by Tressel Holton
art by Gabriella Mouris
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“On a scale of one to ten, how would you rate your pain?”
These are among the first words uttered by the ultra-huggable artificial intelligence movie character Baymax in Disney’s 2014 blockbuster Big Hero 6 [1]. The film centers around Baymax’s status as a healthcare provider and his ultimate mission of benevolence; he nimbly dances between the roles of paramedic and superhero. As Baymax treats the various injuries he encounters throughout the film, the progression of his pain response efforts pose a question for scientific readers: how, exactly, do we understand and interpret abnormal pain experiences?
Suppose you are a sailor who regularly encounters hefty objects such as crates and beams. One day, misfortune strikes you on the side of your head in the form of a weighty beam. A few weeks later, your bruising dissipates, yet you are still plagued by headaches, unsteady eyesight, and shaky hearing. Your primary care provider diagnoses you with neuralgia, a form of nerve pain characterized by a stabbing or burning sensation [2]. You are then immediately prescribed the traditionally accepted treatment: leeches, controlled venous bleeding, and a starvation plan designed to deprive the demons in your head of their nutrition. You may have guessed by now that this is no modern scenario; in fact, this is a French case study that dates back to 1826 [3]. Following unsuccessful bleeding treatments, the patient in question underwent a surgical procedure to remove a portion of the scalp where he was initially injured, while leaving normal brain functions intact. Remarkably, the process was entirely successful in remedying his nerve pain, indicating a connection between pain and nerve damage. This study marks a major turning point in modern medicine because it pertains to a concept we still seek to understand: neuropathic pain [3].
In general, pain functions as an alarm system to alert the body of imminent danger. Pain is inherently unpleasant, but it plays a critical evolutionary role in self-preservation [4]. Neuropathic pain is a specific category of pain relegated to abnormalities within the nervous system; it indicates that the alarm system itself is broken. When a person experiences neuropathic pain, their ability to judge other pain stimuli and respond appropriately is significantly limited [2]. Such a patient is immediately considered at high risk for further injury because they become incapable of discerning whether or not any pain is associated with real injury. For example, a young man experiencing piercing pain throughout his left arm with no detectable injury would be experiencing neuropathic pain. If he could not feel actual injuries to his left arm, the preexisting neuropathic pain would make diagnosing new wounds much more challenging for his physician.
When you experience an aversive (or painful) stimulus, like stepping on a thumbtack while barefoot, the sensation of the thumbtack piercing the bottom of your foot is immediately felt by your skin. Throughout the human body, afferent neurons—sensory nerves that send signals from organs to the brain—and efferent neurons—motor neurons that send signals from the brain to muscles—innervate each muscle and patch of skin. The thumbtack activates the afferent neurons at the bottom of your foot, firing an electrical signal that ascends to the base of the spinal cord [5]. This signal triggers a near-instantaneous, unconscious reflex throughout the spinal cord, causing you to flinch away from the aversive stimulus—thereby preventing further harm [5].
Depending on the patient’s pain experience, neuropathic pain can also be characterized as spontaneous, evoked, or referred. Spontaneous pain is self-explanatory via sudden and seemingly random pain spikes, often generated by ectopic (abnormal) electrochemical activity in the primary somatosensory pathways [6]. The definition of evoked pain is more implicit; afferent neurons responsible for transmitting signals from the body to the brain incorrectly interpret a stimulus as painful and provide a corresponding signal [7]. Referred pain is typically considered the most complex category of pain [8]. Associated with painful “aftersensations” that echo spikes of pain, referred pain involves an incorrectly “wired” afferent neuron that doesn’t connect to the proper organ or receptor cluster [8]. Referred pain is the most challenging patient-centered classification to address; the preferred method of treatment is currently routinely administered medication, although neurosurgeons are working towards developing a permanent solution [8]. This patient-centered approach to diagnosis has risen in popularity due to a movement toward individualized medicine, a philosophy that promotes holistic healthcare that varies depending on the unique physiology of each patient.
