Also see Role of Disc Degeneration in Pain Explored, NIH Record (January 16, 2015) Scroll down to fifth item.
Neck and back pain is a significant public health problem in the United States. Approximately 11-14 percent of working age adults will experience work-related activity limitations due to neck pain.1 Many more are affected by low back pain; 70 percent of Americans experience low back pain that is serious enough to disrupt daily routines during their lifetime.2
Chronic spinal pain is often progressive, and its causes can be difficult to determine. It also is expensive. Low back pain and neck pain are the first and fourth leading causes, respectively, of years lived with disability.3 In 2005, costs associated with spinal pain in the United States totaled $86 billion.4
Much of that expense is due to chronic, rather than acute, pain. For example, despite comprising only 5 percent of the people who have back pain, patients with chronic back pain consume 90 percent of all the healthcare costs associated with the condition.2 Chronic back pain’s costs to society, and the opportunities to reduce those costs, have earned the condition a place in Healthy People 2020 as part of the objective “Reduce activity limitation due to chronic back conditions.”
Early identification and treatment of those individuals with acute neck or back pain who will go on to develop chronic pain could possibly lessen the prevalence and severity of these public health problems. This unmet clinical need could be addressed by innovative research to:
- Better understand the mechanisms underlying chronic neck and back pain,
- Identify predictive markers of chronic spinal pain so that appropriate preventive strategies can be undertaken, and
- Develop methodologies and model systems for identifying and studying disease subtypes and for testing potential treatments.
Many of the common causes of neck and back pain involve instability or degeneration of the intervertebral disc. Therefore, as part of the Institute’s annual planning process, NIAMS held a roundtable discussion on the current state of the science related to the following questions:
- What are the links between biochemical and biomechanical features of disc degeneration and OA of the spine, and generation of back and neck pain? How can this knowledge be leveraged to develop tools that can distinguish between structural, biochemical or biomechanical changes in discs and surrounding structures (e.g., facet joints) that lead to pain and those that are asymptomatic?
- What are the greatest scientific challenges related to understanding pathological changes leading to disc degeneration? What are the greatest scientific challenges related to understanding pathological changes leading to OA of the spine? How will overcoming these challenges contribute to the identification of potential therapeutic targets?
- What new knowledge is needed to develop in vivo and in vitro models for studies of the links between disc degeneration and OA of the spine and their connection to the development of pain?
- How can the community adapt high throughput or emerging technologies to identify promising new biochemical, imaging, and genetic biomarkers of symptomatic disc degeneration and spinal pathology? This latter point could include analysis of images collected from existing cohorts.
- What are the most pressing scientific questions regarding the structural, biochemical, and biomechanical mechanisms leading to back and neck pain?
Participants were asked to canvass their colleagues in advance of the meeting, and their responses served as the basis for the discussion. Although not all of these topics were discussed in depth at the roundtable, NIAMS leadership and the appropriate program staff read each comment. The NIAMS greatly appreciates the community’s input on these questions.
Opportunities to Understand the Biochemical and Biomechanical Features of Disc Degeneration and their Connections to Neck and Back Pain
Normal disc development and anatomy
Investigators who are exploring disc degeneration could benefit from knowledge about how discs develop and how the body maintains mature discs. Molecular, cellular, and animal studies across different developmental stages and cell types could provide knowledge about normal, healthy tissues. This information could contribute to the discovery of therapeutic compounds and regenerative medicine strategies and could provide target benchmarks against which to measure an intervention’s success.
Disc degeneration is a broad term that encompasses factors such as loss of disc height, vertebral subluxation, disc bulging or herniation, and osteophyte formation. Because most patients do not receive medical attention for back and neck pain at the earliest stages of degeneration, little is known about the changes that occur during the initial phases of the process in humans. However, patients who have spinal fusion often develop disc degeneration in adjacent segments. If investigators could determine which biochemical and structural changes are due to the fusion process, they could also track the earliest steps of the degenerative process in these patients.
Examining gene and protein expression patterns in tissue from humans and animals, and how they change over the lifespan, might identify markers that could be used to monitor disc degeneration and response to interventions meant to restore or stabilize discs. This research also may help differentiate between structural changes and the pain experience.
There are various strategies for identifying biomarkers of disc degeneration (e.g., circulating microRNAs, exosomes, hypertrophic chondrocytes, the presence of inflammatory markers). Some markers from degenerating discs can be distinguished from those produced by other cartilaginous tissues. While the discovery of biochemical or biomechanical signs pointing to the degenerative changes that lead to pain would be useful, markers that are associated with a person’s risk of developing neck or back pain prior to becoming symptomatic may be easier to identify via existing technologies.
