Research Review By Dr. Brynne Stainsby©

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Date Posted:

February 2020

Study Title:

Diverse role of biological plasticity in low back pain and its impact on sensorimotor control of the spine

Authors:

Hodges PW, Barbe MF, Loggia ML, Nijs J & Stone LS

Author's Affiliations:

Clinical Centre for Research Excellence in Spinal Pain, Injury and Health, School of Health and Rehabilitation Sciences, The University of Queensland, Brisbane, Australia; Anatomy and Cell Biology, Lewis Katz School of Medicine, Temple University, Philadelphia, PA, USA; Athinoula A. Martinos Center for Biomedical Imaging, Massachusetts General Hospital, Harvard Medical School, Charlestown, MA, USA; Physiotherapy, Human Physiology and Anatomy, Faculty of Physical Education and Physiotherapy, Vrije Universiteit Brussel, Brussels, Belgium; Pharmacology and Therapeutics and Department of Anesthesiology, McGill University, Montreal, Canada; Alan Edwards Centre for Research on Pain, Faculty of Dentistry and Faculty of Medicine, McGill University, Montreal, Canada.

Publication Information:

Journal of Orthopaedic & Sports Physical Therapy 2019; 49(6): 389-401.

Background Information:

It is commonly believed that pain and injury are complex processes, leading to multi-system adaptation beyond changes in neural excitation, inhibition and processing. While ‘plasticity’ is a term commonly ascribed to the nervous system, ‘biological plasticity’ is a broader term that has been used to capture the number of biological processes that undergo change in the presence of pain and shape the response of the individual. Pain is no longer considered simply the response to nociceptive stimuli, it requires the understanding of different underlying mechanisms, activation of neural systems (beyond simply the nociceptive neurons), the interactions of the neural and immune systems, tissue changes and the implications on the psychological and social domains. All of these systems have a potential role in the sensorimotor adaptations to pain, as well as the potential for the maintenance of the pain response.

The goal of this commentary is to present a current view of the implications of the biology of pain and injury for sensorimotor function, particularly in the spine.

Summary:

Contemporary View of Biology of Pain:

