Messaged received: Ouch.
Pathophysiology is one of my favourite things to research. This type of research looks into the details of exactly how processes in the body happen, down to the tiniest details. The reason I love this so much is because if I understand the HOW, I can figure out how to treat it. So the following is really science heavy, but I think it’s important to understand how pain happens and then we can figure out what is most likely to work or why some treatments didn’t work.
The perception of pain is a function of the nervous system, which also detects touch, proprioception (where your body is in space), and thermal (hot and cold). The sensory nerve endings that detect pain are called “nociceptors” and different kinds of these receptors can detect mechanical/pressure, thermal, or chemical stimuli. Therefore we can have different combinations of these three types of pain that result in different types of pain sensations. On top of this, the activity of these nociceptors are further influenced by different pain chemicals.
So you can see how pain is a complicated sensation that is governed by many, many pathways. One of the pathways that gets the most attention is the prostaglandin pathway. This is where arachidonic acid (an inflammatory fatty acid) gets turned into prostaglandin (a pain chemical) by the COX enzymes. It’s this pathway that is targeted by NSAIDs or non-steroidal anti-inflammatories, one of the most common pain drugs, otherwise known as the anti-inflammatory and anti-fever drugs aspirin, ibuprofen, naproxen and nabumetone. These drugs have no effect on pain thresholds, but only have an effect on abnormal pain signals from inflammatory conditions.
The nitty gritty
COX-1 and COX-2 are responsible for the first steps in prostaglandin synthesis. COX-1 is normally active and mediates many physiological processes. COX-2 however is only induced during inflammatory conditions and produces prostaglandins in acute inflammatory states and has been found active in human rheumatoid arthritis, but not so much in osteoarthritis.
There are different types of prostaglandins produced by these enzymes (namely PGE2, PGD2, and PGI2) work on different receptors called prostanoid receptors. One of the major effects of some of these prostaglandins is to sensitize neurons in the periphery of the body to noxious or irritating stimuli (which can be either chemical, thermal or mechanical). Hence, prostaglandins help nerves perceive painful stimuli.
Prostaglandins don’t just have a role in your every day aches and pains either. Dysmenorrhea is a word that describes pain during menstruation and has been specifically linked to a particular kind of prostaglandin called PGF2a in the endometrium. As levels of this chemical go up, so does the perceived levels of pain and often the amount of mensural flow as well. These chemicals, as well as other arachidonic acid metabolites, are what stimulate uterine wall contractions that cause the amount of available oxygen levels in the uterine tissues to decrease, thus causing pain.
Ok, now how do I get rid of them?
So we can decrease prostaglandins by interfering with their production by inhibiting COX enzymes with NSAIDs. However, these drugs have undesirable side effects like allergic reactions, increased bleeding, and stomach ulcers. So what other ways do we have of influencing prostaglandin levels? One major way is reducing the amount of arachidonic acid available to make prostaglandins. You can do this through diet by eating less trans fats and other foods with high levels of omega 6 fatty acids, and increasing your dietary intake of foods high in omega 3 and 6 fatty acids, like sardines or olive oil. Supplementation with glucosamine and chondroitin have been found to lower levels of prostaglandin E2, as has Vitamin E supplementation, and use of the herbs paeonia lactiflora, ginger, and commiphora myrrha.
So what else could be involved?
Inhibiting prostaglandins is only a part of the picture of pain. Depending on the original cause of pain, prostaglandins may not even factor in much. To give you an idea of how many other possible pathways could be involved here is a short list of other chemical mediators of pain (other sources could be damage to the nervous system, compression of nerve roots, damage to tissues including muscle and ligaments, or referred pain from organs):
Leukotrienes is a chemical we know contributes to pain but we are less clear on how. Levels are increased in inflammatory conditions but their direct role in pain is unclear. Lipoxygenases convert EPA and DHA into signalling molecules via COX-2 or the liver, these products are called resolvins because their level increase as tissue inflammation is resolving and can potentially be used as analgesics. Serotonin is released by injured or inflamed tissues by platelets and mast cells in the blood, and if it is injected into the muscle it elicits burning and a pressure like pain. It is the different types of receptors for serotonin that determine the type of pain perceived. Bradykinins have long been studied as major contributors to pain from both chronic and acute inflammation. Nitric oxide definitely has a central role on pain in the spinal cord and is produced in the periphery during inflammation as well. However, on human volunteers an injection of nitric oxide caused a dose related response in pain, whereas a topical application relieved pain. ATP is a chemical our cells use as energy, but when applied topically causes a sensation of pain and has been found to enhance the effect of C fibres (pain nerve endings). Low pH is also a chemical mediator of pain, and is a naturally produced by a lack of oxygen to the tissues. This creates pain by activating sensory nerves and results in a sharp stinging type pain. Glutamate has a role in both brain and spinal cord sensitization of pain, and the peripheral transmission of rapid pain signals. Substance P has many functions in the body and is found in many places, but when it comes to pain has been found to be involved in chronic pain and the slow transmission of long term pain. Opiates probably work by decreasing level so of substance P, and people with high pain tolerance have been found to lack nociceptors with substance P in the dorsal horn area of the spinal cord.
As you can see, there are many chemicals involved in the perception of pain and many medicinal substances that target different ones. Part of the difficulty in treating pain is that it can be coming from so many different sources, and when we are treating pain we have to choose which to target because no one medicine gets them all. Additionally, some conventional pain medications have very serious side effects, so it’s not always in the best interest of the person experiencing pain to be on these medications long term. While these aspects of treating pain can be frustrating, it is also means that if one treatment doesn’t work for you, there are lots of others to try! In my experiencing treating pain is like solving a puzzle, so keep trying pieces until you find the ones that fit your picture!
References
Dawes JM et. al. Inflammatory Mediators and Modulators of Pain. Wall and Mezack’s Textbook of Pain 6th ed. Elsevier Ltd. 2013. 48-67.
Gatchel RJ et al. The Neuroscience of Pain: A primer on the neurobiology of pain pathways. Practical Pain Management. 2016. 16(5).
Kantor ED et. al. Associations between glucosamine and chondroitin supplement use and biomarkers of systemic inflammation. J Altern Complement Med. 2014. 20(6): 479-85.
Mendiratta V, Lentz GM. Primary and secondary dysmenorrhea, premenstrual syndrome, and premenstural dysphoric disorder: ethology, diagnosis, management. Comprehensive Gynecology 3rd ed. 2017. 37: 815-828.
Miner JR, Burton JH. Pain management. Rosen’s Emergency Medicine: Concepts and Clinical Practice 2nd ed. 2018. 34-51.
Su S et. al. Anti-inflammatory and analgesic activity of different extracts of commiphora myrrha. J Ethnopharmacol. 2011. 134(2): 251-8).
Zhang W, Dai SM. Mechanisms involved in the therapeutic effects of Paeonia lactiflora Pallas in rheumatoid arthritis. Int Immunopharmacol. 2012. 14(1): 27-31.
