Subclassification of Radicular Pain Using Neurophysiology and Embryology

Editor's note: The following article originally appeared in the Proceedings of the 7th Interdisciplinary World Congress on Low Back & Pelvic Pain in 2010; it is reprinted with permission from the authors and the congress.

Introduction

Radicular pain remains a topic of debate and confusion within the field of spine care.¹ Although by definition the term dictates the source of the pain as the radix, or nerve root, it has become a generic term for leg pain related to the lumbar spine, without appropriate consideration of the structures involved or the related neurophysiology. Since pain is a neurophysiological phenomenon, understanding, and therefore classification, must include neurophysiological mechanisms. These mechanisms then must be applied to the involved structures, which have different embryological derivations. By using a combination of embryology and neurobiology, it is possible to classify any pain, including radicular pain, as nociceptive or neuropathic, no matter what anatomical region or source.

Why Pain Can Only Be Nociceptive or Neuropathic: Embryological Basis

Whether a patient presents with shoulder pain, back pain, radicular pain, peripheral nerve pain, or headaches, the pain can only be nociceptive or neuropathic.^2-9 The basis of this tenet is that pain-generating structure is either neural or not neural. If the damaged or diseased structure is neural, the pain is neuropathic. If the structure is not neural, the pain is nociceptive. This distinction related to radicular pain is clear from the perspective of embryology.

Shortly after fertilization, the blastocyst implants in the endometrial wall, and the inner cell mass differentiates into the epiblast and hypoblast. All human structures ultimately derive from the epiblast, which differentiates into embryonic ectoderm, mesoderm, and endoderm.¹⁰

Embryonic ectoderm differentiates into surface ectoderm, which becomes the epidermis, and neuroectoderm, which differentiates primarily into peripheral axons and the central nervous system. Embryonic mesoderm differentiates into paraxial, intermediate, and lateral plate mesoderm, which subsequently differentiate into all somatic and visceral structures.¹⁰ The only somatic structures not derived from mesoderm are the bones and connective tissues of the cranium, which derive from neuroectoderm-generated mesenchyme; however, these are unrelated to spine pain. Surface ectoderm and endoderm-derived structures are also unrelated to spine and radicular pain.

Most spinal structures are derived from mesoderm, and can generate pain when diseased, dysfunctional, or injured. Examples of such structures are ligaments, discs, zygapophysial joints, sacroiliac joint, dura mater, and muscles.¹ In such cases, the dysfunction, injury, or disease resides within the affected mesodermal structures.

Many different cells within the affected structures release a variety of inflammatory mediators that can lead to the depolarization of the receptive terminals of the neurons that innervate the injured/diseased structures. These receptive structures, called nociceptors, are not injured; they are simply responding normally to damaging or potentially damaging stimuli.

In such a scenario, inflammatory chemistry within the mesodermal structures is the generator of impulses in the normal receptive portions of the uninjured nociceptive neurons. This activation subsequently leads to the conduction of axon potentials by the axon to the central nervous system. This is nociceptive pain,^2-9 no matter which mesoderm-derived structure is the generator, and no matter if the pain is acute or chronic, moderate or severe, and/or local or referred.^1,7

Most presenting spinal and referred pains are nociceptive; very rarely is pain neuropathic. Mooney¹¹ alerted us to this fact when he stated: "depending on what country and what series, perhaps 1% have a disk injury that is 'noncontained' and presses upon the nerve root creating irritation sufficient enough that sciatica is unremitting and needs to be resolved by surgical removal."

Neuropathic pain is by definition due to injury or malfunction of neural tissue, which is derived from neurectoderm. Neuropathic pain can be central or peripheral, depending on the area of neural tissue injury. Central neuropathic pain occurs only when the injured neuroectoderm-derived central nervous system begins to fire ectopically and functions as the pain generator.^12-13 Peripheral neuropathic pain occurs only when the neuroectoderm-derived peripheral axons are injured. Injured axons no longer function solely as conductors of sensory input; rather, the injured axons spontaneously generate action potentials.¹⁴ This is called "ectopic electrogenesis," which is thought to be caused by local axonal changes such as demyelination, ephaptic cross talk, and sodium channel abnormalities.^14-17

With the above information as a framework, it should be clear that the term radicular pain describes the anatomical source, but does not address or explain the nature of the pain. A key question needs to be asked: "is radicular pain nociceptive or neuropathic?" The answer to this question can be best determined by considering the anatomy and neurophysiology of nerve roots and peripheral nerve fibers.

