Pain Neurophysiology and Phenotypes

Pain Neurophysiology and Phenotypes

Angela Starkweather

Pain takes on many different forms and can change over time. Pain terminology is important for defining the type of pain and informs the range of different treatment strategies that are most effective. Whether the pain originates from a known cause, such as injury, or has no known cause, the patient’s description of their pain can provide insight into potential therapeutic modalities. Additionally, phenotyping, or characterizing the pain by its attributes, can help to identify strategies for reducing pain and improving function. In all situations concerning pain, it is important to provide multimodal options and assist the patient in problem-solving their pain—what makes it better, what makes it worse, and how they can strengthen their own coping skills to maximize their function. In this chapter, the pathophysiology of pain is reviewed along with terminology to guide the clinical descriptions used. Types of pain that arise due to injury, disease, and/or infection are then reviewed along with a description of common signs and symptoms.

Neurophysiology of Pain

In the past, pain was thought to originate from a passive system initiated by stimulation or injury of neural tissue (A-delta and C-fibers), which subsequently sends signals to the spinal cord and brain where pain is interpreted and perceived. This is known as the Cartesian model of pain because it was promoted by the philosopher Descartes (1633/2003) hundreds of years ago. The Cartesian model of pain still holds true when we investigate the neurophysiology of nociceptive and neuropathic pain in animal models and in some situations in humans. Nociceptors are high-threshold sensory receptors of the peripheral somatosensory nervous system that are capable of transducing and encoding noxious stimuli (International Association for the Study of Pain, 2017). Pain that arises due to the activation of nociceptors is referred to as nociceptive pain. This term is in contrast to neuropathic pain in which pain is caused by a lesion or disease of the peripheral or central nervous system. Nociceptive pain serves a useful purpose because it helps humans recognize when there is
real or potential tissue damage, such as when touching a hot stove, cutting a finger, or with appendicitis. In these instances, there is an identifiable cause of the pain, and once it is removed, we anticipate that the pain will dissipate quickly. Nociceptive pain is studied in animals by administration of noxious stimuli, whereas neuropathic pain can be induced through surgery or traumatic injury. However, often in the work-up of humans, there is no identifiable source of pain and no pathology that could compromise the health or neurologic function. In other words, people have gone through surgeries or procedures and continue to experience pain long after tissue healing has taken place. In these instances, the pain no longer serves a useful purpose and is viewed as a condition or disease in and of itself.

Human beings are much more complex than what a rodent model can mimic, and clinical observations have led to more advanced theories to explain the mechanisms of pain under various conditions—particularly because it is well known that the degree of injury in humans does not correlate with the level of pain intensity (Balague, Mannion, Pellise, & Cedraschi, 2012; Guermazi et al., 2012; Register et al., 2012). In 1999, Melzack posited the neuromatrix theory of pain in order to understand the independence between tissue injury and the experience of pain. The neuromatrix theory incorporates the role of pain genomics, each individual’s genetic make-up, as producing variability in pain perception as well as coordination among the spinal cord and multiple areas of the brain (prefrontal cortex, motor cortex, somatosensory cortex, insular cortex, limbic system, brain stem, and thalamus) that generate pain. Each area of the brain contributes a different dimension to the experience:

  • ▶ Making sense of pain/pain behavior—prefrontal cortex

  • ▶ Where pain is felt in the body—motor and somatosensory cortex

  • ▶ Emotional aspects—limbic and insular systems

  • ▶ Consciousness of pain—brain stem and thalamus

Each of these dimensions has been studied and verified in humans as playing a significant role in how individuals experience and report pain, including the cognitive-behavioral aspects of pain (Atlas & Wager, 2012; Flor, 2012), the somatosensory aspects of pain (Bushnell et al., 1999; Haggard, Iannetti, & Longo, 2013; Lenoir, Huang, Venadermeeren, Hatem, & Mouraux, 2017), and attention to pain (Bantick et al., 2002; Sloan & Hollins, 2017). This lens is consistent with the biopsychosocial model of pain discussed in Chapter 1 and will be expanded upon throughout the remainder of the book.

Phenotyping pain can help in understanding the underlying neuropathophysiology especially regarding whether the pain is caused by peripheral, central, or both pathways. For instance, inflammatory joint pain
is primarily a peripherally driven condition that occurs through sensitization of nociceptors by inflammatory mediators, such as proinflammatory cytokines. Noninflammatory muscle pain, as seen in fibromyalgia, is caused by a centralized mechanism that is independent of peripheral afferent input. Current theories of the transition from acute to chronic pain propose that aberrant neurochemical processing of sensory signals in the central nervous system lowers pain thresholds and amplifies normal sensory signals, thereby leading to hypersensitivity and central sensitization. In addition, the normal descending inhibitory pathways involving the rostral ventromedial medulla, nucleus raphe magnus, and dorsolateral posterior tegmentum are not effective in reducing pain signals (Arnold et al., 2016). These alterations lead to the phenotypic characteristics of chronic pain.

Phenotyping Pain

Pain phenotyping is the method of gathering and categorizing the various characteristics of pain, which can help to provide insight on potential therapeutic targets. Some of the characteristics are gathered during the physical examination such as:

  • ▶ Location of pain

  • ▶ Intensity of pain (worst pain, least pain, average pain, current pain)

  • ▶ Frequency of pain

  • ▶ Duration of pain

  • ▶ Aggravating and alleviating factors

  • ▶ Health/social status at the time of onset (stress, trauma, surgery)

However, other aspects can be extremely helpful in guiding which treatments may be most effective, including:

  • ▶ Additional information about the pattern of pain throughout a typical day, week, month, and year

  • ▶ Identifying whether other symptoms are associated with the pain, such as anxiety, depression, fatigue, sleep disturbance, or cognitive impairment

  • ▶ Detecting whether the pain follows a specific distribution neuroanatomically (specific to neuropathic pain)

  • ▶ Evaluating the effect of the pain on psychological, social, and physical functioning

  • ▶ Examination of the somatosensory changes associated with the pain and endogenous pain-modulatory processes (such as with quantitative sensory testing)

  • ▶ Linking the somatosensory descriptors of the pain (Table 2-1)

TABLE 2-1. Common Pain Terms


Pain because of a stimulus that does not usually provoke pain


An unpleasant sensation that is either spontaneous or evoked


Increased pain from a stimulus that usually provokes pain


Increased sensitivity to stimulation (both allodynia and hyperalgesia)


Diminished response to a stimulus that is normally painful

Neuropathic pain

Pain caused by a lesion/disease of the somatosensory nervous system (can be classified as central or peripheral)


The neural process of encoding noxious stimuli (pain sensation is not necessarily implied)

Nociceptive pain

Pain because of actual or threatened damage to non-neural tissue and to activation of nociceptors


High-threshold sensory receptor of the peripheral somatosensory nervous system capable of transducing and encoding noxious stimuli

Pain threshold

Minimum intensity of a stimulus that is perceived as painful

Pain tolerance

Maximum intensity of a pain-producing stimulus that a subject is willing to accept in a given situation


Abnormal sensation that is either spontaneous or evoked


Increased responsiveness of nociceptor neurons to normal input and/or recruitment of a response to normally subthreshold inputs (can be peripheral and/or central)

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Apr 16, 2020 | Posted by in NURSING | Comments Off on Pain Neurophysiology and Phenotypes
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