Ouch, That Hurts!

Pain Pathway
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A schematic of how pain is processed from the stimulus to the brain.
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Pain is an unpleasant sensation often indicative of damaging, noxious stimuli that is a part of everyday life. Almost everyone in the world experiences pain in some shape or form in their lifetime. Although it is unpleasant, it is a generally adaptive trait that serves as motivation to avoid dangerous behaviours and to protect the body as it heals. When a region of the body is damaged, it activates pain receptors that send signals through the peripheral nervous system (PNS) to the central nervous system (CNS) where response may be triggered. There are 2 types of neuronal fibers that carry the pain signal in the PNS. The faster fiber elicits a sharp pain sensation and the slower fiber eliciting a more burning pain sensation [1]. Treatment for pain includes different analgesic drugs that target different parts of the afferent pathway to modulate pain. Higher cognitive functions such as expectation and distraction have also shown to modify the experience of pain. Genetic predispositions to pain sensitivity and neuroimmune interactions allows for a subjective interpretation of pain and pain thresholds. Although pain is an adaptive trait, the painful sensation sometimes persists after the stimulus has been removed, resulting in pain disorders such as neuropathic pain. By researching the underlying neurobiological intricacies of pain, more effective treatments, as well as pain modulation techniques would be derived to better the pain management of patients in the hospital, as well as regular people in everyday life.

1. Almeida, T.F., Roizenblatt, S., Tufik, S. Afferent pain pathways: a neuroanatomical review. Brain Res. 1000, 40-56 (2004)

Analgesic Pharmacology

main article: Analgesic Pharmacology
author: Marinie Joseph

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This image was adapted from

Pain has been defined by the International Association for the Study of Pain (IASP) as an unpleasant sensory and emotional experience associated with actual or potential tissue damage[1]. Types of pain range across a broad spectrum, from neuropathic to somatosensory. As such, the multifaceted symptoms of pain require a treatment approach capable of targeting such a vast array of symptoms in order to achieve effective relief. As such, painkillers, also known as analgesics, are faced with the responsibility of ameliorating a subjective symptom ranging a broad spectrum of intensities[1]. It is important to study analgesics because pain is one of the most common complaints when seeking medical help, and thus analgesics are frequently prescribed. Classical analgesics target opioid receptors and cyclooxygenases while co-analgesics target a specific subunit of voltage gated calcium channels, NMDA channels and noradrenaline transporters[2]. Combining analgesics that act on different mechanisms of pain perception offers synergistic advantages and can decrease the incidence of adverse side effects[3].

1. Dharmshaktu, P., Tayal, V. & Kalra, B. S. (2012). Efficacy of antidepressants as analgesics: a review. Journal Clinical Pharmacology. 52, 6-17. doi: 10.1177/0091270010394852
2. Lotsch J, Geisslinger G. (2011). Pharmacogenetics of new analgesics. Brittish Journal of Pharmacology. 63, 447–460. doi: 10.1111/j.1476-5381.2010.01074.x
3. Camu, F., & Vanlersberghe, C. (2002). Pharmacology of systemic analgesics. Baillière's Best Practice and Research in Clinical Anaesthesiology, 16(4), 475-488. doi: 10.1053/bean.2002.026

Genetics of Pain

main article: Genetics of Pain
author: Vernie Aguda

"Studying genetics is important, there is so much power in knowing what lies within the human genome. And only by understanding this can we begin to shed light on the mechanisms underlying ordinary human sensation." - E.C. Geneticist

12-Year Old Girl Unable to Feel Pain
A rare genetic disorder inhibits this girl from feeling pain.
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The sensation of pain is a very complex phenotype, which arises from complex polygenic and environmental interactions. The modulation of pain, such as changing or inhibiting the transmission of pain impulses, has been implicated to have a heritable genetic component 1. The increase or decrease in the amount of pain sensitivity is linked to certain genes that code for a variety of different proteins in the body, such as different channels, enzymes, and cytokines. The variation found within these genes account for the differences in pain perception between individuals.

1. Young EE., Lariviere WR., Belfer I. Genetic basis of pain variability: recent advances. J Med Genet 2012;49:1-9.

Neuroimmune Interactions of Pain

main article: Neuroimmune Interactions of Pain
author: Sponge-Boob

Figure 1
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Activation of a microglia cell can occur in multiple ways.
This activation results in the release of many proinflammatory molecules.
Image source: Watkins and Maier (2002)

Pain is a product of various pathways and mechanisms within the nervous system in response to inflammation or trauma. Within the last couple of decades, more research has shown the important roles the immune system plays in the maintenance and modulation of pain. Many different types of immune cells and glial cells, such as microglia and astrocytes, play key roles in the pain response by releasing various molecules into their surrounding environment [1]. Microglial cells can release proinflammatory cytokines which act on surrounding neurons, triggering a intracellular cascade leading to hyperexcitability of these neurons. This hyperexcitability causes a more intense and longer sensation of pain [1]. Some immune cells also contain opioid peptides which can be released to reduce the sensation of pain by acting on opioid receptors on sensory neurons [2]. Continued research into the neuroimmune interactions of pain will help increase our understandings of pain and could potentially lead to new treatments.

