THE BRAIN IN PAIN IV

The neurophysiology of chronic idiopathic pain

PARTICIPANT INFORMATION SHEET
VERSION 1.6: Cases
12/09/2013

FOR FURTHER INFORMATION PLEASE CONTACT:

Dr. Julius Bourke, MBBS, MRCPsych
Prinicipal Investigator for The Brain in Pain Study,
Clinical Lecturer and Honorary Consultant,
The Wolfson Institute of Preventive Medicine,
Barts and The London School of Medicine and Dentistry,

Room 3.111, 3rd floor Dominion House

59 Bartholomew Close
London EC1A 7ED
Tel: +44 (0)20 346 57232
Fax +44 (0)20 346 57082
[email protected]

1. Introduction

You are being invited to take part in a research study as a patient volunteer with fibromyalgia
or non-cardiac chest pain without other significant illnesses. Before you decide, it is important
for you to understand why the research is being done and what it will involve. Please take time
to read this information sheet carefully and discuss it with friends, relatives or your GP if you
wish. Please ask us if there is anything that is not clear or if you would like more information
(contact details above right). This study is organised and sponsored by Barts and The London
School of Medicine and Dentistry at Queen Mary University London (QMUL) and has been
funded by the Barts and The London Charity. This study has been reviewed by the London: City
& East Research Ethics Committee and by Ms Pam Stewart in her capacity as Chair of The
Fibromyalgia Association UK, who has offered the support of The Association.
2. The Sciencey stuff
The normal physiology of pain: The nerves in our body carry information to and from our
brains. They communicate information by passing electrical impulses down their length. The
electrical impulses will only fire down these cables when they are caused to fire by the
release of particular chemicals. These chemicals may also have the reverse effect and
prevent the firing of impulses, depending on what needs to be communicated. Specialised
nerves are used to send information about pain. These run from places like the skin to the
spinal cord in our back. Here they communicate with other nerves that in turn send messages
up to the brain. Once these impulses reach the brain, the information is sent to a special area
involved in the assessment of pain the pain matrix. This area compares the information
received to prior experiences of pain and tells us how important the information is, how
upsetting and unpleasant it is and what we should do in response to it. For example, if
something is hurting us from outside our body, we would look around to identify it and move
away; if the pain is inside our body, we might seek help or rest the part of the body that is
hurting. Whilst this occurs, impulses are also sent back down the spinal cord in our back in an
effort to stop the pain spreading and becoming unmanageable. These impulses are like
brakes and use the bodys natural pain killing chemicals to dampen the feeling of pain.
The whole process is a little like an army fighting in a battle. Imagine that soldiers on the front
line are attacked by the enemy (pain starts in the skin), this information would need to be
relayed (down the nerves) to headquarters (the brain) where the generals are (the pain
matrix). Once this information reaches headquarters, the Generals might send reinforcements
(the brakes), whilst assessing the situation and thinking about how to respond to the attack
based on their prior experience of warfare.
Central sensitization and pain: In some cases, we can become sensitised to pain. This
happens as a result of changes that take place in the nervous system (the brain, the spinal
cord and the nerves). When we become sensitised to pain, the way in which we feel pain and
the way in which information about pain is communicated down the nerves becomes faulty.
This is referred to as central sensitisation. It can be divided into two parts:
1.
Spinal sensitisation: this part involves the communication between the nerves in the skin
(in our example), the spinal cord and the brain.
a. Non painful sensations are felt as painful because even nerves that are not specialized
in detecting pain are able to tell the spinal cord that what is being felt is hurting us: The

The Brain in Pain IV: The neurophysiology of chronic idiopathic pain


2
nervous new recruits on the frontline start shooting at civilians, thinking they are the
enemy
b. Mildly painful feelings are felt as being unbearable because the brakes dont work: the
soldiers on the frontline come under attack and send word to headquarters but there are
no reinforcements available.
In practice, these two processes occur at the same time, so that more pain is felt more
frequently without the natural relief that the brain normally provides.
2.

