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Chapter 7 Nerve Root Pain in Disc Herniation and Spinal Stenosis 123
patients with obvious symptoms of disc herniation but with
no visible herniation at radiologic examination or surgery.
54,55
e potential of nucleus pulposus material to induce pain has
also been indicated in clinical studies that showed that noncontained herniations (the nucleus pulposus was in contact
with the epidural space) were much more painful and had a
more pronounced straight-leg raising test result than contained herniations.
56-58
Studies on rats using pain behavior assessment indicated
that the nucleus pulposus is involved in pain production.
Pain behavior in this context refers to response thresholds
to thermal and mechanical stimulation. e role of the
various anatomic components of the nerve root complex for
the production of spinal pain was further elucidated by
Cavanaugh and colleagues31 and Weinstein and colleagues.32
Other studies33 suggest a dose-response relationship between
pain behavior and the amount of nucleus pulposus material
in the epidural space. e combination of nucleus pulposus
herniation and mechanical injury produces pain.33 is observation is consistent with the neuropathologic understanding
of pain and the consequences of combined mechanical and
inammatory injury to nerve bers that are superimposed to
increase the number of bers injured and the corresponding
increase in proinammatory cytokines.
40,41
ese experimental studies on pain behavior suggest that
the presence of nucleus pulposus has sensitized the nerve
tissue. Minor compression of peripheral nerves is not painful,
and touching of a normal nerve root during local anesthesia is
not painful.59 Touching of a nerve root exposed to a disc herniation oen reproduces the sciatic pain, however.59 Although
the combination of a mechanical component and the presence
of nucleus pulposus seems to be a prerequisite to produce
changes in the in vivo situation, more recent neurophysiologic
studies have shown that the mere application of nucleus
pulposus may induce increased neuronal pain transmission.
60
e spinal dura mater is known to contain nerve endings,
and stimulation of the dura has been suggested as a mechanism for sciatic pain.
42,59,61,62
Irritation or stimulation of the
dura as one important factor for sciatica is an interesting
theory that could explain many clinical features. One may
assume that the dura is segmentally innervated, the sensory
nerves travel in a caudal-lateral direction, and the dura is
drained to the corresponding nerve root by the nerve of
Luschka.63 Stimulation of the dura at a point where dorsolateral disc herniations appear (1 in Fig. 7.3) might be recorded
by the corresponding nerve root. At this location, the irritation
may spread medially to the contralateral segment, producing
bilateral symptoms, or laterally, producing symptoms from
levels above. Similarly, a lateral disc herniation (2 in Fig. 7.3)
could produce symptoms in the lower level.
If the pain of the straight-leg raising test is the result of dura
irritation owing to friction to the herniated mass, one may
consider the phenomenon of crossed straight-leg raising to be
based on simultaneous stimulation of the contralateral dura.
Such a “radiculitis” or “local meningitis” probably could be
regarded as similar to peritonitis. When there is peritonitis,
there is usually a reectory muscle contraction present over
the aected area. An analogue for this local meningitis could
2
FIG. 7.3 Suggested area of innervation by one recurrent sinuvertebral
nerve (nerve of Luschka). Disc herniation at location 1 may be recorded by
the same nerve and by the nearby innervation areas, laterally and
contralaterally, as indicated by arrows. At location 2, lateral disc herniation of
disc one level below may aect same nerve root but also root one level
below, located medial to this root, as indicated by arrows. A, Thecal sac; B,
dorsal root ganglion; C, intervertebral disc. (From Olmarker K. The
experimental basis of sciatica. J Orthop Sci. 1996;1:230-242.)
A
B
C
be the reectory ipsilateral contraction of the spinal muscles,
producing the “sciatic scoliosis” or lateral bending of the spine
at the level of herniation.
Other Consequences of Herniated Nucleus Pulposus
Histologic observations have indicated that nerve root changes
caused by nucleus pulposus are focal and mainly found in the
center of the nerve roots, resembling a mononeuritis simplex
that is induced by nerve infarction secondary to embolism of
the intraneural vessels.
Jayson and colleagues
venous outow from the nerve roots owing to periradicular
vascular changes, one must consider vascular impairment as
one factor.
e inammatory components of nucleus pulposus may be
involved in vascular and rheologic phenomena, such as coagulation, and may be involved in nerve root vascular embolism.