Applying Embryology to Nerve Anatomy

The terms nerve root and peripheral nerve refer to substantially different structures. The nerve root, or "radix," is a purely neuroectoderm-derived structure; in other words, it is purely neural. It is not ensheathed in connective tissues like peripheral nerves. Dorsal and ventral roots float within cerebral spinal fluid, which separates them from the dura mater.

In contrast, a peripheral nerve is a mixed structure, consisting of neuroectoderm-derived axons that are surrounded by mesoderm-derived epineurium and perineurium, which make up the peripheral nerve sheath. A peripheral nerve thus consists of a connective tissue tube that surrounds bundles of axons.

Dural and Nerve Sheath Nociceptive Pain

The dura is a somatic structure; it is a mesoderm-derived connective tissue and, as mentioned above, it is anatomically distinct from the nerve root or radix that it surrounds. However, what can be confusing is that at the intervertebral foramina, the dura becomes continuous with the spinal and peripheral nerve epineurium, which is considered to be part of the peripheral nerve.

We know that both the dura and epineurium are innervated by nociceptors,^18-21 such that inflammation of the dura and epineurium can lead to nociceptive pain. As the dura and epineurium are mesoderm-derived somatic structures, the painful symptoms are likely to be similar to those generated by other somatic structures of the spine, such as muscles, disc, ligaments, and joints.

Nociceptive pain is typically described as a deep, non-cutaneous pain that is dull and achy, but can also have sharp, throbbing, gnawing, and burning qualities.^2,4-5 Normal movements and physical examination procedures can reproduce the painful symptoms; however, patients with nociceptive pain do not suffer from dynamic tactile allodynia, which is reserved for patients with neuropathic pain.²²

Radicular Neuropathic Pain

Some 20 years ago, Devor and Rappaport stated that "the acquisition by injured nerve fibers of ectopic pacemaker capability is among the fundamental pathophysiologic changes that underlie the emergence of neuropathic pain."¹⁴ Pain that is generated by neural structures can only be neuropathic (or ectopic nociceptive; see below). This is a key distinction from nociceptive pain, in which uninjured nociceptors function normally by transducing and transmitting impulses that are damaging or potentially damaging. In contrast, as mentioned previously, neuropathic pain emerges when injured axons begin to fire spontaneously at the site of injury.

Superficially, it appears that radicular pain would be neuropathic pain; however, this is not necessarily the case. For "radicular pain" to be neuropathic, dynamic tactile allodynia must be present, which is experienced as excruciating pain every time clothes touch the skin.²² It is a crushing pain that is distinct from nociceptive pain. Patients with true neuropathic pain will also suffer from brutal spontaneous pain than can feel like boiling water and/or bursts of painful "pins and needles."²²

The term dysesthesia is used in reference to neuropathic pain, and refers to abnormal sensations that are new to the patient and are intensely painful. For example, one of our patients provided the following description: "When my sister leaned over to hug me, her long hair gently touched my resting arm, and it felt like 10,000 feathery razor blades digging into and burning my skin."

Commonly used nerve tension tests, such as the straight leg raise, almost never elicit neuropathic pain descriptions described above, which suggests that the nerve root and spinal nerve axons are not injured in the vast majority of patients with radicular pain. However, clinicians are aware that radicular pain is different from nociceptive pain, such that it can be spontaneously produced while lying supine and it radiates sharply upon nerve root tension tests.²³

Clinicians know that most disc herniation patients, especially non-surgical candidates, do not suffer from dynamic tactile allodynia, and do not perceive skin pain even during a straight leg raise test.²³ These observations form the root of the confusion associated with radicular pain, suggesting a nociceptive/neuropathic variant. However, relatively recent research offers a solution to this confusion.

Radicular Ectopic Nociceptive Pain

We have recently coined the term ectopic nociceptive pain to describe symptoms that do not fit with the above clinical observations, but are consistent with recent advances in the understanding of axonal physiology. Several studies have demonstrated that mid-axonal application of inflammatogenic agents to the rat sciatic or spinal nerve can lead to focal hyperexcitability without damaging the axons.^24-27 In other words, inflammatory substances applied to the nerve's connective tissue sheaths leads to focal inflammation that affects the sheathed axons within, but does not injure them.

