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Understanding Pain Physiology: Foundations for Effective Chronic Pain

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 Understanding Pain Physiology: Foundations for Effective
Chronic Pain Management (Part 1)
Indunil Karunarathna 1, K.Kusumarathna1, P.Jayathilaka2, B.Rathnayake 2, N Priyalath 3, I Gunarathna 4, D Disanayake 5, P
Kurukulasooriya 5, A Samarasinghe 6, D Halahakoon 7, K H Walgama8

1. Department of Anaesthesiology , Intensive Care and Pain Medicine, Teaching Hospital Badulla, Sri Lanka.
2. Department of Medicine, Teaching Hospital Badulla, Sri Lanka.
3. Department of Emergency Medicine, Teaching Hospital Badulla, Sri Lanka.
4. Department of Anaesthesiology , Intensive Care and Pain Medicine, National Hospital Kandy, Sri Lanka.
5. Department of Surgery, Teaching Hospital Badulla, Sri Lanka.
6. Department of Surgery, Base Hospital Diyatalawa, Sri Lanka.
7. Department of Neurology, Teaching Hospital Badulla, Sri Lanka.
8. Department of Psychiatry, Teaching Hospital Badulla, Sri Lanka.

The Abstract: Chronic pain is a widespread health concern with profound impacts on individuals and society. This review
explores the physiology of pain as a crucial framework for understanding and managing chronic pain effectively. Beginning with
the current definition and classification of pain, the review delves into pain processing pathways, including transduction,
conduction, modulation, and perception. Special attention is given to the Gate Control Theory of Pain, shedding light on how
different nerve fibers interact to modulate pain signals. Furthermore, the emotional, motivational, and cognitive components of
pain perception are discussed, highlighting the subjective nature of pain experiences. The review underscores the importance of
multidisciplinary pain management approaches that integrate pharmacological and non-pharmacological interventions. By
considering the complex interplay of physiological, psychological, and social factors, healthcare providers can develop
personalized strategies to alleviate chronic pain and enhance overall well-being.

Keywords: pain, chronic pain, pain physiology, pain processing, Gate Control Theory of Pain, pain modulation, pain perception,
multidisciplinary pain management.

Key Points: Introduction:

1. Chronic pain is a significant health burden affecting Chronic pain imposes a significant burden on individuals and
individuals and society worldwide, with approximately society, affecting well-being, quality of life, and productivity.
20% of the global population affected. With a prevalence of approximately 20% worldwide, chronic
2. Understanding the physiology of pain, including pain affects a substantial portion of the population,
transduction, conduction, modulation, and perception, is contributing to considerable socioeconomic costs. Despite
essential for effective management of chronic pain. advancements in pain research, effective management of
3. The Gate Control Theory of Pain provides insights into chronic pain remains elusive. Understanding the physiology of
how different nerve fibers interact to modulate pain pain is essential for improving diagnosis and treatment
signals, offering potential avenues for pain relief strategies. This review aims to explore the intricate
strategies. mechanisms underlying pain processing, from transduction to
4. Pain perception involves complex interactions between perception, with a focus on their relevance to chronic pain. By
sensory, emotional, motivational, and cognitive elucidating these physiological processes, healthcare providers
components, highlighting the subjective nature of pain can develop more targeted and comprehensive approaches to
experiences. managing chronic pain and improving patient outcomes.
5. Multidisciplinary pain management approaches,
integrating pharmacological and non-pharmacological Definition:
interventions, are crucial for addressing the multifaceted
nature of chronic pain and improving patient outcomes.
Pain is a multifaceted phenomenon that encompasses both
sensory and emotional experiences. In 2020, the International