It has been observed that the presence of nucleus pulposus
may induce thrombus formation in microvessels.49 Inammatory mediators may also exert a direct eect on the myelin
sheaths, as indicated by an electron microscopic study of nerve
roots exposed to autologous nucleus pulposus in the pig.44
ere were signicant injuries of Schwann cells with vacuolization and disintegration of Schmidt-Lanterman incisures,
which closely resembles the injury pattern of inammatory
43,44
Particularly in view of the work of
64,65
indicating an impairment of the
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I
124 BASIC SCIENCE
nerve disease.
66,67
As previously described, epidural application of nucleus pulposus induces an increase of the vascular
permeability and a subsequent reduction of the blood ow in
the adjacent nerve roots, which suggests vascular impairment
as being of pathophysiologic importance.
It has also been suggested that because the nucleus pulposus
is avascular and “hidden” from the systemic circulation, a
presentation of the nucleus pulposus could result in an autoimmune reaction directed to antigens present in the nucleus
pulposus and that bioactive substances from this reaction may
injure the nerve tissue.
68-75
e work of Li and colleagues76
has demonstrated that there are autoimmune reactions not
only to the disc but also to components from the nerve tissue
that are released as the result of injury, such as basic myelin
proteins. Another study also assessed the presence of immune
complexes in herniated disc tissue obtained at surgery as an
indicator of immunoactivation.77 Immunoglobulin G (IgG)
was found in close relation to the disc cells in herniated disc
material. No IgG was found, however, in the residual disc that
was evacuated at the time of surgery. No immune complexes
were found in control disc material obtained at spine surgery
for other causes than pain.
Chemical Components of Nucleus Pulposus
e nucleus pulposus is composed mainly of proteoglycans,
collagen, and cells.
gained the most attention and has been suggested to have a
direct irritating eect on nerve tissue.
gen nor the cells have previously been suggested to be of
pathophysiologic importance. More recent studies of the cells
of the nucleus pulposus have shown, however, that these cells
are capable of producing metalloproteinases such as collagenase or gelatinase and interleukin (IL)-6 and prostaglandin E2
and do so spontaneously in culture.
Substances such as IgG, hydrogen ions, nitric oxide, and
phospholipase A2 have also been suggested to be responsible
for the pathophysiologic reactions.
produced by the disc cells that has similar pathophysiologic
eects as nucleus pulposus is tumor necrosis factor (TNF)-α.
78,79
e proteoglycan component has
74,80,81
Neither the colla-
74,82-86
Another substance
87
Cytokines as Mediators of Nerve Dysfunction and Pain
TNF is known to be a regulatory proinammatory cytokine
that has specic biologic eects and the ability to upregulate
and act synergistically with other cytokines such as IL-1β
and IL-6.
and upregulated by Schwann cells at the site of nerve injury91;
this is followed by release and upregulation of TNF in many
other endoneurial cells, including endothelial cells, broblasts,
and mast cells. is local production of TNF is the stimulus
that results in macrophage attraction to the injury site,39
which contributes massively to the concentration of proin-
ammatory cytokines in the injured tissue. Several studies
have shown that blocking TNF production or delaying the
invasion of macrophages to the site of nerve injury results
88-90
Immediately aer nerve injury, TNF is released
in reduced or delayed neuropathologic change and reduced
hyperalgesia.
52,92
TNF is known to induce axonal and myelin injury similar
96,98,103,104
93-99
intra-
and to
to that observed aer nucleus pulposus application,
vascular coagulation,
102
it y.
TNF is also known to be neurotoxic
induce painful behavioral changes
activity when applied locally.
100-102
and increased vascular permeabil-
93,105
94,104
and ectopic nerve
TNF is sequestered in a
membrane-bound form and is activated aer shedding by
certain enzymes. Matrix metalloproteinases (MMPs) are
particularly important in this regard. MMP-9 and MMP-2 are
upregulated immediately aer a nerve injury.
106
MMPs process
the inactive, membrane-bound form of TNF and its receptors
to the biologically active form and are directly associated with
breakdown of the blood-brain and blood-nerve barriers.
MMP-9 and TNF receptors are also retrogradely transported
from the site of nerve injury to the corresponding dorsal root
ganglion and spinal cord,
107
where they may have a direct role
in gene regulation. is may relate to the observation that cell
membranes of disc cells are sucient to mediate the nucleus
pulposus–induced eects.
