Effectiveness of Clonidine for the treatment of radicular pain: A randomized, double-blind and prospective study. (EFFOC study)

1.1. Radicular pain

It is estimated that 5-10 % of all patients with low back pain also have
radicular pain in the lower extremities [1]. Many synonyms for lumbar radicular
pain appear in the literature: sciatica, ischias, nerve root pain or nerve root
entrapment. The annual prevalence of lumbar radicular pain is estimated at 2,2%
[2]. Radicular pain is mainly diagnosed by history taking and physical
examination. It is characterized by its radiation in a dermatomal pattern.
There can also be sensory symptoms. Physical examination largely depends on
neurological testing. The most applied investigation is the straight leg
raising test (Lasegue). Patients with radicular pain may also show lower back
pain, which is usually less severe than the pain in the leg. The diagnosis of
radicular lumbar pain (sciatica) seems to be justified if a patient reports the
typical radiating pain in one leg combined with a positive result on one or
more neurological tests indicating nerve root tension or neurological deficit.
The value of imaging techniques is still under debate, as in several studies on
people with clinical symptoms of radicular pain it was not possible to verify
their symptoms with MRI or CT scanning techniques [3]. However, it is customary
in studies assessing the effectiveness of a specific interventional therapy for
radicular pain, to assess the spine with radiological imaging (MRI, CT) in
order to quantify the extent of a disc extrusion beforehand [4,5].

1.2. Transforaminal epidural injection of corticosteroids as interventional
treatment modality for lumbar radicular pain

Transforaminal epidural steroid injections are a well established,
target-specific treatment modality for lumbar radicular pain. It is
target-specific because it is a way to inject an anti-inflammatory agent in the
ventral epidural space, right next to the dorsal root ganglion. In a recent
systematic review [6] four randomized trials were included.
All of them could show pain relief in a period until 6 months (termed
short-term). Only two of these studies could also indicate pain relief longer
than 6 months. One study had as primary outcome, wether patients with radicular
pain could avoid spine surgery [7] following transforaminal epidural steroid
injections either with Bupivacaine alone or with Bupivacaine and Betamethasone
(6 mg). 55 patients were randomized into one of the study groups. They were
allowed up to 4 injections of the same study drug during the evaluation.
Follow-up was between 13 and 28 months. At the end of the evaluation period 18
out of 27 patients receiving only Bupivacaine had chosen to undergo surgery. Of
the 28 patients receiving the combination of Bethametasone and Bupivacaine,
only 8 had undergone surgery.

Manchikanti et al [6] are giving the following indications for transforaminal
epidural injections:
1. Intermittent or continuous pain causing functional disability;
2. Chronic low back and/or lower extremity pain resulting from herniated discs
and radiculopathy, spinal stenosis and failed back surgery syndrome (FBSS);
3. Chronic low back and/or lower extremity pain which has failed to respond or
poorly responded to non-interventional and non-surgical conservative management.

The most serious complications of transforaminal epidural steroid injections in
the lumbar spine are related to neural and vascular trauma, intravascular
injection and infection. Side effects related to the administration of steroids
are generally attributed either to the chemistry or to the pharmacology of
these substances.

1.3. Clonidine

Alpha-2-agonists have been in clinical use for decades, primarily in the
treatment of hypertension. In recent years alpha 2 agonists have found wider
application, particularly in the field of anesthesia and pain management [8].
Clonidine is the most widely used of the alpha 2 agonists. It has been used in
the management of acute and chronic pain. Clonidine has been shown to provide
benefit when utilized in plexus anesthesia, peripheral nerve blocks, as an
adjuvant for epidural anesthesia and in the management of cancer pain. It is a
selective partial agonist for alpha-2-adrenoceptors, with a ratio of
approximately 200:1 (α2 : α1) [9].

Alpha-2-receptors are G-protein linked receptors. When these receptors are
activated, they exert their effects partly via the inhibition of cyclic
adenosine monophosphate 3*,5*-monophosphate (cAMP) formation. Potassium
channels also open, allowing the efflux of potassium from the neuronal cell,
thereby resulting in cell hyperpolarization and decreased impulse transmission
through affected nerve fibers. Yet another means by which this may occur is a
decrease in calcium-channel dependent neurotransmitter release from affected
neurons. Decreased calcium conductance via voltage-gated calcium channels may
be responsible for this effect. This may also result in a diminished release of
substance P.