While pain is an individualized experience, there are some consistent underlying biological mechanisms, which affect the sensorimotor control of the spine. Below the common mechanistic descriptors are outlined:
  • Nociceptive pain (may also be referred to as “pain associated with ongoing nociceptive input”) is defined as pain that is experienced with real or threatening damage to nonneuronal tissues and is driven by the activation of the nociceptors (1). It is typically not evaluated clinically, but the term is commonly used to describe pain that is considered “proportional” to the input, and present within a normally functioning somatosensory system (1-3).
  • Neuropathic pain is defined as pain associated with a lesion or disease of the somatosensory nervous system (1).
  • In many patients, a clear origin is lacking or not severe enough to explain the pain experienced by the patient, and there is no evidence of damage/disease in the somatosensory nervous system. This is often explained by the concept of central sensitization(4), broadly defined as “an amplification of neural signalling within the central nervous system (CNS) that elicits pain hypersensitivity” (5) or “increased responsiveness of nociceptive neurons in the CNS to their normal or subthreshold input” (1). This is a common descriptor for chronic pain states. It should be noted that central pain (6), centralized pain (7) or central sensitization pain (8, 9) are terms that are often used interchangeably, but do not necessarily refer to the neurophysiological process of sensitization. The related term nociplastic has been defined by the International Association for the Study of Pain to describe “pain that arises from altered nociception despite no clear evidence of actual or threatened tissue damage causing the activation of peripheral nociceptors or evidence for disease or lesion of the somatosensory system causing the pain” (10).
  • Central sensitization can be demonstrated by altered sensory processing, including increased activity of brain-orchestrated nociceptive faciliatory pathways (11), poor functioning of descending antinociceptive mechanisms (12), and increased activity of brain-orchestrated nociceptive facilitatory pathways (11). Clinically, psychological attributes (such as fear of pain or catastrophizing) are common, and can affect sensitization.
  • Patients may also present with mixed presentations of chronic pain, and there is some evidence that a group of patients may have predominantly psychogenic pain, and present mainly with maladaptive, illness behaviours (8).
  • The presentation and relevance of sensorimotor features may differ between nociceptive, neuropathic and nociplastic/central pain, and likely require different approaches to management and rehabilitation. For example, tailoring treatment to optimise loading by rehabilitating the motor control system would be important for those with nociceptive pain, while those with nociplastic/central pain may require cognition-targeted exercises with pain neuroscience education (13, 14).
Neuroimmune Interactions in the Nervous System:
  • It is believed neuronal mechanisms are likely critical in the development of chronic pain, and in the past decade, animal research has highlighted the role glial cells may play in the development/maintenance of persistent pain conditions (15-17).
  • In the presence of a pain-initiating event such as an injury, microglia and astrocytes because “activated” (16,17) and upregulate the expression of receptors, increase the release of enzymes, inflammatory mediators, proinflammatory cytokines and chemokines, which sensitize the neural pathways involved in pain (18). In the acute phase, this can be protective as it limits further damage and promotes healing, however, if the activation is recessive or does not dissipate after the injury, glial activation creates a “pain produces pain” loop and is believed to be a critical event in central sensitization.
  • Pain-related neuroinflammation has been observed in the spinal cord (16) and sensory ganglia (19) and recently, has been discovered in the brain as well (20-25).
  • Recent human studies have provided in vivo evidence that glial cells may have a role in human LBP, using positron emission tomography (PET) scans to identify increased tracer binding in regions of the brain in those with chronic low back pain (26).
  • In another human study, authors found increased signals in the spinal cord of those with lumbar radiculopathy and noted the amount of inflammation predicted the amount of perceived relief after epidural steroid injection (27). Further research is required to better interpret results, but these findings do suggest the role of the neural system in the dysfunction related to the sensorimotor control of the spine.
  • Glial cells may also influence the availability of neurotransmitters (28), remove unused synapses and release molecules that regulate neuron structure, function and connectivity (29). It is therefore plausible that glial activation may play a role in modified motor and sensory function in those with persistent pain. This hypothesis has the potential to inform therapy; both pharmacological interventions and possibly even exercise to moderate glial activation.
Neuroimmune Interaction in the Somatic Tissues:
  • In the musculotendinous tissues, the role of the immune system is to phagocytose injured cells. The release of immune mediators sensitize the primary afferent terminals and increase vascular permeability. Typically, these are short-lived, reversible markers of acute inflammation but if the tissue does not have the opportunity to complete the healing process, persistent/chronic inflammation may develop (30).
  • At the cellular level, chronic inflammation is characterized by the prolonged presence of macrophages in/around tissues, which may contribute to secondary tissue damage.
  • In animal studies, the prolonged presence of inflammatory cytokines can lead to the production of an even greater number of cytokines and chemokines, increase the permeability of vessel walls, promote fibrosis and sensitize primary afferent terminals (increasing pain) (31-33). It is also possible that inflammatory cytokines can enter the blood stream and lead to systemic inflammatory effects, tissue damage and pain hypersensitivity (31). The pain-related neuropeptide, substance P, is produced by both neurons and peripheral immune cells, and can be linked to peripheral immune responses, central sensitization and enhanced pain behaviours in animals, though further research regarding its effects on humans is required. It is possible that substance P release may impact structural changes in back muscles of those with LBP (though this data is not yet published).
  • Peripheral immune system changes have possible relevance regarding the sensorimotor control of the spine. Sensitization decreases the threshold for nociceptor discharge (32) and may lead to increased muscle guarding. Tissue changes are also likely to impact muscle control and may limit or distort movement. Exercise can theoretically impact immune system activity and reverse tissue changes, however, the appropriate time course and movement specifics must be carefully determined.
Brain and Peripheral Tissue Interaction:
  • Mouse models have suggested that age-related intervertebral disc (IVD) degeneration increases disc innervation loss of disc height, muscle inflammation, sensory neuron plasticity and neuroinflammation in the spinal cord, which may contribute to chronic LBP (34-37). Interestingly, providing animals with a running wheel for several months attenuated behavioural indices of pain and histological/biochemical signs of disc pathology (unpublished data).
  • If peripheral structures such as the IVD contribute to chronic LBP, and the brains of those who have chronic pain are different from pain-free controls, it is important to consider whether chronic pain drives brain changes, or if there may be cortical features that could predispose one to chronic pain. In rats, it appears that peripheral input drove CNS pathology, however future research is required. In humans, subjects with chronic LBP underwent functional MRI, and changes in the prefrontal cortex and function both improved as subjects reported improvement in pain and disability (38,39). In contrast, in another study of subjects with chronic LBP, subjects who responded well to conservative treatment did not demonstrate any gray matter morphological changes (40). Further research is required.
  • Peripheral nociceptive input mediated by suboptimal sensorimotor control of the spine can cause and maintain maladaptive brain structural and functional changes. Combination of pharmacological and nonpharmacological interventions that target peripheral inputs from the spine and pathological CNS plasticity should be considered.

Clinical Application & Conclusions:

This body of literature is in its early stages, however, this commentary summarized the impact of biological processes on the pain experience and sensorimotor control. It highlighted the importance of considering targeted interventions to address both peripheral input and CNS plastic changes and identified the potential opportunity for exercise therapy to impact pain. Importantly however, the authors identified that further research is required before identifying specific clinical recommendations.

Study Methods:

This was a clinical commentary that did not report methodology.