There are two known effects of inflammation on nociceptor axons. The most clinically important effect is that some nociceptor axons become mechanically sensitive, whereas they are normally mechanically insensitive.²⁴ This phenomenon only occurs in slowly conducing axons, and primarily in those innervating non-cutaneous structures. This is consistent with pain elicited in the leg during a straight leg raise, which applies mechanical force to the inflamed nerve, and which leads to the perception of deep pain.

The other effect is that the inflammation causes spontaneous discharge of normally silent nociceptors. This is expected to lead to pain at rest. It is not clear at this point if this effect is limited to deep neurons or not, but does occur with some cutaneous nociceptors.²⁸

In the framework that we have presented, although the effects of inflammation on nerves are on neuroectodermally derived structures (axons) the resulting symptoms are by definition nociceptive pain because the inflammation is affecting nociceptors without damaging them. It is of note that it has recently been shown that reduced axoplasmic flow, independent of inflammation, is sufficient to cause ectopic axonal mechanical sensitivity.²⁹ Mechanical pressure is sufficient to reduce axoplasmic flow. These data support that pressure on a nerve, while acutely applied is not normally painful, can lead to axonal mechanical sensitivity if maintained.

Of further clinical significance is that the time course of experimental ectopic nociceptive pain mirrors that of patients suffering with acute radicular pain, due to presumed disc herniation, who initially express pain symptoms that are quasi-neuropathic, and yet improve as if they are nociceptive. Experimentally, peak ectopic electrogenesis occurs at 4-7 days post-initiation, and then decreases to insignificance or "heals" within two months of the initial insult,²⁵ assuming that there is no continuing source of inflammation. In humans with persistent ectopic nociceptive pain, it is likely that there also is persistent initiator of the inflammation; otherwise the pain would subside with the inflammation.

Summary and Conclusion

In this short manuscript, we have outlined embryological and neurophysiological data that are necessary in any classification scheme for radicular pain. True radicular pain can only be neuropathic or ectopic nociceptive. Neuropathic radicular pain will have associated abnormal sensory symptoms, including mechanical and thermal allodynia, and these symptoms are more likely to be cutaneous. Ectopic nociceptive radicular pain will not have these abnormal sensory symptoms, and is most likely to be perceived in deep structures. In neither case will palpation or other testing of the painful distal structure reproduce the pain or other symptoms.

It is understood that the distinction we have proposed between nociceptive and neuropathic pain will not easily explain all cases of patients presenting with leg pain due to lumbar spinal pathology. This does not detract from the concepts; it only highlights the potential complexity of radicular pain. For instance, ectopic nociceptive and neuropathic radicular pain will coexist in many cases, such as when there has been frank damage to a nerve root while other non-damaged axons are suffering the effects of the inflammation. It is our goal that this information will provide a framework for clinical decision-making.