Three subtypes of the alpha-2-receptor have been identified: alpha-2A, alpha-2B
and alpha-2C adrenoceptors. 95% of the alpha-2 adrenergic receptors in the
human dorsal root ganglia are of the alpha-2B and 2C subtypes [10]. In studies
on rats where sciatic nerves were intentionally injured it was found that
alpha-2-receptors were absent in normal nerves. Whereas alpha 2 receptors were
found in the lesioned nerves due to the expression by recruited macrophages,
lymphocytes and other immune cells. Peri-sciatic clonidine at the site of the
nerve injury both prevents and reverses neuropathic pain [11].
This effect is associated with a reduction of the pro-inflammatory IL-1 and TNF
in the sciatic nerve as well as with an elevation of the anti-inflammatory
cytokine TGF-beta.
At the level of the dorsal root ganglion (DRG) acute mechanical compression of
the DRG is sufficient to produce spontaneous activity in sensory afferents and
to upregulate DRG mRNA and protein levels of proinflammatory cytokines.
In addition to the direct effects of DRG mechanical compression, herniated
discs are perceived by the immune system as *foreign* and so induce a localized
inflammatory response. Even in cases of contained herniation of a disc this
inflammatory cascade can be induced by mere exposure of nucleus pulposus
material to the DRG.
Proinflammatory cytokines, chemokines and the so called *inflammatory
soup*(bradykinin, serotonin, PGE2 and histamine) can all enhance excitability
of DRG neurons in normal rats, an effect that is greatly increased in neurons
from rats with chronically compressed DRG neurons [12]

1) To study the effect of Clonidine on lumbar radicular pain with a
transforaminal epidural injection after 1 week, 1, 3 and 6 months using a BPI.

2) To study the effect of Clonidine on lumbar radicular pain with a
transforaminal epidural injection after 1 week, 1, 3 and 6 months using the
Ostwestry index

The design of the study is prospective and double-blind. It is going to be an
injection of a medication to one of the lumbar or sacral dorsal root ganglions
depending on the prior results of medical history and physical examination.
All patients will have undergone radiological imaging of their spine before the
intervention in order to assess the location and extent of the disc protrusion.

There are going to be two groups with 20 patients each:

- Group I will receive a standard treatment which is a combination of
Ropivacaine 0.2% 2ml + Depomedrol 40 mg (i.e. 1 ml)
- Group II will receive a combination of standard treatment (Ropivacaine 0.2%
1.0 ml + Depomedrol 40 mg + Clonidine 150 mcg (i.e. 1.0 ml)

After inclusion each subject will be randomized to one of the study groups by
our research nurse. The physician performing the intervention will be fully
blinded to the combination of the medication. The total amount of medication is
going to be 3 ml in each group.

Control group: Transforaminal epidural steroid injection
Intervention group: Transforaminal epidural steroid injection with Clonidine

We verwachten een minimale belasting voor de patient omdat het om patienten
gaat die sowieso kandidaten zijn voor een transforaminale epidurale injectie
van steroiden. De injectie op een lokaal omschreven plek van Clonidine laat
geen systemsiche effect verwachten - zoals b.v. bloedrukdaling
Als het na 3 maanden na de initiele interventie niet goed gaat met de pijn dan
kan een gewone transforaminale steroidtoediening gedaan worden als "rescue" -
onafhankelijk van de groep van de patient

We expect a minimal burden for patients who are included in the study. Patients
who are included are all candidats for a transforaminal epidural steroid
injection. From the injection of Clonidine in a circumscript area (i.e. Dorsal
root ganglion) we expect minimal effect on cardiovascular parameters e.g.
bloodpressure.
Next to their regular therapy (medication, TENS, fysiotherapy etc) patients who
do not improve after our intervention are eligible for a "rescue"
transforaminal epidural steroid injection 3 months after the initial
intervention.