Study Strengths / Weaknesses:

Strengths:
  • This commentary summarizes theoretical constructs related to the biological plasticity in a well-organized, well-described manner.
  • The authors carefully identify the limitations in the literature, particularly animal models and unpublished research, and caution readers from drawing unsupported conclusions.
  • The authors helpfully identify the fact that this field literature is characterized by inconsistency in findings.
  • Clinical suggestions for multimodal treatment approaches are provided.
Weaknesses:
  • The greatest weakness of this study is the lack of methodology reported. Without this, we cannot be confident that the conclusions were not subject to high risk of bias.
  • While this article provides a summary of the literature included, there is no formal assessment of the methodology or research quality. The authors included a number of unpublished and animal studies.
  • There is no comment on the participants or clinical setting of the included studies, thus limiting the external validity of the review.

Additional References:

  1. Merskey H, Bogduk N, International Association for the Study of Pain Task Force on Taxonomy. Part III: pain terms: a current list with definitions and notes on usage. In: Classification of Chronic Pain: Descriptions of Chronic Pain Syndromes and Definitions of Pain Terms. 2nd ed. Seattle, WA: IASP Press; 1994: 209-214.
  2. Kosek E, Cohen M, Baron R, et al. Do we need a third mechanistic descriptor for chronic pain states? Pain 2016; 157: 1382-1386.
  3. Smart KM, Blake C, Staines A, et al. Mechanisms-based classifications of musculoskeletal pain: part 3 of 3: symptoms and signs of nociceptive pain in patients with low back (±leg) pain. Man Ther 2012; 17: 352-357.
  4. Ross E. Moving towards rational pharmacological management of pain with an improved classification system of pain. Expert Opin Pharmacother 2001; 2: 1529-1530.
  5. Woolf CJ. Central sensitization: implications for the diagnosis and treatment of pain. Pain 2011; 152: S2-S15.
  6. Gleeson M, Bishop NC, Stensel DJ, et al. The anti-inflammatory effects of exercise: mechanisms and implications for the prevention and treatment of disease. Nat Rev Immunol 2011; 11: 607-615.
  7. Clauw DJ. Diagnosing and treating chronic musculoskeletal pain based on the underlying mechanism(s). Best Pract Res Clin Rheumatol 2015; 29: 6-19.
  8. Nijs J, Apeldoorn A, Hallegraeff H, et al. Low back pain: guidelines for the clinical classification of predominant neuropathic, nociceptive, or central sensitization pain. Pair Physician 2015; 18: E333-E346.
  9. Smart KM, Blake C, Staines A, et al. Mechanisms-based classifications of musculoskeletal pain: part 1 of 3: symptoms and signs of central sensitisation in patients with low back (±leg) pain. Man Ther 2012; 17: 336-344.
  10. International Association for the Study of Pain. IASP Terminology. Available at: https://www.iasp-pain.org/Education/Content. aspx?ltemNumber=1698. Accessed November 25, 2018.
  11. Staud R, Craggs JG, Robinson ME, et al. Brain activity related to temporal summation of C-fiber evoked pain. Pain 2007; 129: 130-142.
  12. Yarnitsky D. Conditioned pain modulation (the diffuse noxious inhibitory control-like effect): its relevance for acute and chronic pain states. Curr Opin Anaesthesiol 2010; 23: 611-615.
  13. Malfliet A, Kregel J, Meeus M, et al. Applying contemporary neuroscience in exercise interventions for chronic spinal pain: treatment protocol. Braz J Phys Ther 2017; 21: 378-387.
  14. Nijs J, Uuch Girbes E, Lundberg M, et al. Exercise therapy for chronic musculoskeletal pain: innovation by altering pain memories. Man Ther 2015; 20: 216-220.
  15. Nijs J, Uuch Girbes E, Lundberg M, et al. Exercise therapy for chronic musculoskeletal pain: innovation by altering pain memories. Man Ther 2015; 20: 216-220.
  16. Gritsch S, Lu J, Thilemann S, et al. Oligodendrocyte ablation triggers central pain independently of innate or adaptive immune responses in mice. Nat Commun 2014: 5: 5472.
  17. Ji RR, Berta T, Nedergaard M. Glia and pain: is chronic pain a gliopathy? Pain 2013; 154 suppl 1: S10-S28.
  18. Ji RR, Chamessian A, Zhang YQ. Pain regulation by non-neuronal cells and inflammation. Science 2016; 354: 572-577.
