Sensory alterations and immunological changes during the chronification of postsurgical pain

Chronic postsurgical pain (CPSP), pain that newly develops or changes in
characteristics after a surgical procedure and persists at least three months
after surgery, constitutes a widely underdiagnosed and often poorly treated
medical problem affecting 10 to 50 percent of all surgical patients.1,2,3,4
Since pain is a common indication for surgery and surgery itself may result in
CPSP, patient selection is of the utmost importance in evaluating a patient for
a surgical procedure intended to relief pain.

In a previous study we have developed and validated a postoperative prediction
model for the identification of patients at risk for CPSP following a wide
range of surgical interventions. The strongest determinant associated with the
development of CPSP was the presence of a painful cold two weeks following
surgery.5 Since the presence of a painful cold is considered a characteristic
of neuropathic pain, this leads to the hypothesis that surgical stimuli may
cause sensory alterations in the early postoperative period ultimately
resulting in the development of a chronic neuropathic pain state. Although
chronic pain may appear to be a disorder of the nervous system, immune cells
and their mediators have been identified as important contributors in pain
regulation.6
The aim of the present study is to assess the extent of sensory alterations and
the role of immunological inflammatory parameters in the transition from an
acute into a chronic postsurgical neuropathic pain state. This is important
because the efficacy of pain treatment is associated with the pain phenotype
based on sensory alterations.7 Combining the information on sensory alterations
and the immunological response after surgery may eventually lead to improved
pain phenotyping creating opportunities to initiate more mechanism-based
treatment regimens for patients at risk for CPSP with neuropathic
characteristics.

1. Macrae WA. Chronic post-surgical pain: 10 Years on. Br J Anaesth. Published
online 2008. doi:10.1093/bja/aen099
2. Kehlet H, Jensen TS, Woolf CJ. Persistent postsurgical pain: risk factors
and prevention. Lancet. Published online 2006. doi:10.1016/S0140-6736(06)68700-X
3. Crombie IK, Davies HTO, Macrae WA. Cut and thrust: Antecedent surgery and
trauma among patients attending a chronic pain clinic. Pain. Published online
1998. doi:10.1016/S0304-3959(98)00038-4
4. Macrae WA. Chronic pain after surgery. Br J Anaesth. Published online 2001.
doi:10.1093/bja/87.1.88
5. Driel, M.E.C., Rijsdijk M, Baart S HFJPM. Development and validation of a
multivariable prediction model for the early prediction of chronic postsurgical
pain - In preparation. Published online 2021.
6. Raoof R, Willemen HLDM, Eijkelkamp N. Divergent roles of immune cells and
their mediators in pain. Rheumatol (United Kingdom). Published online 2018.
doi:10.1093/rheumatology/kex308
7. Forstenpointner J, Otto J, Baron R. Individualized neuropathic pain therapy
based on phenotyping: are we there yet? Pain. Published online 2018.
doi:10.1097/j.pain.0000000000001088

The primary objective is to identify sensory alterations and changes in
immunological parameters that are related to the development of chronic pain
with neuropathic characteristics in postsurgical patients within three months
after surgery.
The secondary objective is to develop a prediction model for the early
identification of patients at risk for CPSP with neuropathic characteristics
after elective orthopedic surgery of lower extremities.

Prospective observational cohort study.

Benefit: Postoperative pain will be treated according to routine clinical care.
Identified patterns of sensory alterations will not influence pain treatment
regimens. Patients, therefore, do not have direct benefit of participation in
this study. The obtained knowledge, however, may guide pain treatment regimens
and potentially improve treatment efficacy in future patients at risk for CPSP.
Burden/risk: Study participants fill in questionnaires, undergo Quantitative
Sensory Testing (QST) measurements (for the identification of sensory
alterations) and blood withdrawal (for analysis of immunological parameters) at
four different time points (before surgery, directly after surgery (POD0), in a
time window between two to four weeks following surgery (POD14) and
postoperative day 90 (POD90)). In addition, participants are asked to complete
a pain diary daily for the first two weeks after surgery, which will take
approximately 5 minutes a day. Completing the questionnaires will take
approximately 15 minutes. One QST test session takes approximately one hour to
be completed. Blood withdrawal may be painful and takes approximately five
minutes to complete.
The health risk of completing questionnaires and undergoing QST testing, both
non-invasive, are negligible. The collection of blood via venipuncture or from
a previously inserted IV line are low-risk procedures with negligible chance on
severe adverse events when performed correctly. The additional health risk of
this study is, therefore, classified as negligible. Because the risks of
participating in this study are deemed negligible, a request for exemption from
the research subject insurance obligation is submitted.
The time burden and the number of site visits associated with this study will
be limited in some extent by combining the baseline visit with the appointment
at the preoperative assessment clinic. Besides, the QST assessment on POD14 may
be combined with a home visit for wound control and removal of stitches. Travel
expenses (and parking costs) shall be reimbursed for the extra two scheduled
visits.

Risk assessment with regard to the COVID-19 pandemic: Recognizing that the risk
of COVID-19 cannot be completely eliminated, this study adds limited risk to
the spread of COVID-19 because of the aim to implement research visits in
standard care, and the strict adherence to the RIVM policy. The study is
compliant with CCMA policy, IGJ policy, EMA guidance and meets the conditions
set out by the UMCU. Risks will be reassessed as the situation develops.