TNF induces activation of endothelial adhesion molecules
such as intercellular and vascular cell adhesion molecules,
adhering circulating immune cells to the vessel walls (Fig.
88,108,109
7.4).
As a consequence of the TNF-induced increased
vascular permeability, these cells migrate into the endoneurial
space where the axons are located. e cells release their content
of TNF and other cytokines, which may induce accumulation
of ion channels locally in the axonal membranes.
110-112
e
channels may allow for an increased passage of sodium and
potassium, which may result in spontaneous discharges and
in discharges of ectopic impulses aer mechanical stimula-
tion. TNF by itself can cause spontaneous electrical activity in
A-delta and C nociceptors.
104
Such discharges, whether they
come from a pain ber or a nerve ber transmitting other
sensory information, are interpreted as pain by the brain.
Previous studies have also indicated that local application of
nucleus pulposus may disintegrate the myelin sheath
also a known eect of TNF.
113
is injury could also contribute
42,43
; this is
to the formation of ectopic impulses and to the sensitization
to mechanical stimulus. Experimental and clinical studies
have shown that nerve root compression and disc herniation
can induce increased concentrations of neurolament in the
cerebrospinal uid.
114,115
Increased levels of serum antibodies
against one or more nervous system–associated glycosphingolipids have been shown in patients with sciatica and disc
herniation, indicating a possible autoimmune response.
116
More recent work regarding molecular events in the pathophysiology of neuropathic pain has suggested a potential role
of TNF for inducing allodynia.
94,117,118
TNF may mediate the
formation of allodynia in the dorsal root ganglion and at the
spinal cord level because of its local upregulation, which
occurs via a positive feedback loop caused by TNF itself. is
cycle seems to be broken by a direct eect of TNF on the
upregulation of antiinammatory cytokines such as IL-10,
which eventually leads to a reduction of TNF and the physiologic balance of proinammatory and antiinammatory
cytokines. Such regulation seems to be induced by mechanical
TNF
C
Pain and nerve dysfunction
Aggregation of
Endoneurial capillary
Chapter 7 Nerve Root Pain in Disc Herniation and Spinal Stenosis 125
3)
1) Adhesion of
circulating WBCs
thrombocytes
and formation of
a thrombus
SECTION
I
A
FIG. 7.4 Suggested mechanism of action for tumor necrosis factor (TNF). (A) TNF from cells of herniated
nucleus pulposus enters endoneurial capillaries and activates endothelial adhesion molecules. (B) Circulating
white blood cells (WBCs) adhere to vessel walls (1) and extravasate from capillaries out among axons owing to
TNF-induced increase in vascular permeability (2). TNF also induces accumulation of thrombocytes that form
intravascular thrombus (3). (C) There is local release of TNF from extravasated WBCs among axons that induce
myelin injury, accumulation of sodium channels, and allodynia in the dorsal root ganglion (DRG) and at the
spinal cord level. Thrombus, together with edema owing to increased permeability, induces nutritional decit in
the nerve root. Local eects of TNF and nutritional decit may induce pain and nerve dysfunction. CAM, cell
adhesion molecule; VCAM, vascular cell adhesion molecule. (From Olmarker K, Myers R, Kikuchi S, et al.
Pathophysiology of nerve root pain in disc herniation and spinal stenosis. In: Herkowitz H, Dvorak J, Bell G, et al,
eds. The Lumbar Spine. 3rd ed. Philadelphia: Lippincott Williams & Wilkins; 2004:11-30.)
Activation of adhesion
molecules (ICAM, VCAM)
Local release of TNF
Myelin injury
Accumulation of
Na-like channels
Induction of allodynia
in DRG and spinal cord
B
Decreased blood flow and
increased permeability
Nutritional deficit
2) Extravasation
of WBCs
Thrombus
injury to peripheral parts of the axons and by a direct eect
of TNF exposure and further enhances the impression that
TNF may be an important mediator of neuropathic pain. TNF
is a potent activator of cells; because it is retrogradely transported from the site of nerve injury to the dorsal root ganglion
and spinal cord, it may be this proinammatory stimulus that
activates central glia and neurons.
107
Apart from directly aecting the endoneurially located
axons, TNF may also indirectly interfere with the axons by
compromising the nutritional transport. TNF can induce
intravascular coagulation aer local application
the local blood ow in the intraneural capillaries.