Central augmentation: this part involves the pain matrix in the brain (the Generals at
headquarters), which becomes very sensitive and reacts faster than normal to the
possibility of pain, which it interprets as being more painful and unpleasant: The General
has lost his confidence and always thinks his men are under attack but feels unable to
send reinforcements.

Central sensitisation has been found in a number of functional conditions where normal
function is disrupted but there is no evidence for a causative illness. Examples include
fibromyalgia, non-cardiac chest pain and the functional gastrointestinal disorders and chronic
fatigue syndrome. All of these conditions are linked by a common symptom chronic pain.
These conditions are difficult to treat and pain in particular is very resistant to the methods of
treatment routinely employed. Medications that do seem able to successfully treat these
disorders point towards two particular brain chemicals: dopamine and the opioids. Dopamine
helps us determine what is important and what we pay attention to as well as being involved in
memory. In the analogy given above, it focuses the troops on the front line so that they dont
shoot civilians and makes sure that the General compares the current situation with a similar
prior experience of battle so that he employs the most appropriate tactics. The opioids are the
bodys natural pain killers but also help to ensure that when we choose to do something that
reduces the pain, we choose the same action the next time we are confronted by the same
pain. The two of these together also act as the brakes, preventing the spread of pain by
communicating with the nerves down the spinal cord.
Our study is the first of its kind to try to tie all this information together in these disorders by
looking at how the nerves and the brain feel and detect pain, how they respond to pain, which
parts of the brain are involved and which chemicals are used by the brain to communicate
between these areas. By comparing individuals with and without these functional conditions,
we hope to gain a much better insight into what causes these disorders and how we might
better treat them in the future.
3. Participation
Can I take part?: We are looking for volunteers aged between 18 and 65 years old, who are
free from serious medical illnesses, including major psychiatric disorders such as depression
and anxiety. We cannot include subjects who may be pregnant or are currently breastfeeding, or those currently taking an antidepressant, antipsychotic, anticonvulsant or a strong
or specialist pain medicine.
You have been approached as you have been diagnosed with either non-cardiac chest pain
of fibromyalgia. These commonly occur together and we would be unable to include you if you
have both of these conditions. We are looking at a process called sensitisation which will be
assessed for by special sensory tests. You will need you to demonstrate sensitisation on this
set of tests in order to progress to the scanning stage of the study there is a good chance
that you will, as it is thought to be part of the reason that people develop these disorders.
4. What your participation will involve (see figure 1)
If you wish to take part, the first step would be to contact Dr Bourke to ask any questions and
arrange an initial appointment if you wish to volunteer. We will post you a booklet of
questionnaires to complete prior to this initial appointment but if you wish, you can complete
these on the day of the appointment. The booklet will take around 45 minutes to complete

The Brain in Pain IV: The neurophysiology of chronic idiopathic pain


3
although people often finish it faster than that. These questionnaires relate to how you feel,
how you think, how you experience tiredness, pain, anxiety and bodily sensations. These are
all important as they differ between individuals and explain some of the variation in the
experience of pain.

First appointment (1 hour)

Location: Dominion House, Bartholomew Close, London EC1A 7ED
At the first appointment you will be able to ask any final questions you might have. You will
then be asked to sign a consent form confirming your wish to volunteer for the study. We will
not collect the questionnaires from you unless you are willing to volunteer.
Once the consent form is signed, there will be a clinical interview that is designed to detect
major psychiatric disorders. At the end of this appointment, with your agreement, we will also
send a letter to your GP letting them know that you have agreed to take part in our study.
For appointments 2,3,4 & 5 You will need to ensure that you have not drunk alcohol for
24 hours prior to the appointments. You may need to abstain from taking regular painkillers
but how long for will depend on the type of pain killer you use. If you use over the counter
painkillers on occasion, we would ask that you do not take these for the 24 hours prior to
these appointments.
Appointments 2: sensory testing appointments (2.5 hours)
Location: Dominion House, Bartholomew Close, London EC1A 7ED
These appointments are to for spinal sensitisation. We will do this using tests that are in
common use. These will look at the way on which the outside of the body (the skin, muscles
and joints) detect pain. The skin tests will measure pain thresholds using different types of
pressure. In our experience, people do not find them uncomfortable enough to ask for them to
be stopped. This appointment will start with the completion of some questionnaires that look at

