Pain perception and chronic pain in humans: in search of genetic factors and biomarkers

Pain is the most frequent cause of suffering and disability in society. Chronic
pain seriously impairs the quality of life of millions of people worldwide.
10-50% of surgical patients (i.e. up to 10% of Western populations) report
chronic pain after surgery; up to 10% report severe pain. Thus chronic pain is
a significant medical and financial burden on society.
Pain shows substantial heritability. In mice, pain sensitivity has a strong
heritable component, ranging from 30% to 76%. Recent human twin studies confirm
the role of genetic factors in (experimentally induced) pain, with estimates
ranging from 22% to 60% heritability. Despite the considerable involvement of
genetic factors in pain sensation and sensitivity, the individual genes
involved remain largely unidentified.
Knowledge of genetic factors, including gene expression and protein levels,
their phenotypic expression in pain processing, and their link to neuronal
correlates can improve our understanding of pain aetiology and the processes
involved in pain perception and chronification. In addition, they can serve as
biomarkers. These biomarkers can be useful to predict chronic pain development
and progression in individual patients and help early individual treatment
adaptation.

In this long term study programme we wish to establish a prospective database
and biobank of patients undergoing elective major surgery and healthy subjects.
Using the data collected in the patient database and biobank, we will perform
analyses linking genetic factors, markers at the level of gene expression and
protein levels and their phenotypic expression via measures of pain processing,
and neuroimaging to the development of chronic pain after surgery. Furthermore,
we will set up a database of healthy subjects to investigate risk factors for
high pain sensitivity and the development of chronic pain.

Over a period of approx. 10 years we will prospectively include up to 10000
patients for elective major surgery. Moreover, we will include a sample of up
to 10000 healthy volunteers to be able to define risk factors for higher pain
sensitivity. Data will be collected defining participants demographics, medical
history and questionnaire data investigating life style, life events,
personality and behavioural traits. To store and administer data and tissue (50
ml blood/patient, or 2ml saliva per healthy participant), a dedicated data- and
biobank will be set up. From patients, additionally details of surgery and
perioperative management, genotype and gene and protein expression, pain
processing phenotype, and surgical and pain outcomes will be stored.
Electroencephalography (EEG) and/or magnetoencephalography (MEG) as well as
magnetic resonance imaging (MRI) will be performed on subgroups.

Data and measures concerning demographics, surgical and perioperative
management, blood for DNA, RNA and protein extraction and pain processing
phenotypes will be collected at the preoperative anaesthesia outpatients*
clinic visit. Data and blood collection will add between 30 and 40 minutes to
the duration of the normal visit. Healthy subjects will be asked to come to the
hospital for a 60 minute visit, in which demographic and medical data will be
collected, and questionnaires will be handed out for filling out at home (max.
120 minutes homework). Outcome data in patients will be collected shortly after
surgery as well as 6, 12, and 24 months postoperatively by questionnaires and
phone interviews. Based on interviews/questionnaires and/or outcome data,
subgroups of patients and healthy subjects will be asked to participate in EEG
and MRI experiments at a later date (visit to the hospital for 120-150
minutes). Apart from interviews and questionnaires, the major extra burden for
the patient is 1) collection of 50 ml of blood by venapuncture, and 2)
quantitative sensory testing (QST) for pain thresholds, windup and DNIC
paradigm (cold pressor task). Venapuncture is a standard diagnostic procedure
associated with minimal risk and physical discomfort; QST is a non-invasive
procedure, well tolerated by patients, and part of the standard clinical
diagnostic workup of chronic pain patients at the Radboud University Nijmegen
Medical Centre. Also EEG and MRI are non-invasive, low-risk procedures. Risk
factors for chronic pain development after surgery can only be investigated in
patients undergoing surgery.