119
; this reduces
54
TNF was found in disc cells and there is evidence that
elevated levels of TNF and its receptor, TNFR1. In herniated
lumbar discs correlated with the chronicity of postoperative
sciatic pain.
120
Specic TNF inhibitors, such as a monoclonal
antibody to TNF (iniximab) and a soluble TNF receptor
(etanercept) can inhibit pathophysiologic dysfunction. It has
been shown that iniximab may attenuate immunoreactivity
of brain-derived neurotrophic factor and may prevent neurologic and histologic changes in dorsal root ganglion in rats
aer experimental disc herniation.
121
More recent studies
reinforce the potential utility of cytokine inhibition in treating
the inammatory hyperalgesia induced by nucleus pulposus
and spinal nerve injury.
123
122
Application of certain cytokines to intraspinal nerves may
also increase the somatosensory neural response.
124
Discharges
from wide-dynamic-range neurons aer stimulation of a recep-
tor eld of a dorsal root ganglion exposed to nucleus pulposus
increased signicantly aer application. is increase may be
related to the sensitization of the sensory system caused by
proinammatory cytokines and the production of low-grade
spontaneous electrophysiologic activity in nociceptors by
104
TNF,
which by itself is an important factor that contributes
to sensitization. Administering an antibody specic for TNF
eciently inhibited this eect. An in vivo study assessing
changes in spontaneous behavior clearly showed that changes
induced by the combined action of mechanical deformation
126 BASIC SCIENCE
and disc incision were markedly inhibited by intraperitoneal
injection of a monoclonal antibody specic for TNF.
55
TNF seems to be an important mediator for the observed
eects on nerve function and for pain induced by local application of nucleus pulposus. Additional support for this
hypothesis comes from previous work that showed that
blockade of TNF upregulation in macrophages by thalidomide92 and downregulation of TNF by IL-10 administration
reduced the magnitude and duration of hyperalgesia aer
nerve injury. Because cytokine interactions are complex, other
cytokines such as IL-1β and IL-6 may be involved as well.
Because these cytokines are induced by TNF, as well as inducing TNF, their role is complex.
e possible role of brain-derived neurotrophic factor in
nerve root pathophysiology and experimental disc herniation
has been analyzed.
125
e appearance and distribution of
macrophages and TNF in the dorsal root ganglion of rats aer
experimental disc herniation and the relationship between
nerve growth factor and pain behavioral changes have been
described.
126
It has also been shown that disc-related cytokines
can inhibit axonal outgrowth from dorsal root ganglion cells
in vitro.
127
Clinical Use of Cytokine Inhibitors for Treatment of Sciatica
On the basis of the experimental ndings that TNF may mimic
nucleus pulposus–induced nerve dysfunction and pain, pilot
clinical trials regarding the possible use of TNF inhibition
for the treatment of sciatica were initiated. Karppinen and
colleagues
for TNF (iniximab [Remicade]) to 10 volunteers waiting
for surgery for radiologically veried disc herniations with
severe sciatica. In this open-label study, iniximab reduced
pain assessed by visual analog scale by 50% at 1 hour aer
infusion. Aer 2 weeks, 60% of the patients were pain free.
At 3 months aer the single infusion, 90% were pain free. No
adverse drug reactions were noted, and no patients required
surgery. A 1-year follow-up
iniximab showed that the benecial eect of a single infusion
of 3 mg/kg of iniximab for disc herniation–induced sciatica
was sustained in most patients. e authors also noted that
iniximab did not seem to interfere with spontaneous resorption of disc herniations.
the form of a soluble TNF receptor (etanercept [Enbrel]) by
three subcutaneous injections to 10 patients with severe sciatica. e patients had a 70% reduction of leg pain assessed
by visual analog scale 10 days aer starting the treatment. At
6 weeks, the reduction was 83%. e results were statistically
signicantly better than for 10 patients treated with three
intravenous injections of methylprednisolone.
leagues,
the TNF inhibitor etanercept was eective. e investigators
randomly assigned 24 patients with subacute radiculopathy
into three groups each consisting of eight patients. e patients
in each group received either 2, 4, or 6 mg on two occasions,
128
administered a monoclonal antibody specic
129
of the 10 patients treated with
Genevay and colleagues
130
administered a TNF inhibitor in
In one randomized study published by Cohen and col-
131
treatment of sciatica by local epidural injections of
and two of the eight patients were saline controls. All
etanercept-treated patients had signicant improvement 1
month aer treatment compared with saline-treated patients
regarding leg and back pain. e eects persisted 6 months
aer treatment in all but one patient. e authors concluded
that “etanercept holds promise as a treatment for lumbosacral
radiculopathy.”