The Brain in Pain IV: The neurophysiology of chronic idiopathic pain


4
anxiety, pain and fatigue, which will take approximately 10 minutes. The appointment will
finish with a questionnaire that asks questions about your experience of the tests.
You are unlikely to experience any lasting discomfort after these appointments.
However we will provide you with a dedicated mobile telephone number with which you
will be able to contact the research team, should you feel concerned about any ill effect
subsequent to these appointments.
Third, fourth & fifth appointments: Neuroimaging (190 minutes each)
Location: Imanova Centre for Imaging Sciences, DuCane Road, W12 0NN
We will be using Functional MRI (Magnetic Resonance Imaging). This is a type of specialized
MRI scan. It measures the change in blood flow related to brain activity. This means that by
detecting different changes in the rate of blood flow in different parts of the brain, we can
recognise which parts of the brain are more active at any one time than others. The scanning
process is no different to that of a normal MRI scan where the individual being scanned is
concerned. The difference lies in the way in which the image is created and analysed by the
scanning equipment. It does not involve X-rays or radiation but a big magnet instead. It is due
to the different magnetic properties of components of the blood that we are able to detect
changes.
We will need you to register as a patient with the Hammersmith Hospital. This allows us to use
the services provided by the hospital in case of a medical emergency. This will be done for
you, with your consent. If you are female, you will be required to provide a urine sample for a
pregnancy test. Although there is no data to demonstrate adverse effects of magnetic or
radiofrequency fields on the developing foetus, the effects are unknown. It is therefore the
policy of the Imanova centre for imaging sciences to screen all female volunteers for
pregnancy and exclude those with a positive pregnancy test.
Because we will want to look at the brain chemicals, we will be using medicines that work in a
known way. These will only be used once. We will use low doses. We are not using the drugs
to gain an effect but rather to briefly alter the way in which the areas of the brain
communicate. We will be using two medicines: one that will enable us to look at dopamine
(amisulpride) and one that lets us look at the opioids (naltrexone). These will be in tablet form.
There will be a third tablet, which will be a vitamin pill like you might buy from the chemist.
This has no effect on the brain chemicals but means that we can compare the change in brain
chemistry on the scan to a normal condition. There will be one scan for each tablet (i.e. three
scans in total with one tablet taken before each scan). The tablet will be given to you
approximately 2 hours prior to the scan. During this waiting period, we will ask that you
complete some questionnaires similar to those you have already done and we will do a tracing
of your heart.
During each scan we will look at how the brain responds to different pressures. Because we
are interested in pain responses specifically, some of these will be painful but do not worry!
We are only interested in moderate pain and what constitutes moderate will be determined
by you and not us! This will be done before each scan because we know that peoples
threshold to pain can fluctuate over time. This will ensure that we never cause you more
discomfort than you are expecting! The stimuli will be a mixture of non-painful, just painful
and moderately painful. Each of these will last 5-10 seconds each and will be separated by
15-25 seconds.
We will look at the response to pressures on the thumbnail, using a specially designed device
(a dolorimeter) that delivers pressure to the nailbed. During the scan here will be 5 minutes of
pressures followed by a rest of one minute before the cycle repeats to a total of 3 cycles for
the thumbnail pressures.. The dolorimeter will be attached to your thumb prior to the start of
the scan.

