Cytokine Alterations and Chronic Post-Surgical Pain

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). The investigators 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 60 patients who will be undergoing a thoracotomy procedure (surgery of the chest area).

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 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 a multitude of procedures, from amputation to hernia repair, are prone to develop CPSP with variable incidences.

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). 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 alterations that may regulate cytokine production at the transcriptional and post transcriptional levels. 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 versa. In this study the investigators wish to investigate how these mechanisms could be implicated in the expression of cytokines and chemokines in CPSP.

Patients undergoing unilateral thoracotomy 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 day 1 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 occurrence 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.

Eligibility Criteria:
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 malignancy that needs thoracotomy for surgical resection.

Exclusion Criteria:

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