Clinical Trial Details
— Status: Recruiting
Administrative data
| NCT number |
NCT06022848 |
| Other study ID # |
210723 |
| Secondary ID |
|
| Status |
Recruiting |
| Phase |
N/A
|
| First received |
|
| Last updated |
|
| Start date |
September 1, 2019 |
| Est. completion date |
November 2024 |
Study information
| Verified date |
September 2023 |
| Source |
Barts & The London NHS Trust |
| Contact |
Theresa Wodehoise |
| Phone |
07866813990 |
| Email |
theresa.wodehouse[@]nhs.net |
| Is FDA regulated |
No |
| Health authority |
|
| Study type |
Interventional
|
Clinical Trial Summary
The primary aim of this study is to assess the reversibility of a range of psychophysical
markers of pain processing in patients with chronic migraine or cluster headache before and
after ONS insertion and comparing to patients having a general anaesthetic (GA) for a
non-painful aetiology at Barts Health NHS Trust. We will also compare with healthy volunteers
not undergoing surgery.
To establish whether pain perception alters in patients with chronic migraine/cluster
headache having ONS using questionnaires and compare to patients having a general anaesthetic
for a non- painful procedure D & C at Barts Health NHS Trust.
Are pain markers (Glutamate, TGF-B1) altered with ONS?
Description:
Headache is one of the most common neurological problems accounting for 4% of primary care
consultations and up to 30% of neurology appointments. Even though considerable advances in
the understanding of the pathogenesis of migraine, new pharmacologic treatments and the
emergence of new innovative interventions for difficult cases, in many patients with migraine
remain intractable to medical therapy.
The trigeminocervical complex (TCC) has a crucial role in the pathophysiology of migraines.
The TCC is a common convergent pathway by which both trigeminal (dural) and cervical (mainly
via the greater occipital nerve) afferent inputs project into higher centres in the thalamus
and cortex. This afferent pathway is further influenced by the conditioned pain modulation
(CPM) pathway originating from the brainstem structures including periaqueductal grey matter,
nucleus raphe magnus, and the rostroventral medulla. There is some evidence to suggest that
increased peripheral sensitization of the afferent inputs of the TCC, generalized central
sensitization of the trigemino-spinal or the second order trigeminal neurons and impaired
descending pain inhibitory pathway, may all contribute to the development of the chronic
intractable or treatment resistant primary headache disorder Neurostimulation techniques for
treating intractable headache range from invasive deep brain stimulation to less invasive
peripheral implantation and stimulation. In 1999 Weiner and Reed described the beneficial
effects of subcutaneous Occipital nerve stimulation (ONS) in patients with medically
intractable, highly disabling chronic headache disorders Open-label studies have suggested
that this treatment modality is effective and safe (Lambru and Matharu 2012). Although the
exact mechanism of action is poorly understood, ONS is thought to act by stimulating the
distal branches of C1, C2 and C3 in turn influencing the TCC favourably by inhibiting the
nociceptive process, resulting in an improvement of symptoms. Previous work has demonstrated
a consistent and sustained improvement in conditioned pain modulation (CPM) following ONS as
confirmed with quantitative sensory testing (QST) (Wodehouse et al, 2014). QST has the
particular advantage of being a functional test that provides a quantitative pain stimulus
and assesses the subject's individual response to the stimulus. QST also provides a reliable
assessment of changes in pain thresholds and the benefit of ONS. However general anaesthetic
has also been demonstrated to cause changes/improvements in pain thresholds, peripheral and
central sensitisation and this effect can be long lasting and may account for
changes/improvements as measured by QST in subjects having ONS that the anaesthetic provides
relief as opposed to the ONS intervention.
Quantitative sensory testing (QST) QST is a term used to describe different forms of
psychophysical testing of skin, mucosa, or muscle tissue that assess sensory and pain
perception pathways. Nociception inputs can trigger a prolonged but reversible increase in
the excitability and synaptic efficacy of neurons in central nociceptive pathways, the
phenomenon of central sensitisation in turn manifesting as pain hypersensitivity,
particularly dynamic tactile allodynia, and secondary punctate or pressure hyperalgesia and
enhanced temporal summation.
QST has been used for measuring thresholds for different sensations in neuropathic pain
reflecting the possible nerve fibres that may be implicated in the pathogenesis. Heat
sensation threshold reflects the unmyelinated C-fiber function, cold sensation threshold
reflects the thinly myelinated A-fiber function and vibration threshold reflects the thickly
myelinated AB- fiber function.
QST tests can be classified into the following:
Measurement of pressure pain thresholds (PPT) (Static measure): This test measures
sensitivity of peripheral pain pathways to increasing mechanical pressure. A
computer-controlled pressure algometer (available as a bed side instrument) is used to
measure PPTs at a standardized point and compared with the affected area. A standardized
speed of pressure increase of 0.3kg/s is kept constant during pressure application to the
point when perception changes from pressure to pain (pressure pain threshold). This is useful
for confirming small fibres neuropathic lesion.
