Why Pain Control is Important

We all want to avoid pain, and it seems that controlling pain, particularly after surgery when nerves are damaged and inflamed, is important. Our sensory nerves are effectively a system of reporters that tell us what is going on inside a joint, and nerves also have important roles in health. It has long been known that nerves are essential in the wound healing process [1], but the focus has largely been on treating a lack of nerve signalling due to paralysis and diabetes. Now, it’s becoming increasingly clear that chemicals released from overstimulated, upset nerves are important players in the pathology of fibrosis.

Normal signalling in sensory nerves begins when receptors in nerve cells detect mechanical or temperature stimuli from the environment, triggering nerve impulses. These electrical signals travel along the nerve fibre to the central nervous system in the spinal cord, creating awareness in the brain. The same processes are responsible for pain after injury, except the stimulus is tissue damage. Acute (short term) pain is caused by “noxious stimuli” – for the readers of the IAA, that’s usually an insult such as an injury or surgery, although the damage may not be so obvious, as often happens in frozen shoulder. Immediately after the insult inflammatory cytokines are released by different types of cells, signalling nerves to release neuromodulators (potent signalling molecules) that create the sensation of pain [2]. In addition to pain, these factors sensitise nerves, making them extremely reactive to stimuli such as touch [3,4]. This is a natural protective response to prevent use of the limb and further injury.

Unfortunately, surgery inevitably damages nerves, and after major surgeries such as ACL repair and total knee replacement there are often numb areas where sensory nerves were cut and have died. However, in nearby areas the nerves can become chronically inflamed and painful. The infrapatellar fat pad (IFP or Hoffa’s Fat Pad) is frequently cut during major knee surgeries, and the resulting nerve damage, inflammation and pain can set up a fibrotic feedback that becomes self-sustaining. Fat pads are associated with all major joints, including shoulders, and are packed full of immune cells and nerves that are primed to protect the joint. Many of these nerves are capable of releasing Substance P (think P for pain) and consequently the IFP and other fat pads are a “potent source of pain” [5,6].

Substance P and other nerve factors increase inflammation and fibrosis

In addition to pain, Substance P and other nerve factors increase inflammation [5] and fibrosis. Nerve growth factor (NGF) is produced in response to inflammatory cytokines (TNF-α and IL-1β) and also contributes to pain [7]. Activated nerves are also a source of matrix metalloproteinase 2 (MMP2), which activates another inflammatory cytokine, IL-1β, and sustains nerve activation. Calcitonin gene-related peptide (CGRP) is released by upset nerves, and appears to be a powerful profibrotic stimulator, upregulating the key pro-fibrotic cytokines TGF-β and CTGF.8 The scientific literature tells us that Substance P, NGF and CGRP all promote fibrosis, causing an increase in scar tissue and immune cells [9].

Unfortunately, feedback effects between upset nerves and myofibroblasts (the cells that create fibrosis) begin to appear over time. While nerve factors promote myofibroblast activation and fibrosis [2,7], fibrosis of the IFP (and other tissues) increases nerve signalling, the number of nerve fibres and pain [6,10]. At the same time, nerves, myofibroblasts and immune cells create more inflammatory cytokines in response to each other. It’s this feedback that needs to be “nipped in the bud” early after surgery, and one reason why we need to be very careful about exercising the affected limb and not “push through the pain”.

It’s this feedback that needs to be “nipped in the bud” early after surgery, and one reason why we need to be very careful about exercising the affected limb and not “push through the pain”.

With ongoing pain the central nervous system and peripheral nerves become sensitised, increasing the number of receptors for pain signalling. This can make the joint hypersensitive to normal stimuli. The nerves themselves can also become fibrotic [11] and neuropathy can occur, with symptoms that can include pain, cramps, tingling, muscle loss and abnormal skin, hair and nails. There may be an abnormal pain response to normal changes in temperature, and even warm sunlight can be experienced as a painful burning sensation.