  19. Mika J. Modulation of microglia can attenuate neuropathic pain symptoms and enhance morphine effectiveness. Pharmacol Rep 2008; 60: 297-307.
  20. Laursen JC, Cairns BE, Dong XD, et al. Glutamate Glutamate dysregulation in the trigeminal ganglion: a novel mechanism for peripheral sensitization of the craniofacial region. Neuroscience 2014; 256: 23-35.
  21. Roberts J, Ossipov MH, Porreca E. Glial activation in the rostroventromedial medulla promotes descending facilitation to mediate inflammatory hypersensitivity. Eur J Neurosci 2009; 30: 229-241.
  22. Wei XH, Wei X, Chen FY, et al. The upregulation of translocator protein (18 kDa) promotes recovery from neuropathic pain in rats. J Neurosci 2013; 33: 1540-1551.
  23. Lee S, Zhao YQ, Ribeiro-da-Silva A, et al. Distinctive response of CNS glial cells in orofacial pain associated with injury, infection and inflammation. Mol Pain 2010; 6: 79.
  24. Okada-Ogawa A, Suzuki I, Sessle BJ, et al. Astroglia in medullary dorsal horn (trigeminal spinal subnucleus caudalis) are involved in trigeminal neuropathic pain mechanisms. J Neurosci 2009; 29: 11161-11171.
  25. LeBlanc BW, Zerah ML, Kadasi LM, et al. Minocycline injection in the ventral posterolateral thalamus reverses microglial reactivity and thermal hyperalgesia secondary to sciatic neuropathy. Neurosci Lett 2011; 498: 138-142.
  26. Zhao R Waxman SG, Hains BC. Modulation of thalamic nociceptive processing after spinal cord injury through remote activation of thalamic microglia by cysteine-cysteine chemokine ligand 21. J Neurosci 2007; 27: 8893-8902.
  27. Loggia ML, Chonde DB, Akeju 0, et al. Evidence for brain glial activation in chronic pain patients. Brain 2015; 138: 604-615.
  28. Albrecht DS, Ahmed SU, Kettner NW, et al. Neuroinflammation of the spinal cord and nerve roots in chronic radicular pain patients. Pain 2018; 159: 968-977.
  29. Hirrlinger J, Nave KA. Adapting brain metabolism to myelination and long-range signal transduction. Glia 2014; 62: 1749-1761.
  30. Gomez-Casati ME, Murtie JC, Rio C, et al. Nonneuronal cells regulate synapse formation in the vestibular sensory epithelium via erbB-dependent BDNF expression. Pro c Natl Acad Sc/ USA 2010; 107: 17005-17010.
  31. Barr AE, Barbe MF. Inflammation reduces physiological tissue tolerance in the development of work-related musculoskeletal disorders. J Electromyogr Kinesiol 2004; 14: 77-85.
  32. Barbe ME Barr AE. Inflammation and the pathophysiology of work-related musculoskeletal disorders. Brain Behav Immun 2006; 20: 423-429.
  33. Bove GM, Weissner W, Barbe ME. Long lasting recruitment of immune cells and altered epiperineurial thickness in focal nerve inflammation induced by complete Freund's adjuvant. J Neuroimmunol 2009; 213: 26-30.
  34. Fisher PW, Zhao Y, Rico MC, et al. Increased CCN2, substance P and tissue fibrosis are associated with sensorimotor declines in a rat model of repetitive overuse injury. J Cell Commun Signal 2015; 9: 37-54.
  35. James G, Millecamps M, Stone LS, et al. Dysregulation of the inflammatory mediators in the multifidus muscle after spontaneous intervertebral disc degeneration [in] SPARC-null mice is ameliorated by physical activity, Spine 2018; 43: E1184-E1194.
  36. Millecamps M, Tajerian M, Naso L, et al. Lumbar intervertebral disc degeneration associated with axial and radiating low back pain in ageing SPARC-null mice. Pain 2012; 153: 1167-1179.
  37. Millecamps M, Tajerian M, Sage EH, et al. Behavioral signs of chronic back pain in the SPARC-null mouse. Spine 2011; 36: 95-102.
  38. Miyagi M, Millecamps M, Danco AT, et al. ISSLS Prize winner: increased innervation and sensory nervous system plasticity in a mouse model of low back pain due to intervertebral disc degeneration. Spine 2014; 39: 1345-1354.
  39. Ceko M, Shir Y, Ouellet JA, et al. Partial recovery of abnormal insula and dorsolateral prefrontal connectivity to cognitive networks in chronic low back pain after treatment. Hum Brain Mapp 2015: 36: 2075-2092.
  40. Seminowicz DA, Wideman TH, Naso L, et al. Effective treatment of chronic low back pain in humans reverses abnormal brain anatomy and function. J Neurosci 2011; 31: 7540-7550.
  41. Malfliet A, Kregel J, Coppieters I, et al. Effect of pain neuroscience education combined with cognition-targeted motor control training on chronic spinal pain: a randomized clinical trial. JAMA Neurol 2018: 75: 808-817.