The Brain in Pain IV: The neurophysiology of chronic idiopathic pain


5
You will be asked to lie on the scanning couch. This extends from the scanner so that you can
climb onto it easily. Once you are comfortable, you will be given protective headphones to
wear (this is because of the noise that the scanner makes when it is operating.) The members
of the research team will leave the room and move to the adjoining observation room where
they will be able to operate the scanning equipment and the equipment, whilst still being able
to see and hear you. They will be able to hear anything you say and will be able to speak to
you. You will have access to a stop button which you can press at any time in order to stop
the session. The scanning couch will slide inside the scanner which is shaped like a large
cylindrical tube, with an opening at each end. We will then measure your pain thresholds on
the thumbnail. These will be used to calculate the pressures used during the scan: nonpainful, just painful and moderately painful.
When you are ready, the scanning session will then begin. It will start with a normal 'structural' MRI
scan of your brain that makes sure that there are no abnormalities that might further exclude
you from taking part or which might require a doctor's opinion. A doctor who specialises in
looking for these kind of abnormalities (a neuroradiologist) will review the scans after the
scanning session to check for this. Whilst we would not expect anything abnormal to be
discovered, should this be the case, we will discuss this with you and, with your permission,
your general practitioner to ensure that further care and if necessary, treatment is provided.
There will then be some images presented to you on a screen, and you will be asked to
respond to them in particular ways (e.g. reading them). This will last around five minutes.
Once this is completed we will let you know before we begin the third part, which will be the
scan for moderately painful pressures on your thumbnail.
You will be able to stop any of these sessions at any time for any reason, using the stop
button that will rest in your hand during the scan.
After the scan is complete, we will do a tracing of your heart whilst you complete some brief
questionnaires. If you feel any ill effect from the drugs, we will keep an eye on you in our
observation area until you feel able to leave. The most likely ill effect will be drowsiness. You
should not drive after the scanning appointments. We will provide a taxi to take you home after
each scanning appointment. Should you experience any ill effect after returning home, we
will provide you with a dedicated mobile phone number with which you will be able to
contact the study team. With a single dose of the medicines used and the methods of
moderate pain delivery, which are very well rehearsed, we would consider it unlikely
that you experience such difficulties.
Summary of scanning appointments:
T = 0 mins: arrive at Imanova
T = 0-10 mins: tracing of heart, administration of medicine (one tablet per scan)
T = 10-60 mins: completion of pre-scan questionnaires
T = 120 mins: scanning starts
T = 180 mins: scan finishes
T = 180-190 mins: tracing of heart and completion of post scan questionnaires
T = 190 mins: depart by taxi
T >190 mins: additional observation period as required prior to departure by taxi
5. What will happen to the data collected from my participation?
All the data collected from the questionnaires and interviews that you complete and from the
scanning are pseudo-anonymised immediately using a unique identifiers (your identification
number for the study). Data obtained from the study will only be available to this study team
and will only be used for this study. This will include the data obtained from the interviews and
questionnaires, the Thresholding sessions and the scanning sessions. This information will be
stored on a password protected database on a password and firewall protected computer. All
identifiable data in paper form will be stored in a locked filing cabinet on locked premises at