The study of the origin and nature of pain dates back to English neurologist and scientific pioneer Sir Henry Head [9]. Legendary for experimenting on his own brain, Head pioneered the field of neurology by proposing a relationship between pain processing and the somatosensory cortex—a strip of tissue that maps out the sensory levels of the skin, located in the parietal lobe which governs sensory perception and integration [4]. Head’s theories regarding the somatosensory cortex laid the groundwork for the homunculus map of localization, a diagram that approximates how much brain tissue is dedicated to each
area of the human body [10]. Most of Head’s work focused on aphasia, a condition that presents as painlessly inhibited speech and language processing due to degeneratively damaged brain tissue [9]. Head noted that some patients experienced peculiar shooting pains not typically associated with aphasia, a harbinger of neuropathic pain. This discovery led him to theorize that damage to a specific area of the nervous system could disrupt pain processing via localization. Head’s theories about neuropathic pain and localization were not entirely right or wrong. The brain itself has no pain receptors, but neuropathic pain can occur throughout the rest of the central nervous system (CNS), which includes the brain and spinal cord, and the peripheral nervous system (PNS), which includes the neurons that connect the CNS with the body [9].
In order to understand a neurological disorder, the most reliable strategy is often to study the disorder’s individual symptoms. In a healthy patient’s nervous system, aversive stimuli, such as touching a piping hot mug of cocoa, trigger a targeted pain response from a closely associated receptor on sensory neurons in the palm of their hand. Neuropathic pain is distinct because it does not occur in response to a traditional stimulus; rather, it is representative of an overarching disruption to the nervous system [11]. Therefore, patient observation of neuropathic pain is critical to effective treatment. From the patient’s perspective, neurologic dysfunction can be divided into two categories: epicritic and protopathic. Epicritic pain is acute, piercing discomfort that can incapacitate an entire limb or area [11]. Protopathic pain, less localized than epicritic pain, is a physiologically broad aching or throbbing sensation [11]. One can imagine an epicritic headache as a shooting spike of pain at the base of the skull. In contrast, a protopathic headache might present as a dull pulsating sensation. The capacity for differentiation between these two pain types is an invaluable investigative skill, as it can significantly aid a healthcare provider's patient evaluation.
From a physician’s diagnostic perspective, neurologic dysfunction can be split between central and peripheral nervous pain. Neurological dysfunction is due to areas of damaged brain tissue called lesions, which impact the CNS by interfering with somatosensory pathways surrounding the spinal cord and brain [12]. Several CNS conditions that induce lesions exist: major disorders related to central nervous pain include spinal cord injury, neurodegenerative diseases like Parkinson’s, and demyelinating disorders like multiple sclerosis that strip away protective layers of fat from neurons [13]. In contrast to central nervous pain, peripheral neuropathies include two subdivisions, generalized and localized. While generalized neuropathies are applicable to the entire PNS, localized neuropathies are restricted to a specific area [12]. Peripheral nervous pain may present alongside metabolic dysfunction like diabetes, infectious diseases like HIV and leprosy, immune disorders, and genetically inherited conditions known as channelopathies [21]. The key takeaway: neuropathic pain can be the result of a neurological condition or rooted in an entirely separate bodily system.
From a biochemical standpoint, neuropathic pain acts through a sequence of multifaceted biological processes called mechanisms. By tracing the mechanisms behind neuropathic pain, the scientific community can develop more effective treatment plans. However, this process is inherently compounded by the molecular mysteries of neuropathic pain. Since neuropathic pain can be associated with any lesion to the CNS or PNS, each case of neuropathic pain can wildly differ between the specific nerves impacted. To counter this problem, neuropathic pain is often treated by examining the prefrontal cortex, a section of the brain responsible for advanced cognition, emotional intelligence, and pain perception. When someone experiences neuropathic pain, the damaged nerves transmit pain signals to the prefrontal cortex [14]. These signals typically produce an imbalance in the patient’s neurotransmitter levels, which dictate the process of intercellular communication. This imbalance is often the effect perceived by the patient—the actual feeling of neuropathic pain.
Due to the complex localization of neuropathic pain and its complex biochemical mechanisms, researchers must perform a closer examination of the unique pain-related functions of the neuropathic system. In 2006, a 47-year-old woman requested an intensive
medical examination following a textbook mastectomy (the surgical procedure for breast removal) [15]. Despite completely healing from the procedure, the patient experienced intense epicritic pain around the scar tissue from stimuli as gentle as a cotton T-shirt. The patient also described significant “pain attacks” that occurred infrequently throughout her day, which we would now characterize as protopathic pain [11]. This dual diagnosis of acute and localized pain indicated that the woman was suffering from neuropathic pain, but researchers pondered how such a case could arise.
Medical researchers concluded that her neuropathic symptoms were due to localized lesions within her nervous system. In other words, damaging the nervous system does not
necessarily provoke neuropathic pain; rather, a lesion on a targeted nerve or brain tissue will express pain in a particular anatomical location and with intensity proportional to its size [16]. This marked a major development in the study of neuropathic pain, enabling physicians to individualize their treatment plans based on the structure of each patient’s nervous system.