References

1. Bogduk N. On the definitions and physiology of back pain, referred pain, and radicular pain. Pain, 2009 Dec. 15;147(1-3):17-9.
2. Bonica JJ. Introduction: Semantic, Epidemiologic, and Educational Issues. In: Casey KL, editor.Pain and Central Nervous System Disease: The Central Pain Syndromes. New York: Raven Press; 1991:13-29.
3. Haanpaa ML, Backonja MM, Bennett MI, Bouhassira D, Cruccu G, Hansson PT, et al. Assessment of neuropathic pain in primary care. Am J Med, 2009 October;122(10 Suppl):S13-S21.
4. Marchand S. The physiology of pain mechanisms: from the periphery to the brain. Rheum Dis Clin North Am, 2008 May;34(2):285-309.
5. Portenoy RK. Mechanisms of clinical pain. Observations and speculations. Neurol Clin, 1989 May;7(2):205-30.
6. Rondinelli RD. Changes for the new AMA Guides to Impairment Ratings, 6th Edition: implications and applications for physician disability evaluations. PM R, 2009 July;1(7):643-56.
7. Seaman DR, Cleveland C, III. Spinal pain syndromes: nociceptive, neuropathic, and psychologic mechanisms. J Manipulative Physiol Ther, 1999 September;22(7):458-72.
8. Treede RD, Jensen TS, Campbell JN, Cruccu G, Dostrovsky JO, Griffin JW, et al. Neuropathic pain: redefinition and a grading system for clinical and research purposes. Neurology, 2008 April 29;70(18):1630-5.
9. Schestatsky P, Nascimento OJ. What do general neurologists need to know about neuropathic pain? Arq Neuropsiquiatr, 2009 September;67(3A):741-9.
10. Moore KL, Persaud TV. The Developing Human: Clinically Oriented Anatomy, 6th Edition. Phildelphia: WB Saunders; 1998.
11. Mooney V. Impairment, disability, and handicap. Clin Orthop Relat Res, 1987 August;(221):14-25.
12. Hulsebosch CE, Hains BC, Crown ED, Carlton SM. Mechanisms of chronic central neuropathic pain after spinal cord injury. Brain Res Rev, 2009 April;60(1):202-13.
13. Tasker RR, de Carvalho G, Dostrovsky JO. The History of Central Pain Syndromes, With Observations Concerning Pathophysiology and Treatment. In: Casey KL, editor. Pain and Central Nervous System Disease: the Central Pain Syndromes. New York: Raven Press; 1991:31-58.
14. Devor M, Rappaport ZH. Pain and the Pathophysiology of Damaged Nerve. In: Fields HL, editor. Pain Syndromes in Neurology. Oxford: Butterworth-Heinemann; 1990:47-83.
15. Ueda H. Peripheral mechanisms of neuropathic pain - involvement of lysophosphatidic acid receptor-mediated demyelination. Mol Pain, 2008 April 1;4:11.
16. Thakor DK, Lin A, Matsuka Y, Meyer EM, Ruangsri S, Nishimura I, et al. Increased peripheral nerve excitability and local NaV1.8 mRNA up-regulation in painful neuropathy. Mol Pain, 2009 March 25;5:14.
17. Rush AM, Cummins TR, Waxman SG. Multiple sodium channels and their roles in electrogenesis within dorsal root ganglion neurons. J Physiol, 2006 December 7.
18. Bove GM, Moskowitz MA. Primary afferent neurons innervating guinea pig dura. J Neurophysiol, 1997 January;77(1):299-308.
19. Bove GM, Light AR. The nervi nervorum: missing link for neuropathic pain? Pain Forum, 1997;6(3):181-90.
20. Levy D, Strassman AM. Mechanical response properties of A and C primary afferent neurons innervating the rat intracranial dura. J Neurophysiol, 2002 December;88(6):3021-31.
21. Strassman AM, Raymond SA, Burstein R. Sensitization of meningeal sensory neurons and the origin of headaches. Nature, 1996;384(6609):560-4.
22. Costigan M, Scholz J, Woolf CJ. Neuropathic pain: a maladaptive response of the nervous system to damage. Annu Rev Neurosci, 2009;32:1-32.
23. Bove GM, Zaheen A, Bajwa ZH. Subjective nature of lower limb radicular pain. J Manipulative Physiol Ther, 2005 January;28(1):12-4.
24. Bove GM, Ransil BJ, Lin H-C, Leem JG. Inflammation induces ectopic mechanical sensitivity in axons of nociceptors innervating deep tissues. J Neurophysiol, 2003;90:1949-55.
25. Dilley A, Bove GM. Resolution of inflammation induced axonal mechanical sensitivity and conduction slowing in C-fiber nociceptors. J Pain, 2008;9(2):185-92.
26. Dilley A, Lynn B, Pang SJ. Pressure and stretch mechanosensitivity of peripheral nerve fibres following local inflammation of the nerve trunk. Pain, 2005 October;117(3):462-72.
27. Amaya F, Samad TA, Barrett L, Broom DC, Woolf CJ. Periganglionic inflammation elicits a distally radiating pain hypersensitivity by promoting COX-2 induction in the dorsal root ganglion. Pain, 2009 March;142(1-2):59-67.
28. Bove GM. Focal nerve inflammation induces neuronal signs consistent with symptoms of early complex regional pain syndromes. Exp Neurol ,2009 May 27;219:223-7.
29. Dilley A, Bove GM. Disruption of axoplasmic transport induces mechanical sensitivity in intact rat C-fibre nociceptor axons. J Physiol, 2008 January 15;586(Pt 2):593-604.