1. Griffis, C.A. (2011). Neuroimmune Activation and Chronic Pain. American Association of Nurse Anesthetists, 79 (1), 31-37.
2. Hua, S., & Cabot P.J. (2010). Mechanisms of peripheral immune cell-mediated analgesia in inflammation: clinical and therapeutic implications. Trends in Pharmacological Sciences, 31, 427-433.

Neuropathic Pain

main article: Neuropathic Pain
author: Even Le

Figure 1. Aetiology, mechanisms, and symptoms
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Image source: Medscape adapted from Woolf & Mannion (1999)

Pain is commonly thought as a symptom of diseases but, with neuropathic pain, it is often regarded as the primary diagnosis of the disease state. Neuropathic pain is uniquely distinguished from nociceptive pain because it does not require continuous noxious stimuli in order for the pain to persist. Nociceptive pain is usually caused by an external stimulus and stops when the stimulus is removed because the production of abnormal afferent signals ceases. With neuropathic pain, however, there is no cessation as it is pain that does not originate from an external stimuli[1]. Neuropathic pain is normally caused by traumas, lesions, diseases, or cellular malformations in the central or peripheral nervous system which is, more often than not, more difficult to diagnose and treat. It is not uncommon for neuropathic pain to last months or even years. Mechanisms of neuropathic pain indicate independency from etiological factors and pathophysiological treatment of neuropathic pain appear to be more effective than disease driven treatments[2]. Mechanism dependent treatment is often challenging as it is diagnostically difficult to isolate. Pharmacological treatments such as opioids, anticonvulsants, and antidepressants, are often used for trauma or cellular malformations to block sensory fibres[3]. Electrotherapy and neurostimulation therapy is shown to provide significant relief for neuropathic pain but current techniques can be invasive and is extremely risky for older patients[4].

1. Belfer, I., & Dai, F. Phenotyping and genotyping neuropathic pain. Current Pain and Headache Reports 14, 203-212 (2010)
2. Scholz, J., Mannion, R.J., Hord, D.E., Griffin, R.S., Rawal, B., Zheng, H., Scoffings, D., Phillips, A., Guo, J., Laing, R.J., Abdi, S., Decosterd, I., & Woolf, C.J. A novel tool for the assessment of pain: validation in low back pain. PLoS Medicine 6 (2009)
3. Bonezzi, C., Allegri, M., Demartini, L., & Buonocore, M. The pharmacological treatment of neuropathic pain. European Journal of Pain Supplements 3, 85-88 (2009)
4. Lefaucheur, J., Drouot, X., Cunin, P., Bruckert, R., Lepetit, H., Créange, Wolkenstein, P., Maison, P., Keravel, Y., & Nguyen, J. Motor cortex stimulation for the treatment of refractory peripheral neuropathic pain. Brain 132, 1463-1471 (2009)

Psychology of Pain

main article: Psychology of Pain
author: Ji Haeng Lee

Overview of Psychology of Pain
Cursory overview of pain psychology by Dr. Beth Darnall,
a Clinical Associate Professor in the Division of Pain Medicine at Stanford University

The psychology of pain is the study of the nociceptive (pain) experience, and the intricate interplay between the experience and an individual’s higher cognitive functions. It has been previously shown that while the body physiologically responds to painful stimuli, there are also higher brain areas that respond to pain to produce behavioural responses to minimize or avoid damage to the body [1]. Pain can affect the higher cognitive processing in a bottom-up manner, disrupting attention in the short term and possibly causing depression or hyper-vigilance in the long term [2]. On the other hand, the higher cognitive abilities can in turn affect the experience of pain by modulating its intensity. This can be from expectation, like the well-known placebo and nocebo effects [3], as well as from emotions that the individual is feeling. The importance of a patient’s mental state with respect to pain is stressed by the argument that the fear of pain can be more debilitating than the pain itself [2]. Consequently, the study of pain psychology yields valuable information in planning pain management in clinical settings.

1. Eccleston, C. (2013). A normal psychology of everyday pain. International Journal of Clinical Practice, 67, 47-50. doi:10.1111/ijcp.12051
2. Eccleston, C. (2001). Role of psychology in pain management. British Journal of Anaesthesia, 87(1), 144-152.
3. Manchikanti, L., Giordano, J., Fellows, B., & Hirsch, J.A. (2011). Placebo and Nocebo in interventional pain management: A friend or a foe – or simply foes? Pain Physician, 14, E157-175.

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