Chronic Pain Clinical Trial
Official title:
Painful Channelopathies Study
To understand the pathophysiological basis of heritable pain syndromes. This will consist of
a number of components:
- Determine the genetic basis for heritable pain syndromes.
- Investigate the pain symptoms, psychological co-morbidity and quality of life in
patients with heritable pain syndromes.
- Use quantitative sensory testing to investigate abnormalities in sensory processing.
- Use imaging modalities to investigate the neural correlates of pain perception in
heritable channelopathies.
- In select patients to perform skin biopsy to determine if there has been any damage to
C-fibres.
- To perform skin biopsy in order to culture fibroblasts and neural crest stem cells for
future studies into the molecular basis of altered pain perception.
- To use neurophysiological tests, the axon reflex, and conditioning challenges to
determine how peripheral nerves, in heritable channelopathies and unusual pain
syndromes, have been altered.
- Microneurographic recordings for directly detecting the function of pain fibres in
peripheral nerves. Knowledge gained from the study will be used to aid the further
development of genetic testing and specific pain questionnaires for the diagnosis of
heritable pain syndromes secondary to channelopathies.
- Ultimately better knowledge of underlying pathophysiology in these heritable pain
conditions may inform the development of novel treatments.
Very little is currently known about the sensory characteristics and central processing of
pain in patients with heritable channelopathies. The investigators will carefully study the
phenotype of such patients in terms of pain symptomatology, sensory processing as revealed by
quantitative sensory testing and correlate this with genotype. In select patients the
investigators will perform skin biopsy to determine whether there is any evidence of damage
to small fibres and would also like to generate fibroblast and neural crest stem cell
cultures for future studies of the molecular basis for channel dysfunction.
The study will provide new insights into the peripheral and central nervous system mechanisms
involved in the processing of pain.
The investigators will restrict themselves to channelopathies causing somatic pain syndromes
and will not be investigating migraine. The following conditions will be considered:
Erythromelalgia, Paroxysmal extreme pain disorder, Familial episodic pain syndrome, patients
with episodic pain symptoms for which a cause cannot be found and patients with reduced pain
sensibility.
1.2.1 Quantitative sensory testing (QST)
QST is a method for accurately determining sensory thresholds in human skin and is
particularly useful for determining dysfunction in the nociceptive smaller diameter nerve
fibres, although the precise utility of QST in routine clinical neuropathic pain management
perhaps requires some further evaluation. There is also increasing interest in using QST in
combination with assessment of pain descriptors to give insights into the underlying
pathophysiological mechanisms of chronic pain. For example, the presence of brush evoked
dynamic allodynia indicates sensitisation at the spinal level. The investigators will use a
standardized protocol developed by the german neuropathic pain consortium in which they have
great experience. Only limited studies have been performed on inherited painful
channelopathies in assessing sensory function. The investigators will correlate findings in
QST with pain symptoms and quality of life. The investigators would like to see if specific
abnormalities of sensory processing are associated with particular channelopathies.
1.2.2 Skin biopsy.
Measurement of intra epidermal nerve fibre density (IENFD) is a relatively simple assay which
can be performed in relatively innocuous 3mm punch biopsies of skin, a routine dermatological
investigation. Its utility in the assessment of small fibre function in peripheral
neuropathies is clear. Peripheral neuropathies of diverse aetiologies are associated with
reduced epidermal innervation density. The investigators have extensive experience in this
technique which has minimal morbidity and would like to establish in painful channelopathies
whether the anatomy of C-fibres innervating the skin is normal. Patients can opt out of this
and still be included in the study. Fibroblasts can be cultured from 4mm skin biopsy
(obtained as described above). These represent a useful tool in the future as a source of
cells the phenotype of which can be modulated for instance to generate induced pluripotent
stem cells followed by induction of neural crest differentiation in order to understand the
molecular basis of altered pain perception. A further approach is to isolate neural crest
stem cells directly from hair follicles a technique pioneered by Prof Sieber-Blum at
Newcastle University. The investigators subsequently aim to generate sensory neurons from
these cells and compare the behaviour of sensory neurons from control subjects to those
generated from patients with heritable pain syndromes.
1.2.3 Electrodiagnostic tests
Electrodiagnostic tests: These assess the integrity of the peripheral large nerve fibres.
Nerve conduction studies (NCS) are used extensively in clinical practice to diagnose
peripheral neuropathies and are safe procedures in which the integrity of the axon and its
myelin sheath are tested using external electrical stimuli. Threshold tracking techniques,
the electrical threshold at which nerve respond to electrical stimulation, will also be used
to study the peripheral nerves.
If NCS have been performed as part of the patient's routine medical care these results will
be recorded.
Microneurography: Traditional nerve conduction studies only detect activity in the largest
nerve fibres. To record from the smallest nerve fibres the investigators may perform
microneurography. This is a minimally invasive technique in which the activity of single
nerve fibre is recorded from peripheral nerves and is for directly detecting the function of
pain fibres in peripheral nerves in humans. In this test a thin micro-electrode is placed
next to the nerve fibres. This provides the only direct means to directly record C-fibre
activity in humans. J Serra a co-investigator in this study and has a long track record in
using microneurography.