131
Genevay and colleagues
132
published the
results of a multicenter, double-blind, placebo-controlled trial
on the use of the TNF inhibitor adalimumab (Humira) subcutaneously injected in 31 patients with severe, acute sciatica
caused by disc herniation. Two injections were given 7 days
apart; 30 control patients received placebo injections in the
same manner. e results showed that there was a signicantly
more favorable evolution of leg pain in the adalimumab group
than in the placebo group, but the eect size was relatively
small. ere were twice as many patients in the adalimumab
group who fullled the criteria for “responders,” and there
were signicantly fewer surgical discectomies in this group
compared with the placebo-treated controls.
e issue of anti-TNF therapy for human sciatica remains
complex. In spite of encouraging basic science studies in
experimental animals, its ecacy and utility in humans
remains unsettled.
positive results in animals and humans,
center, randomized trial by Cohen et al.
133
While there continues to be reports of
134
a second multi-
135
of 84 adults with
lumbosacral radiculopathy revealed only a short-term relief
for some of their patients. Issues of experimental design and
placebo eects complicate the interpretation of the results.
Indeed, this point is emphasized by Williams et al.,
119
who
performed a systematic review and meta-analysis of biologic
treatments targeting TNF-α for sciatica and concluded that
there was insucient evidence to recommend these agents
when treating sciatica. ey concluded, however, that additional studies are warranted.
Taken together, these observations indicate a potential
clinical eect of TNF inhibition in the treatment of sciatica.
It is unconrmed although provocative that early treatment
with TNF inhibition seems superior to late antiinammatory treatment by nonsteroidal antiinammatory drugs,
methylprednisolone, or even morphine in many patients. We
suggest that it is more ecient to target the responsible media-
tors of neuropathic pain early and directly before additional
dysfunction occurs than to treat a patient with conventional
antiinammatory drugs aer the neuropathic pain state has
fully developed. Sciatica has a neuropathic pain component,
and nonspecic antiinammatory medication and morphine
are less ecient in such conditions. Further studies must be
undertaken, however, before any denite conclusions regarding the ecacy of anti-TNF therapy for the treatment of
sciatica may be drawn.
Summary
e pathophysiology of sciatica is complex, with numerous substances and mechanisms acting at various levels of
the neural axis. ese mechanisms have attracted attention of basic scientists, and numerous studies looking into
Chapter 7 Nerve Root Pain in Disc Herniation and Spinal Stenosis 127
neuroimmunologic events have provided important insights
into the pathophysiologic mechanisms of the human disease
state. e intervertebral disc has certain biologic eects
that contribute directly to these pathophysiologic processes.
Epidural application of nucleus pulposus induces structural
and functional changes that relate closely to sciatica. e
nucleus pulposus also sensitizes nerve roots, producing a
painful condition. ese experimental observations correlate
with the clinical impression that preoperative touching of
nerve roots that have been exposed to disc herniation under
local anesthesia reproduces the sciatic pain and that surgical
removal of the mechanical compression of the nerve root oen
relieves symptoms.
e biologic substance of importance in the pathogenesis
of painful radiculopathy seems clearly at this stage of understanding to be TNF-α. e activation and upregulation of this
ubiquitous proinammatory cytokine produces acute pain and
neuropathologic changes associated with chronic pain states.
TNF stimulates broblast scar formation in a vicious cycle
whereby the local presence of TNF stimulates other cells to
upregulate this cytokine. Initiation of this cycle by the leakage
of TNF from herniated nucleus pulposus produces a cascade of
tissue injury, scar formation, and local pain. Superimposition
of mechanical injury to the nerve root in this environment
exacerbates the neural immune insult, causing macrophagemediated wallerian degeneration with signicant increases in
TNF concentrations. We suggest that these combined events
explain the problem of sciatica. Although the pathophysiology
of sciatica is far more complex than one might rst suspect,
future research is certain to reveal substances and mechanisms
of importance to the induction of symptoms in sciatica, and
such research would provide a basis for improved diagnosis
and treatment of this common disorder.
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