Genetics influence both disc degeneration and pain susceptibility. Researchers are beginning to identify genetic variants that protect against pain and disability following spinal fusion.5 They also are beginning to understand the genetics of chronic pain conditions. In contrast, little is known about which variants are protective against disc degeneration and neck or back pain. The ability to distinguish between the genetic influences of disc degeneration and neuronal infiltration also would be useful for identifying the source of neck and back pain.
Immunity and inflammation
In a healthy spine, the nucleus pulposus is protected from the immune system. During the earliest stages of degeneration, the cells comprising the nucleus pulposus produce molecular signals (e.g., cytokines and chemokines) that interact with the anulus fibrosus, bone cells, and innervated tissues such as muscle. As the disc structure changes, inflammation and immune reactions can develop in the discs and the surrounding tissues. Disc degeneration contributes to inflammation, which in turn causes the discs to break down further. Deteriorating discs also secrete factors that sensitize nerves or cause them to infiltrate the disc. These, in turn, can cause additional structural changes and pain. The initial events that trigger cytokine production and the launch of an immune response are unknown. Some suggested that infection may be involved, but this hypothesis is not universally accepted.
Pain and the intervertebral disc in the context of the entire spine
At present, it is impossible to definitively state that a person’s neck or back pain is due to a degenerating disc. Many tissues in addition to the intervertebral disc can cause pain. Much remains to be learned about how other spine components such as damaged vertebral endplates, bone marrow lesions in vertebra, and innervated ligaments also contribute. Moreover, researchers do not fully understand how structural changes in one tissue influence the deterioration of others. For example, altered motion due to facet joint arthritis will impact nearby discs, and degenerated discs will alter facet joint movement. There can be value in studying the spine as an organ system instead of as individual tissues, cell types, and structural components.
Studying the mechanical components of neck and back pain also is important. For many patients, pain disappears at rest and reappears upon loading, while movement provides relief for others. Dynamic imaging tools that correlate with patient experience would be useful for studies of these phenomena.
Challenges Related to Studying the Pathological Changes that Lead to Disc Degeneration and Developing Treatments for Neck and Back Pain
Imaging tools for clinical and preclinical research
Close collaborations with engineers can enable development of the advanced tools needed for studies of neck and back pain. Suggestions at this meeting included strategies to measure fatty infiltration of interspinal muscles as well as changes in intervertebral disc microarchitecture. Discussion also focused on strategies to measure molecular and metabolic changes that occur before structural changes are noticeable. Imaging tools can be valuable even if they are not suitable for routine patient care.
Although much of the imaging work is being done in large animal models, researchers also expressed an interest in the ability to visualize discs of small rodent models such as mice. Creation and validation of high-throughput imaging modalities would allow investigators to track the formation of the intervertebral disc and other tissues during development.
Imaging needs extend beyond the intervertebral discs and surrounding tissues. Advanced brain imaging technologies also could be relevant when studying the link between disc degeneration and neck or back pain.
The distinction between changes at the tissue level and the perception of pain
Some healthy tissues such as the vertebral endplate and intervertebral disc are unable to sense pain until they become innervated following an injury. Although nociception could be a therapeutic target in these situations, researchers would benefit from better strategies to detect new neurons and measure their activity.
A treatment may restore a disc to its original structure without reducing pain. Although researchers conducting preclinical work cannot ask their study animals to say how they are feeling, there are other approaches for assessing an animal’s pain. Although this knowledge could be combined with molecular and structural analyses to develop hypotheses about how biologic changes relate to pain, researchers cautioned that the human pain experience is influenced by factors beyond the tissue level (e.g., psychological phenomenon, cultural roles). This complicates the application of findings from animal studies to humans.
Animal and tissue culture models
All models for disc degeneration and pain have advantages and disadvantages. Discs degenerate quickly in animal models of acute injury, but the processes involved may differ from those that occur in humans as they age. Diffusion allows the small discs in the mouse spine to be better nourished and more metabolically active than those in larger animals.
Tissue culture studies can provide information about interactions among disc cells, the nervous system, and the immune system. Model systems that recapitulate other components of the spine could be informative.
Well-phenotyped human tissue samples
A lack of well-phenotyped human tissue samples is another challenge facing the research community. While cadavers were mentioned as a potential source of human tissue, these donors lack the phenotypic data that would be useful for studies into the role of the degenerating disc in neck or back pain. Researchers would like the ability to perform a “virtual biopsy” on disc tissue because they are not able to collect tissue from people.