So, keeping nerves happy appears to be important for preventing chronic pain and fibrosis, as well as keeping people happy, but achieving this can be difficult. Experienced orthopaedic surgeons may use nerve blocks during and after surgery, including indwelling local pain catheters (adductor canal block and genicular/sciatic block) with continuous infusion of analgesia. In addition, a genicular local nerve block may be placed during surgery (see Surgery). Opioid and opiate medications are often used immediately post-op, but together with NSAIDS they are not recommended for long term pain control due to undesirable adaptations by the body that promote pain.

A variety of pain control methods are used for treating chronic pain, but unfortunately there are few high quality studies that remove the effects of bias, and which provide evidence of efficacy [12]. A useful approach is to test one particular method at a time to determine how effective it is for you, rather than trying multiple approaches at the same time [12]. Methods include low dose aspirin, transcutaneous electrical nerve stimulation (TENS), low dose naltrexone, pregabalin (Lyrica), Botox, cannabinoids, lidocaine, and clonidine. Antidepressants have been shown to be either ineffective for the treatment of neuropathic pain or the evidence available is inconclusive according to Cochrane's systematic reviews.

References

1. Gurtner, G. C., Werner, S., Barrandon, Y. & Longaker, M. T. Wound repair and regeneration. Nature 453, 314-321, doi:10.1038/nature07039 (2008).

2. Lebonvallet, N., Laverdet, B., Misery, L., Desmouliere, A. & Girard, D. New insights into the roles of myofibroblasts and innervation during skin healing and innovative therapies to improve scar innervation. Exp Dermatol 27, 950-958, doi:10.1111/exd.13681 (2018).

3. Cervero, F. & Laird, J. M. Role of ion channels in mechanisms controlling gastrointestinal pain pathways. Curr Opin Pharmacol 3, 608-612, doi:10.1016/j.coph.2003.06.007 (2003).

4. Darby, I. A., Zakuan, N., Billet, F. & Desmouliere, A. The myofibroblast, a key cell in normal and pathological tissue repair. Cell Mol Life Sci 73, 1145-1157, doi:10.1007/s00018-015-2110-0 (2016).

5. Dragoo, J. L., Johnson, C. & McConnell, J. Evaluation and Treatment of Disorders of the Infrapatellar Fat Pad. Sports Med 42, 51-67, doi:10.2165/11595680-000000000-00000 (2012).

6. Onuma, H. et al. Fibrotic changes in the infrapatellar fat pad induce new vessel formation and sensory nerve fiber endings that associate prolonged pain. J Orthop Res 38, 1296-1306, doi:10.1002/jor.24580 (2020).

7. El Baassiri, M. G. et al. Nerve growth factor and burn wound healing: Update of molecular interactions with skin cells. Burns, doi:10.1016/j.burns.2022.11.001 (2022).

8. Yoon, S. P. & Kim, J. Exogenous CGRP upregulates profibrogenic growth factors through PKC/JNK signaling pathway in kidney proximal tubular cells. Cell Biol Toxicol 34, 251-262, doi:10.1007/s10565-017-9399-4 (2018).

9. Vigano, P. et al. Cellular Components Contributing to Fibrosis in Endometriosis: A Literature Review. J Minim Invasive Gynecol 27, 287-295, doi:10.1016/j.jmig.2019.11.011 (2020).

10. Hildebrand, K. A., Zhang, M., Salo, P. T. & Hart, D. A. Joint capsule mast cells and neuropeptides are increased within four weeks of injury and remain elevated in chronic stages of posttraumatic contractures. J Orthop Res 26, 1313-1319, doi:10.1002/jor.20652 (2008).

11. Wang, M. L., Rivlin, M., Graham, J. G. & Beredjiklian, P. K. Peripheral nerve injury, scarring, and recovery. Connect Tissue Res 60, 3-9, doi:10.1080/03008207.2018.1489381 (2019).

12. Aldington, D. & Eccleston, C. Evidence-Based Pain Management: Building on the Foundations of Cochrane Systematic Reviews. Am J Public Health 109, 46-49, doi:10.2105/AJPH.2018.304745 (2019).