The Brain in Pain IV: The neurophysiology of chronic idiopathic pain


6
the medical school, where it will be archived for 20 years for your protection and to follow good
clinical practice guidelines.
We will also need to register you as a patient with the Hammersmith Hospital. This will allow
us to use the services provided by the hospital in the unlikely event of a medical emergency.
You have the right to access all data kept on you under the terms of The Data Protection Act,
1988. should you request to do so, you will be granted access within 40 days. You can also
request that we stop using your data. Should you choose to do this, we would exclude you
from further involvement in the study.
6. What are the side effects/ disadvantages of taking part?
a) The Sensory tests: these tests are in common use for both research and clinical practice. They
are not painful but may cause mild transient discomfort. You will be able to stop them at any time.
Volunteers from our previous studies have not reported any problems.
Note: If you have private medical insurance, please check with the company before agreeing
to take part as to whether participation is considered material fact that should be reported.
b) The MRI scanner: Some people may find being inside the scanner claustrophobic (around 10%
of people). If you're worried about this, talk to the radiographer. The radiowaves used in MRI can
heat tissues and metals. Increased body temperature may cause problems in certain people.
Should it do so in your instance, the scanning session will stop. The most obvious 'discomfort'
caused by the scanning process is the noise that the scanner makes. This is quite normal but is
loud and so you will be given protective headphones to prevent this from being problematic. You
can get burnt if you come into contact with metal objects, such as metal in clothing or equipment.
For this reason, you will be asked to change into a gown and will be provided with a locker for your
clothes and any valuables. Limb to limb skin contact can also create a burn and foam pads may be
placed between your limbs so that this doesn't happen. If you have metal fillings in your teeth you
may also feel a tingling during the scan. One of the questionnaires that you complete at the first
appointment will ensure that you are able to safely undergo this type of scan.
c) The medicines: The two drugs that we are using are safe and are in common clinical use. They
are not new and this study is not testing their effects (which are already known). As with any drug,
they do have side effects but we are using small doses and are only using them once each. This
will minimise the chances of you experiencing any side effects.
Amisulpride: With only a single dose, the most likely effect that you will experience is drowsiness.
It is possible that you might feel your muscles become stiff and we will be prepared with
medication that can reverse this should it occur. With prolonged use, changes in heart rhythm can
occur and we will perform a tracing of the hearts rhythm to test for this. It is unlikely to occur after
one dose but it is the reason that we cannot include anyone with known heart problems in the
study. A rare side effect of this type of medication is called neuroleptic malignant syndrome. This
effects less than 0.2% of people taking this type of medication regularly. This would require
treatment and management in hospital. We would not expect it to occur after a single dose and is
very rare. Common effects with repeated doses (i.e. with daily use) include constipation, nausea,
dry mouth, light-headedness, drowsiness, tremor, stiff muscles, restlessness and excessive
production of saliva. Less commonly people experience painful muscle spasms. These are seen
in individuals taking the medication on a daily basis rather than a one off dose. Rigidity and muscle
spasms can be reversed with an agent, which we would have on site and would be able to
administer if necessary.
Naltrexone: The experience of our team and of others is that a one off dose of naltrexone is not
associated with any ill effect. Those taking it regularly may experience headache, restlessness,
anxiety, abdominal cramps, nausea and joint pain are experienced by some. Less commonly,
thirst, dizziness, shivering, diarrhoea, constipation, chest pain, difficulty urinating, anxiety and
irritability may be experienced in those taking it regularly.