Temperature thresholds: Thermal QST evaluates small nerve fibres, using thresholds for warm,
cold, heat-induced pain and cold-induced pain. It involves altering a thermal stimulus until
a sensation is perceived. Four sensory sub-modalities will be measured; C fibre mediated warm
sensation (WS), A-delta fibre mediated cold sensation (CS), heat induced pain (HP) (mostly C
fibre mediated sensation with some involvement of A-delta fibres) and C- and A-delta fibre
mediated cold induced pain (CP).
Measurement of central sensitisation (Dynamic measure):
This will be done using 2 different techniques as outlined below.
1. Conditional Pain Modulation: Activity within the spinal dorsal horn arising from
peripheral nociceptive inputs can be modulated by powerful descending inhibitory and
facilitatory mechanisms. An example is provided by the phenomenon of conditioned pain
modulation (CPM), also known as diffuse noxious inhibitory control (DNIC) or
heterotrophic noxious conditioning stimulation. This refers to an altered response to a
painful stimulus following the administration of a second conditioning stimulus.
CPM provides one of the main supraspinal pain inhibitory pathways and are impaired in
neuropathic pain. Diffuse noxious inhibitory controls refers to the observation that the
activity of multi-receptive neurons of the spinal cord can be strongly suppressed by an
intensive pain stimulus outside their peripheral receptive field. Induction of CPM can
be done by immersion in ice water (so-called cold-pressor test), or hot water on a
different/distant body part than the one on which the pain perception testing is being
performed. This effect represents a well-established model of endogenous pain
modulation.
2. Measurement of Temporal summation- Repetitive delivery of a painful stimulus leads to an
increased perception of pain which can be used as a marker for central sensitization.
Seventeen, progressively rigid, monofilament, von Frey fibers (filaments represent
stimuli from 0.039 - 4386mN) will be used on a standardised position on the back decided
by the physician. A baseline NRS score will be obtained from the patient. The von Frey
Fibre will first ascertain the least force that measures a sensation of touch or pain
(pressure pain threshold). The exact threshold is found by repetitive testing using the
ascending fibre sizes. The repetitive stimulation consists of 10 repetitions of a
pressure stimulus applied for 1 second duration for 60 seconds. The magnitude of the
stimulus is set at the level of the subjects' pressure pain threshold. Patients rate the
pain intensity on a NRS for each pressure stimulus, and then for 15 sec after cessation
of 10 stimulations.
Clinical Data for QST QST measurements have been used world-wide in the assessment of altered
pain experience and have been demonstrated to be safe and well tolerated. There exists
published evidence of QST measurements in chronic pain conditions like osteoarthritis,
fibromyalgia, migraine and other neuropathic pain conditions.
QST measurements have been used worldwide in the assessment of altered pain experience and
have been demonstrated to be safe and well tolerated. We do not expect any risks associated
with the QST. Any discomfort experienced is transient and patients at all times are in
control with the experience and can stop at any-time.
In addition, there is evidence to suggest that cytokines induce headache and headache pain.
Furthermore a higher level of cytokines can stimulate the activation of trigeminal nerves,
trigeminal nerve fibre sensitisation, the release vasoactive peptides or other biochemical
mediators like nitric oxide, which results in inflammation. Many studies have investigated
the role of different cytokines in the pathogenesis of migraine but the results remain
controversial. One reason for this may be the differing times of measured cytokines in some
cases ictally in others interictally. For this study we propose to takes samples at baseline
and at the follow up visits and investigate whether there is any alteration in levels of
cytokines with the ONS. We will be focusing on transforming growth factor-beta 1 (TGF-1),
which is a multifunctional proinflammatory cytokine involved in the modulation of cell
growth, differentiation and repairs following injury and immune modulation. Ishizaki et al.,
2005 demonstrated that serum levels of TGF-1 were higher in migraine than in controls. TGF-1
has been described as a platelet-derived cytokine as human platelets contain quantities of
dormant TGF-1 and reports have suggested that platelets play an important role in migraine
and therefore maybe in involved in headache pathogenesis and development of migraines.
Glutamate is a prominent neurotransmitter and has been implicated in migraine pathogenesis.
Migraine pain-relay centers, including the trigeminal ganglion, trigeminal nucleus caudalis,
and thalamus, contain glutamate-positive neurons, and glutamate activates the trigeminal
nucleus caudalis. Glutamate is implicated in cortical spreading depression, trigeminovascular
activation, and central sensitization. Glutamate in blood (plasma) and urine will be measured
prior to and after ONS.
