Appendix B — Project example

The following is a project example provided by the course coordinator, Kristian.

Please note that this project is not the officialt project call but serves as an example for supervisors proposing their own project for the course.

Students of the course should also familiarize themselves with the level of a potential exam project at the start of the course, such that they are aware of the “end goal” of the course.

B.1 Project title:

Treatment effect of NSAID and paracetamol pain in knee osteoarthritis.

B.2 Project supervisors:

Kristian

B.3 Number of assigned groups:

The project is open for max 3 groups.

B.4 Project description:

Chronic pain is a major problem that affects 20% of the world’s population. Knee osteoarthritis is characterized by joint degeneration, and the hallmark symptom is chronic pain.

Inflammation is believed to be one of the main drivers for pain in knee osteoarthritis \(^1\) and therefore Non-Steroidal Anti-Inflammatory Drugs (NSAIDs) are one of the clinical recommended treatment for knee osteoarthritis \(^2\). Analgesic effects have been widely documented even though the mechanisms of action are not completely understood \(^3\). Both NSAIDs and paracetamol inhibit the synthesis of prostaglandins modulated through cyclooxygenase (COX). In the rat, non-selective NSAIDs and paracetamol enhance the activity of the cannabinoid system \(^4\), and studies suggest that the analgesic effect of NSAIDs and selective COX-2 inhibitors is dependent on an intact serotonin system 3. Further, COX-2 inhibitors modulate widespread hyperalgesia \(^{5,6}\) suggesting that NSAID treatment may also modulate central pain pathways and that mechanistic pain profiling could identify responders to NSAID treatment. NSAIDs may be potentially harmful \(^6\) and therefore, it is ideal to identify patients benefiting from NSAIDs before administrating the drug.

Pro-inflammatory cytokines are known to sensitize the peripheral nerve endings leading to hyperalgesia \(^7\), which can be assessed as lowered pressure pain thresholds (PPTs). A prolonged intense painful input from the periphery may sensitize the dorsal horn neurons leading to an increased central gain of pain \(^8\). This phenomenon can be assessed as facilitated temporal summation of pain (TSP) \(^9\). Widespread hyperalgesia can in part be explained by impaired descending pain control which is considered the net effect of pain inhibitory and facilitatory pathways \(^{10,11}\). NSAIDs has the potential to lower the inflammation and thereby modulating the pain sensitivity measures. Psychological factors should also be considered, as approximately one-fifth of patients with osteoarthritis experience symptoms of anxiety and depression \(^12\) and a large population-based study across \(^17\) diverse countries found anxiety and mood disorders to be twice as prevalent in patients with arthritis compared to those without \(^13\). Self-reported symptoms of depression and anxiety have previously been correlated to pain in osteoarthritis intensity \(^{14,15}\) and are suggested to be predictive for treatment responses \(^16\).

Assignment

In this study, you are to evaluate if a 3-weeks intervention with NSAID and paracetamol is effective and identify patients who are more likely to respond to therapy.

B.5 Data availability

Data from 100 patients with data before and after therapy is available. The following parameters are available:

table

Treatment

Patients were administered 400 mg ibuprofen three times per day and 1g paracetamol three times per day for a three-week duration. Patients were also administered 20 mg of pantoprazole once per day to prevent ulcers. All patients were instructed to report any adverse and severe adverse events.

B.6 References

  1. Felson, D. T. The sources of pain in knee osteoarthritis. Curr. Opin. Rheumatol. 17, 624–628 (2005).
  2. Bannuru, R. R. et al. OARSI guidelines for the non-surgical management of knee, hip, and polyarticular osteoarthritis. Osteoarthr. Cartil. 27, 1578–1589 (2019).
  3. Graham, G. G., Davies, M. J., Day, R. O., Mohamudally, A. & Scott, K. F. The modern pharmacology of paracetamol: Therapeutic actions, mechanism of action, metabolism, toxicity and recent pharmacological findings. Inflammopharmacology 21, 201–232 (2013).
  4. Ahn, D. K. et al. Blockade of central cyclooxygenase (COX) pathways enhances the cannabinoid-induced antinociceptive effects on inflammatory temporomandibular joint (TMJ) nociception. Pain 132, 23–32 (2007).
  5. Reinold, H. et al. Spinal inflammatory hyperalgesia is mediated by prostaglandin E receptors of the EP2 subtype. J. Clin. Invest. 115, 673–679 (2005).
  6. Malfait, A.-M. & Schnitzer, T. J. Towards a mechanism-based approach to pain management in osteoarthritis. Nat. Rev. Rheumatol. 9, 654–64 (2013).
  7. Schaible, H.-G. G. Nociceptive neurons detect cytokines in arthritis. Arthritis Res. Thera. 16, 470–478 (2014).
  8. Schaible, H.-G. Spinal mechanisms contributing to joint pain. Novartis Found. Symp. 260, 4–22; discussion 22-7, 100–4, 277–9 (2004).
  9. Graven-Nielsen, T. & Arendt-Nielsen, L. Assessment of mechanisms in localized and widespread musculoskeletal pain. Nat. Rev. Rheumatol. 6, 599–606 (2010).
  10. Yarnitsky, D. Role of endogenous pain modulation in chronic pain mechanisms and treatment. Pain 156 Suppl, S24-31 (2015).
  11. Arendt-Nielsen, L. et al. Assessment and manifestation of central sensitisation across different chronic pain conditions. Eur. J. Pain 22, 216–241 (2018).
  12. Stubbs, B., Aluko, Y., Myint, P. K. & Smith, T. O. Prevalence of depressive symptoms and anxiety in osteoarthritis: a systematic review and meta-analysis. Age Ageing 45, 228–235 (2016).
  13. He, Y. et al. Mental disorders among persons with arthritis: results from the World Mental Health Surveys. Psychol. Med. 38, 1639 (2008).
  14. Smith, B. W. & Zautra, A. J. The Effects of Anxiety and Depression on Weekly Pain in Women with Arthritis. Pain 138, 354–361 (2008).
  15. Hadlandsmyth, K. et al. Relationships among pain intensity, pain-related distress, and psychological distress in pre-surgical total knee arthroplasty patients: a secondary analysis. Psychol. Health Med. 22, 552–563 (2017).
  16. Wood, T. J., Gazendam, A. M., Kabali, C. B. & Group, H. A. Postoperative Outcomes Following Total Hip and Knee Arthroplasty in Patients with Pain Catastrophizing, Anxiety, or Depression. (2021) doi:10.1016/j.arth.2021.02.018.