1.2.4 Chemical challenges to measure the axon reflex and condition the sensory nervous system
As a further means of assessing the physiological integrity of the peripheral C fibers in
patients suffering from unusual pain syndromes or reduced pain sensitivity the investigators
will elicit an axon reflex. This reflex involves the transcutaneous application of agents
such as histamine via iontophoresis. The histamine will stimulate the peripheral nerve
endings of the small diameter C fibres. Their stimulation induces a vasodilatation, which is
visible as a flare response of the skin. The evaluation of the extent of the flare response
is used as an indication of the integrity of the small diameter C fibre population. If the
subject has any allergies they will be excluded from this test.
Conditioning challenges are interventions that sensitise the peripheral nociceptive system in
such a way that the nociceptive system either responds more vigorously to noxious stimuli
(hyperalgesia) or responds to non-noxious stimuli (allodynia). The manner in which that
peripheral nociceptive system responds provides important information as to the physiological
functioning of the peripheral nociceptor system. The investigators will apply established
conditioning challenges to the subjects' skin. Topical application of capsaicin and mustard
oil are all well validated, established and safe conditioning challenges that sensitise
peripheral nociceptors. Prof. David Bennett's group has extensive experience in using both
conditioning challenges. In the only study to date investigating alteration of peripheral
fibres after a conditioning challenge in heritable pain syndromes, mustard oil caused an
increased area of hyperalgesia in individuals with Familial Episodic Pain Syndrome as
compared to unaffected individuals. Applying these stimuli could lead to minor skin
irritation and that is they will not be used if there is a history of skin
allergy/sensitivity. In practice having performed such tests hundreds of times this has not
been a problem.
1.2.5 Imaging the Human Brain in Pain
The advent of functional imaging techniques allowed researchers to begin to look within the
human brain to observe what pain looks like in the brain. Initially, pain imaging research
determined that pain is not processed by a single brain region but instead engages several
distributed cortical areas. The group of brain regions that are most active during pain are
commonly referred to as the 'pain matrix'. This includes: primary and secondary somatosensory
cortices (SI, SII), insular, anterior cingulate, and prefrontal cortices and the thalamus.
However, pain is not purely a sensory event but is also reflective of how the person feels
about their pain. Factors that vary widely across a population such as memories, emotion,
pathology, genetics, and cognitive factors all directly affect how an individual experiences
pain. In addition, the way a person responds to pain is modified heavily by what is
appropriate for the situation. For example, a person in pain may hide how unpleasant the
sensation is if they are uncomfortable in their surroundings. Because of this, the pain
matrix provides an incomplete picture of what is happening in the brain during pain. Pain
imaging studies have begun to validate this perspective. For example, Derbyshire and
collaborators showed activation of the key pain matrix regions even when subjects were not in
pain. From a study looking at chronic pain sufferers, it was shown that a series of other key
brain regions were active that were outside the pain matrix. It is essential for brain
imaging research to update the notion of the 'pain matrix' to account for these
inconsistencies.
1.2.6 Psychological co-morbidity, quality of life and pain
Whilst some studies have examined aspects of pain in the context of nerve injury (and very
rarely in relation to inherited channelopathies), these do not go beyond more than simple
measurement of pain intensity or sensory characteristics and there is only a limited
literature which has explored the interactions between pain, psychological status and quality
of life. Neuropathic pain in general is associated with multiple psychological problems which
impact upon quality of life. These include circadian rhythm disturbances (e.g. sleeping
difficulty: moderate to severe in 60% of patients), lack of energy (55%), drowsiness (39 %)
and difficulty in concentration (36%); similar findings have been specifically documented in
erythromelalgia. A poor health perception, poor physical functioning, a high prevalence of
role limitation (physical and emotional), as well as, depressive symptoms (based on the pain
catastrophising scale and on the Center for Epidemiologic Studies Depression Scale) were all
found in patients with Erythromelalgia. In general, beliefs and fears concerning the pain and
its implications contribute substantially to determining mood and behaviour. Since
neuropathic pain is relatively common in the context of peripheral neuropathy the question
arises as to what extent pain is the driver of these co-morbidities - the answer to this is
not known, but large randomised controlled trials of analgesic interventions in neuropathic
pain states indicate that as pain intensity reduces so does the severity of these
co-morbidities. To answer this question the investigators will first need to identify
specific tools for the measurement of neuropathic pain co-morbidity in the context of painful
channelopathies this is one of the aims of this proposal and they will evaluate a variety of
existing assessment tools. Another issue is that it is likely that psychological co-morbidity
influences the self reporting of pain intensity, which is a usual primary outcome measure in
clinical trials of neuropathic pain analgesic agents.
The investigators will use a battery of psychological instruments to determine the
psychological and quality of life in those subjects with painful channelopathies.
1.2.7 Blood samples
The investigators will collect blood samples (30mls) from each subject, which will be stored
at -80 degrees Celsius in a locked freezer. They will sequence known genes associated with
painful channelopathies: SCN9a and TRPA1. The investigators will store DNA in order that it
is possible that other candidate genes associated with pain can be tested.
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