oxygen tension, low pH, and a predominance of lactate over glucose as a metabolic substrate. Age- and injury-related changes to the vertebral endplate region may further compromise diffusion transport of nutrients and waste, creating an increasingly challenging milieu for the survival and proliferation of nuclear chondrocytes. The possibility of improving diffusion transport across the vertebral endplates by 7% to 11% as measured by magnetic resonance imaging (MRI) with use of nimodipine has been reported by Rajasekaran and associates.¹ The minimal reparative capacity of nuclear chondrocytes following injury to the intervertebral disc is compounded by the absence of the typical macromolecular humoral and cellular responses to injury seen elsewhere in the human body. The spectrum of discal response to injury, including the immunobiochemistry of the intervertebral disc, has been recently reviewed by Freemont.²

The posterior annulus of the lumbar intervertebral disc is normally innervated only in its outermost third, with innervation of the middle or inner thirds or of the nucleus limited to pathologically painful states. Mechanical injury to the posterior annulus may tear the posterior annular lamellae, with the result that multiple torn lamellar defects overlap one another in order to combine as radial fissures. The fissure can be confined to the middle or outer annulus, but in painful states, more commonly extends from the nucleoannular junction into or through the posterior annulus. Small tears in the outer annulus appear to accompany neovascularization and neoinnervation of the normally avascular and noninnervated middle and inner third of the annulus. Annular tears and nuclear degeneration may result in compromise of the native broad distribution of loading forces across the intervertebral disc, leading ultimately to a preponderance of load bearing along the annular rim or limbus region, further exacerbating annular wall stress during mechanical loading.

Normal nuclear chondrocytes maintain the hygroscopic nuclear matrix by producing collagen II, aggrecan, and a regulatory protein, SOX-9, with resultant hydrostatic pressure that allows optimal load bearing by distribution of that load across the annulus and vertebral endplates by the intact disco-vertebral unit. While the loss of annular integrity is usually cited as the initiating event in discogenic pain, there is evidence that repetitive mechanical loading stress produces pro-nociceptive changes in the function of nuclear cells.³ Interestingly, it appears that some moderate degree of dynamic cyclical mechanical stress is associated with improved production of collagen and glycosaminoglycan by cells in the annulus fibrosus and nucleus pulposus as compared to cells undergoing either no cyclic loading or those undergoing high compressive stress.⁴ Homeostatic functioning of the nuclear cells also depends upon a delicate balance between cytokine interleukin-1 (IL-1) and its associated receptors and receptor antagonists. Disruption of the IL-1 system can initiate biochemical changes, including a transition from nuclear collagen II to collagen I production, induction of matrix metalloproteinases, and cellular apoptosis. Although tumor necrosis factor (TNF)-α initiates inflammation and pain when applied to a somatic nerve root or to a sciatic nerve, antagonists of TNF-α (such as etanercept) have not proven useful in the treatment of discogenic pain.^5,⁶ TNF-α may also play a role in promoting sensory neoinnervation of the injured disc.⁷ Members of the transforming growth factor (TGF)-β superfamily, which includes the bone morphogenetic protein (BMP) family and SOX-9, have been experimentally demonstrated to result in stimulation of collagen and proteoglycan production as well as the proliferation of nuclear cells; however, the relative stimulatory potency of the different BMPs varies.⁸ BMP-7 (also called OP-1) has been shown to produce restoration of disc height and water content after initiation of degenerative changes using a rabbit stab injury model.⁹ BMP-2 has been used experimentally to achieve intradiscal fusion. Concerns common to most BMPs include avoiding the formation of locally unwanted new bone or blood vessels and maintaining a specific locus of action with predictable termination or modulation of effect so unopposed anabolism does not produce distant or anatomically widespread adverse effects such as proliferative hyperostosis or neoplasm.

The cost of BMPs and injectable growth factors remains a concern. One alternative strategy is to seek inexpensive drugs that stimulate BMP production. Zhang and associates ¹⁰ have demonstrated that injection of intradiscal simvastatin (Zocor) in a PEG-PLGA-PEG gel stimulates BMP-2 and produces improvement in nuclear morphology and anabolic changes in a rat model. Although these growth factors and modulators represent an exciting and potentially transformative treatment for human discogenic pain, research using nonbipedal animal models may not translate to effective human treatments; and much additional research will be required to define optimal combinations of pharmacologic moiety and carrier. Human clinical trials with sufficiently lengthy follow-up to answer concerns regarding long-term potential for efficacy or harm will also be necessary.

Modulation of discogenic pain by a series of three intradiscal injections given at 2-month intervals using a solution of chondroitin sulfate, glucosamine, carboxycellulose, dextrose, and a cephalosporin antibiotic has been pioneered by Eek. Derby and Eek ¹¹

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