Cytokine Alterations and Chronic Post-Surgical Pain

Cytokine Alterations Associated With Persistent Post-surgical Pain and Their Regulation Through Epigenetic Changes - A Pilot Study

Chronic Post-Surgical Pain (CPSP) is a condition that involves experiencing pain and/or discomfort that lasts for more than 3 months following surgery without any explainable cause of this pain such chronic infection or pain caused from a condition preceding surgery. This condition negatively impacts health related quality of life and is associated with significant financial burden both for the patient and health care system. Patients undergoing common surgeries such as amputation, breast surgery, hernia repair, coronary artery bypass, and caesarean section can be prone to developing CPSP. CPSP may be caused by the release and expression of different cellular molecules called cytokines and chemokines that can cause a pain response when they are present in the body at certain levels. After surgical incision, tissue cells have been shown to release cytokines and chemokines, thus increasing the concentration of these molecules in the patient's blood. It is not entirely known what mechanisms cause the increased expression of chemokines and cytokines. One method that may play a role in in this expression is epigenetics which is the alteration of gene expression without permanently altering the structure of DNA. Unlike mutations, epigenetic changes are dynamic, possibly reversible, and are influenced by environmental and behavioral changes such as diet, exercise, disease, stress, toxin exposure etc. Epigenetic changes occur all throughout our life and have been associated with several disease processes such as cancer, diabetic complications, and chronic pain. At the molecular level, certain events take place that can regulate (increase or decrease) the expression of cytokines and chemokines, most notably DNA methylation of their promotor (which involves adding molecules to DNA that does not change its structure but changes it's activity). We are conducting this study to determine if the alteration of specific cytokines are associated with the occurrence of CPSP and whether these cytokines are regulated by DNA methylation at their promoter. This study will take place at London Health Sciences Centre and will recruit up to 50 patients who will be undergoing a thoracotomy procedure (surgery of the chest area).

Study Overview

• Status: Not yet recruiting
• Conditions: Chronic Post Operative Pain
• Intervention / Treatment: Other: Unilateral thoracotomy for non-malignant lung resection

Detailed Description

Chronic Post-Surgical Pain (CPSP), defined by the International Association for the Study of Pain, is a clinical discomfort that lasts more than 3 months post-surgery without other causes of pain such as chronic infection or pain from a chronic condition preceding the surgery1. This condition negatively impacts health related quality of life and is associated with significant financial burden both for the patient and health care system. Patients undergoing a multitude of procedures, from amputation to hernia repair, are prone to develop CPSP with variable incidences2.

CPSP may be a result of peripheral and central sensitization triggered by the release of cytokines and chemokines following surgery due to possible alterations in genetic expression. At the cellular level, after surgical incision, tissue cells from local areas have been implicated to drive synthesis of such cytokines/chemokines leading to alterations of their serum levels, including nerve growth factors (NGF) and interleukins (IL-1β)3. Specific regulatory mechanisms leading to augmented synthesis of these cytokines in the context of CPSP remain elusive. Several regulatory mechanisms may influence production of each cytokine. One method is via epigenetic mechanisms, which are defined as the alteration of gene expression without any structural genomic alterations4,5 that may regulate cytokine production at the transcriptional and post transcriptional levels6. Among these listed epigenetic mechanisms, DNA methylation has been well studied and plays a key role in translation4. In general, hypomethylation of the promoter region leads to increased gene expression and vice versa4. In this study we wish to investigate how these mechanisms could be implicated in the expression of cytokines and chemokines in CPSP.

Patients undergoing unilateral thoracotomy for non-malignant lung resection will be included in this study. Their surgery and follow up care will proceed according to standard of care guidelines. Thoracic epidural analgesia, or patient controlled analgesia (PCA) pumps will be offered to each study participant as per standard of care. Patients' pain will be assessed preoperatively and postoperatively on days 1,2,3 and 3 months. Blood samples will also be taken during these times points and analyzed to determined the concentrations of the following cytokines, chemokines and growth factors: epidermal growth factor, eotaxin, fibroblast growth factor basic, G-CSF, GM-CSF, human growth factor, IFN-α, IFN-γ, IL-1ra, IL-1β, IL-2, IL-2r, IL-4, IL-5, IL-6, IL-7, IL-8, IL-10, IL-12 (p40/p70), IL-13, IL-15, IL-17, IP-10, MCP-1, MIG, MIP-1α, MIP-1β, RANTES, TNF-α, and VEGF. The occurence of DNA methylation at the promotor region of these targets will be assessed via polymerase chain reaction (PCR) analysis. Results of these postoperative analyses will be compared to pre-operative molecular concentrations and pain scores to determine the association between epigenetic modifications (if any) and the development of CPSP and whether these modifications are driven by DNA promotor methylation.

• Study Type: Observational
• Enrollment (Estimated): 60

Contacts and Locations

• Study Contact: Name: Abhijit Biswas; Phone Number: 55956 5196858500; Email: Abhijit.Biswas@lhsc.on.ca

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: No

• Sampling Method: Probability Sample

Study Population

Adult patients scheduled to undergo thoracotomy for non-malignant lung at Victoria Hospital, London Health Science Centre.