The localization of neuropathic pain provides a reasonable foundation for the popular gate-control theory of pain, the postulation that pain can be manipulated via the “opening” and “closing” of a biochemical pathway located in the spinal cord [17]. Proponents of gate-control theory study the relationship between efferent neurons and afferent neurons. They note that slightly increasing a particular hormone concentration can exacerbate an otherwise mild pain response into an overwhelming surge [17]. By questioning the nature of individual neuron activity, researchers can pinpoint the causes of seemingly isolated incidences of neuropathic pain and ultimately alleviate the patient’s pain experience.
From a clinical standpoint, the complex and dynamic nature of the nervous system presents unique challenges for the diagnosis and treatment of neuropathic pain. Given that each neural pathway can perform many unique functions, a comprehensive diagnostic system is imperative. Physiologists, those who specialize in the study of anatomical function, grade pain levels into possible, probable, and definite neuropathic pain based on a variety of criteria. Possible pain is determined by relevant neurological history and plausible neuroanatomical pain distribution, probable pain is based on sensory activity, and definite pain can be confirmed by a bio-psychological diagnostic test (e.g. a simple questionnaire and blood draw) [18]. A non-specialist healthcare provider can perform the majority of these techniques; a definite pain diagnostic test, however, requires a meticulously trained specialist such as a neurologist or neurosurgeon via computed tomography, magnetic resonance imaging, genetic testing, neurophysiological examinations, or similar strategies [18]. Ultimately, employing interdisciplinary testing techniques enables medical professionals to make the most informed decisions regarding pain diagnosis and treatment.
The International Association for the Study of Pain (IASP) recommends combining therapeutic approaches to combating neuropathic pain, as treating neuropathic pain is a significant challenge for physicians [19]. Save for surgical techniques practiced by only the most experienced neurosurgeons, medical efforts tend to target the symptoms rather than the underlying cause due to risks associated with neurological treatment. As such, available treatments currently include both pharmacological and non-pharmacological approaches.
Pharmacologically speaking, treatment options include antidepressants, neurotransmitter reuptake inhibitors, and, occasionally, powerful or diluted opioid medication [19]. Properly prescribed and consumed, each of these drugs plays a role in the inhibition of neuropathic sensory pathways [19]. In particular, neurotransmitter reuptake inhibitors increase activity of biochemicals like serotonin and norepinephrine, each of which mitigates overactivity in the prefrontal cortex that is often associated with neuropathic pain [14]. For a non-pharmacological approach, physicians may provide physical therapies like transcutaneous electrical stimulation (the use of electricity to induce neuro-muscular activity), interventional therapies that include non-medicinal compounds like steroids, or psychological therapy. Depending on the pathology of a patient’s neuropathic pain, a neurologist will recommend an interdisciplinary combination of these available treatment options, which can range from physical therapy to advanced neurosurgery [19].
Much of modern medicine prioritizes the specific treatment of physical illness, but the patient’s perceived state of well-being is of equal importance [20]. In other words, it is important to ask the patient how they are feeling. Pain plays a critical role in the maintenance and fortification of the human body, and although it may seem intuitive, pain hurts. According to Dr. Louis Lasagna’s 1964 rendition of the Hippocratic Oath, healthcare providers “do not treat a fever chart or a cancerous growth, but a human being” [20]. By centralizing a patient's humanity, physicians improve their ability to diagnose and treat any pain-related disorders requiring patient input. Essentially, practicing any form of medicine demands the creation and methodical defense of an honorable patient-physician relationship—and nowhere is this more imperative than in matters of pain.
Let’s return to Baymax’s story: the robotic protagonist of the Disney film Big Hero 6, Baymax perfectly embodies this philosophy as he comforts genius inventor Hiro following the tragic loss of his brother, Tadashi. Hiro barricades himself inside his bedroom and cowers away from social interaction, ignoring his pain instead of facing it. Baymax responds by encouraging Hiro that “it is OK to cry.” Hiro finally allows himself to feel the repercussions of Tadashi’s death, embarking on the first steps of his journey toward recovery. While grief is not perfectly equivalent to neuropathic pain, we must remember that ignoring the symptoms of pain can only beget more pain. The wisest choice is always to seek help. With reinforcement from the healthcare community and your personal support network, overcoming medical challenges becomes more possible.
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