The ability to gather longitudinal data related to back pain during activities of daily living
The research community is interested in being able to gather longitudinal data about neck and back pain and patient function. A device (akin to the heart monitors that cardiac patients wear) that would collect data on people’s behavior, and on how their movements change based on their pain levels, may be useful for this purpose. Combining longitudinal data with clinical information and the as-yet-to-be-discovered markers of early disc degeneration noted above may enable researchers to identify people who are at high risk of developing neck or back pain.
Measures of success
There are several challenges related to evaluating potential therapies. Some treatments, such as microdiscectomy for a herniated lumbar disc, may relieve pain initially, but predispose patients for later problems. Some regenerative therapies could restore discs to their normal anatomy, but they may do little to restore pain and mobility.
Collaborations and partnerships might overcome some of the challenges noted above. Partnerships between investigators and industry might facilitate the development of tools for monitoring behavior, diagnosing painful degenerative discs, and treating disc-associated neck and back pain. The Foundation for the National Institutes of Health (FNIH) Biomarkers Consortium, the NIH Accelerating Medicines Partnership (AMP), and the National Science Foundation’s Industry/University Cooperative Research Centers (I/UCRC) Program were mentioned as potential models. Others noted that the NIH Health Care Systems Research Collaboratory and the National Patient-Centered Clinical Research Network (PCORNet) have large amounts of data that could answer questions about disease progression (e.g., the transition from acute to chronic neck or back pain), the effectiveness of treatments, and health care utilization and costs.
- Hughes SP, Freemont AJ, Hukins DW, McGregor AH, Roberts S. The pathogenesis of degeneration of the intervertebral disc and emerging therapies in the management of back pain. J Bone Joint Surg Br. 2012 Oct;94(10):1298-304. Review. PMID: 23015552
- Lotz JC, Fields AJ, Liebenberg EC. The role of the vertebral end plate in low back pain. Global Spine J. 2013 Jun;3(3):153-64. Review. PMID: 24436866
- Risbud MV, Shapiro IM. Role of cytokines in intervertebral disc degeneration: pain and disc content. Nat Rev Rheumatol. 2014 Jan;10(1):44-56. Review. PMID: 24166242
- Winkelstein BA, Weinstein JN. Pain Mechanisms: Relevant Anatomy, Pathogenesis and Clinical Implications, in The Cervical Spine 4th edition, Clark CR, Ed., 122-132, 2004.
ANDERSSON, Gunnar B.J., M.D., Ph.D., Rush University Medical Center (co-chair)
BOWLES, Robert (Robby) D., Ph.D., University of Utah
DAHIA, Chitra, Ph.D., Hospital for Special Surgery
ELLIOTT, Dawn M., Ph.D., University of Delaware
HARFE, Brian, Ph.D., University of Florida, Gainesville, Florida
IATRIDIS, James C., Ph.D., Icahn School of Medicine at Mount Sinai
KHALSA, Partap S., D.C., Ph.D., National Center for Complementary and Alternative Medicine (NCCAM), NIH
LOTZ, Jeffrey, Ph.D., University of California, San Francisco
MWALE, Fackson, Ph.D., McGill University
PORTER, Linda, Ph.D., National Institute of Neurological Disorders and Stroke (NINDS), NIH
RISBUD, Makarand V., Ph.D., Thomas Jefferson University
SCHIPANI, Ernestina, M.D., Ph.D., University of Michigan
SETTON, Lori A., Ph.D., Duke University (co-chair)
WINKELSTEIN, Beth A., Ph.D., University of Pennsylvania
CARTER, Robert H., M.D.
DRUGAN, Jonelle K., Ph.D., M.P.H.
KATZ, Stephen I., M.D., Ph.D.
KESTER, Mary Beth, M.S.
LESTER, Gayle, Ph.D.
LINDE, Anita M., M.P.P.
McGOWAN, Joan A., Ph.D.
MOEN, Laura K., Ph.D.
PANAGIS, James S., M.D., M.P.H. (co-chair)
SERRATE-SZTEIN, Susana A., M.D.
TYREE, Bernadette, Ph.D.
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4Expenditures and health status among adults with back and neck problems. Martin BI, et al. JAMA. 2008 Feb 13;299(6):656-64. doi: 10.1001/jama.299.6.656. Erratum in: JAMA. 2008 Jun 11;299(22):2630. PMID: 18270354
5Treatment outcome of chronic low back pain and radiographic lumbar disc degeneration are associated with inflammatory and matrix degrading gene variants: a prospective genetic association study. Omair A, Holden M, Lie BA, Reikeras O, Brox JI. BMC Musculoskelet Disord. 2013 Mar 22;14:105. doi: 10.1186/1471-2474-14-105. PMID: 23522322