The Brain in Pain IV: The neurophysiology of chronic idiopathic pain


7
Whilst these side effects are possible, the administration of a single, one off dose makes them
unlikely.
d) The dolorimeter
As the study involves the investigation of pain, the pressure exerted will be painful. However,
as described above, this is only moderate pain and is not continuously applied for more than
10 seconds at any one time and there are rest periods between each pressure. Whilst care is
taken to prevent the development of bruising, in some people this might occur, albeit unlikely
with levels of only moderate pain. Since this may cause problems, should it occur at all, with
day-to-day tasks such as writing, we will use the left thumbnail as most people are right
handed. If you would rather the other thumb was used, please let the research team be aware
of this. If you have any concerns regarding this, please feel free to ask a member of the
research team. Volunteers did not report any problems using this piece of equipment in our
previous study.
7. What are the possible benefits of taking part?
This is a study of the physiology of chronic pain and as such we would not expect you to gain
any benefits from taking part. However, this is an exciting and novel piece of research into a
much-needed area of medicine and the information we get might help improve our
understanding of how pain arises and how it might be better treated. In addition to this, you
will receive an in depth assessment (supplementary to your ongoing medical care) as part of
the research protocol that will include an assessment of different aspects that contribute to
chronic pain, individual to you as well as an assessment for two different ways in which your
central nervous system may be sensitised.
8. Expenses/ Payment
You will be paid 200 for your troubles and participation in the study on your completion
of the six appointments and out of pocket expenses such as travel to a maximum of 50
(receipts will be required for all travel claimed). We will also provide a pre-paid taxi to take you
home after each of the scanning appointments. No additional payment will be given for other
expenses.
9. Will my taking part be confidential?
All information collected about you will be kept strictly confidential. Although your GP will be
informed of your participation with your consent, we will not disclose any of the confidential
material obtained during the study to him/her. If you consent to take part in the research, the
people conducting the study will abide by the Data Protection Act 1998, and the rights you
have under this Act. All information collected about you during the course of this research is
made untraceable to you. All data collected will be stored against a code number, not your
name, in a password-protected computer that only the investigators of the study will have
access to. This will be held securely at the medical school. Personal information such as your
name and address will be kept separately from your data used only to monitor recruitment or to
contact you during the study. Data collected from the initial interview and the questionnaires
will be transferred directly to this database on site (i.e. there will be no transfer or carriage of
data off site from where the interview is conducted). Data collected from the scanning
appointments will be collected at Imanova and will remain stored on their firewall protected
servers and only accessed by members of the research team via password protected
computer terminals able to access this server. The data we collect will be securely stored for 20
years after the end of the trial, for your protection and to follow good clinical practice (GCP).
Imanova retain primary image data generated by the study for 30 years as part of their record
retention policy and as part of good clinical practice. If you join the study, your research
records and the data collected for the study may be looked at by authorised persons from the
joint research office of Barts Health NHS Trust and the medical school for the purposes of

The Brain in Pain IV: The neurophysiology of chronic idiopathic pain


8
research audit. They may also be looked at by independent regulatory authorities to check
that the study is being carried out correctly. All will have a duty of confidentiality to you as a
research participant and nothing that could reveal your identity will be used. Your GP and any
other doctors you are consulting will be informed that you are taking part in our study.
10. What will happen if I dont want to carry on with the study?
You are free to withdraw from the study at any time without having to provide us an
explanation. Information collected will still be used unless you specifically request otherwise.
Any data collected will still be stored at the medical school for due diligence and audit.
11. What happens if there is a problem?
We would not expect you to come to any harm or injury because of your participation in this
study. You will have a dedicated mobile phone number in order to contact the research team
in the event that you should be concerned about any adverse effects after any of the
appointments for the study. Queen Mary University of London has agreed that if you are
harmed as a result of your participation in the study, you will be compensated, provided that,
on the balance of probabilities, an injury was caused as a direct result of the procedures you
received during the course of the study. These special compensation arrangements apply
where an injury is caused to you that would not have occurred if you were not in the study.
These arrangements apply where an injury is caused to you that would not have occurred if
you were not in the study. These arrangements do not affect your right to pursue a claim
through legal action. If you have a complaint, please contact : The Complaints Officer, c/o
Chief Operation Officer for Barts and The London, Queen Mary School of Medicine and
Dentistry, Barts and The London School of Medicine and Dentistry, First floor, Garrod
Building, Turner Street, London E1 2AD.
12. What Will Happen To The Results Of The Study?
Once we have analysed all of the results of our study we will publish our findings in medical
journals. However, you will not be personally identified in any report or publication. Should you
wish to be informed of the results of the study, we will make a note of this and arrange for a
summary of the major findings to be sent to you in addition to a copy of any published article.
13. Is this study local or across the country?
This is a local study to North East London. There are 2 NHS participant identification centres.
They are East London Foundation NHS Trust and Barts Health NHS Trust
Thank you for your interest in our study
Dr Julius Bourke, Principal Investigator, [email protected], 020 346 57232

The Brain in Pain IV: The neurophysiology of chronic idiopathic pain