Description

Inclusion Criteria:

1. 18 years of age or older
2. Undergoing unilateral thoracotomy for the first time on that side
3. Willing to provide informed consent for study participation.
4. Patient with lung cancer

Exclusion Criteria:

1. Chronic pain prior to surgery
2. Pre-existing fibromyalgia
3. Long-term opioid use
4. Diabetes mellitus
5. Pre-existing neurological disease
6. Pre-existing nerve injury
7. Evidence of dementia, delirium or cognitive disorder that may interfere with study participation
8. Malignancy other than lung cancer
9. Autoimmune disorder
10. Pregnancy
11. Inability to communicate in the English language (required for completion of questionnaires and provision of pain scores

Study Plan

How is the study designed?

Number of groups / cohorts

1

Cohorts and Interventions

Group / Cohort

Intervention / Treatment

Unilateral thoracotomy for non-malignant lung resection; Unilateral thoracotomy for non-malignant lung resection to proceed according to standard of care guidelines.

Other: Unilateral thoracotomy for non-malignant lung resection; Unilateral thoracotomy for non-malignant lung resection to proceed as per standard of care guidelines. Thoracic epidural analgesia, or patient controlled analgesia (PCA) pumps will be offered to each study participant as per standard of care. Pre- and post-operative (post-operative days 1, 2, 3 and 3 months) pain scores and blood samples will be collected. Blood samples will be analyzed to determine the concentration of cytokines, chemokines, and growth factors that are potentially associated with CPSP (epidermal growth factor, eotaxin, fibroblast growth factor basic, G-CSF, GM-CSF, human growth factor, IFN-α, IFN-γ, IL-1ra, IL-1β, IL-2, IL-2r, IL-4, IL-5, IL-6, IL-7, IL-8, IL-10, IL-12 (p40/p70), IL-13, IL-15, IL-17, IP-10, MCP-1, MIG, MIP-1α, MIP-1β, RANTES, TNF-α, and VEGF). DNA promotor methylation for these targets will also be investigated.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Identification of temporal alterations of cytokines in patients with CPSP.	Cellular assays will be performed on blood samples obtained pre-and postoperatively to determined the level of expression of certain chemokines, cytokines, and growth factors that have been shown to be potentially related to CPSP. Pre and postoperative results will be compared to determine the association that each may have on the development of CPSP.	3 months
Identification of specific DNA promoter methylation regulating production of specific cytokines	Cellular assays will be performed on blood samples obtained pre-and postoperatively to determine if DNA promotor methylation is associated with changes in expression of the cytokines being investigated. Pre and postoperative results will be compared to determine the impact that this potential epigenetic change (DNA promotor methylation) may have on the development of CPSP.	3 months
Generate initial data to determine the sample size needed to adequately power a larger trial	As this is a pilot study, data will be analyzed to determine the sample size needed to power a larger, randomized controlled trial.	3 months

Collaborators and Investigators

• Sponsor: Lawson Health Research Institute
• Investigators: Principal Investigator: Abhijit Biswas, Western University

Publications and helpful links

General Publications

• Macrae WA. Chronic post-surgical pain: 10 years on. Br J Anaesth. 2008 Jul;101(1):77-86. doi: 10.1093/bja/aen099. Epub 2008 Apr 22.
• Zhang JM, An J. Cytokines, inflammation, and pain. Int Anesthesiol Clin. 2007 Spring;45(2):27-37. doi: 10.1097/AIA.0b013e318034194e.
• Richebe P, Capdevila X, Rivat C. Persistent Postsurgical Pain: Pathophysiology and Preventative Pharmacologic Considerations. Anesthesiology. 2018 Sep;129(3):590-607. doi: 10.1097/ALN.0000000000002238.
• Macrae WA, Davies HTO, Crombie IK, Linton S, Croft P, Von Korff M, LeResche L. Chronic postsurgical pain, Epidemiology of Pain, 1999, Seattle International Association for the Study of Pain (pg. 125-42)
• Aroke EN, Joseph PV, Roy A, Overstreet DS, Tollefsbol TO, Vance DE, Goodin BR. Could epigenetics help explain racial disparities in chronic pain? J Pain Res. 2019 Feb 18;12:701-710. doi: 10.2147/JPR.S191848. eCollection 2019.
• Odell DW. Epigenetics of pain mediators. Curr Opin Anaesthesiol. 2018 Aug;31(4):402-406. doi: 10.1097/ACO.0000000000000613.
• Descalzi G, Ikegami D, Ushijima T, Nestler EJ, Zachariou V, Narita M. Epigenetic mechanisms of chronic pain. Trends Neurosci. 2015 Apr;38(4):237-46. doi: 10.1016/j.tins.2015.02.001. Epub 2015 Mar 9. Erratum In: Trends Neurosci. 2015 Sep;38(9):579.

Study record dates

Study Major Dates

• Study Start (Estimated): January 1, 2025
• Primary Completion (Estimated): December 1, 2026
• Study Completion (Estimated): December 31, 2026

Study Registration Dates

• First Submitted: May 13, 2024
• First Submitted That Met QC Criteria: May 13, 2024
• First Posted (Actual): May 17, 2024

Study Record Updates

• Last Update Posted (Actual): May 17, 2024
• Last Update Submitted That Met QC Criteria: May 13, 2024
• Last Verified: May 1, 2024

More Information

Terms related to this study

• Keywords: chronic pain; epigentics
• Additional Relevant MeSH Terms: Pathologic Processes; Postoperative Complications; Pain; Neurologic Manifestations; Pain, Postoperative
• Other Study ID Numbers: CPSP Epigenetics

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No