Uva Clinical | Understanding Pain Physiology: Foundations for Effective Chronic Pain Management (Part 1) 1
Association for the Study of Pain (IASP) refined its definition Nociplastic pain, on the other hand, involves altered
of pain to capture its complexity, describing it as "an nociception without clear evidence of tissue damage or
unpleasant sensory and emotional experience associated with, somatosensory system dysfunction, such as in conditions like
or resembling that associated with, actual or potential tissue fibromyalgia. It is distinct from psychosomatic disorders.
damage." This definition underscores that pain arises from a
diverse interplay of sensory, emotional, cognitive, social, Fundamental Physiology of Pain Processing:
psychological, and even spiritual factors, which can be
influenced by various individual characteristics and To gain a comprehensive understanding of chronic pain
environmental conditions. The recognition of pain as a mechanisms, it's vital to grasp the fundamental physiology of
subjective experience highlights the importance of considering pain processing. Pain processing encompasses four primary
the perspective of the individual suffering from it, rather than processes: transduction, conduction, modulation, and
relying solely on external observations. perception. Let's break down each of these processes:

Acute pain serves as a protective mechanism, signaling the Transduction: This is the initial step where noxious stimuli,
presence of potential harm and prompting withdrawal such as tissue injury or inflammation, are converted into
responses to prevent further injury. It aids in localizing electrical signals known as action potentials. Specialized
noxious stimuli and limiting mobility, thereby facilitating the sensory receptors called nociceptors detect these stimuli and
healing process. However, pain transitions from being initiate the process of transduction.
adaptive to burdensome when it persists beyond the expected
Conduction: Once the noxious stimuli are transduced into
duration of tissue healing, typically around three months. Pain
electrical signals, they travel along nerve fibers known as
that endures or recurs beyond this timeframe is categorized as
afferent neurons towards the spinal cord and then to the brain.
chronic pain. Importantly, chronic pain can manifest without
This conduction of pain signals occurs through specialized
any apparent injury, highlighting its complex nature and
pathways, including the spinothalamic tract, which carries the
necessitating a comprehensive approach to its management.
signals to various brain regions involved in pain perception.
Classification of Pain:
Modulation: Throughout the pain pathway, various structures
The classification of pain encompasses various criteria, within the central nervous system (CNS) can modulate the
making it intricate and diverse. Pain can be categorized based pain signals, either enhancing or suppressing them. This
on its intensity (mild, moderate, or severe), quality (sharp, modulation occurs through complex interactions involving
burning, or dull), duration (acute or chronic), localization neurotransmitters, neuromodulators, and descending pathways
(superficial or deep, specific or diffuse), or the anatomical area from higher brain centers. Modulation plays a crucial role in
affected (headache, backache, limb ache, neck pain, determining the intensity and duration of pain perception.
abdominal pain, etc.).
Perception: Perception is the conscious experience of pain,
Additionally, pain can be classified based on the conduction where the brain processes and interprets the incoming pain
velocity of the pain stimulus. Fast pain, also known as "first signals. This process involves multiple brain regions,
pain," occurs rapidly upon contact with a noxious stimulus, is including the somatosensory cortex, insula, and anterior
highly localized, sharp, and of short duration. It is transmitted cingulate cortex, which integrate sensory, emotional, and
by myelinated Aδ fibers with a conduction velocity of 5–30 cognitive aspects of pain perception.
m/s. In contrast, slow pain, or "second pain," has a slower
By understanding these four processes of pain processing—
onset, is dull, diffuse, burning, and long-lasting, and is
transduction, conduction, modulation, and perception—we can
transmitted by unmyelinated C nerve fibers with a conduction
begin to unravel the mechanisms underlying chronic pain and
velocity of 0.5–2 m/s.
develop more targeted therapeutic interventions.
Mechanistically, the International Association for the Study of
Transduction:
Pain (IASP) recognizes nociceptive, neuropathic, and
nociplastic pain. Nociceptive pain arises from actual or Transduction involves the conversion of external mechanical,
threatened damage to non-neural tissue, activating nociceptors thermal, or chemical stimuli into electrical signals within the
in the somatosensory nervous system. It serves as a protective context of pain. These stimuli are detected by specialized
response to noxious stimuli, typically acute in nature. sensory receptors known as nociceptors, which are found in
Neuropathic pain results from lesions or diseases affecting the various tissues throughout the body, including joints, skin,
somatosensory nervous system and is often chronic. cornea, and visceral organs. Nociceptors are high-threshold

Uva Clinical | Understanding Pain Physiology: Foundations for Effective Chronic Pain Management (Part 1) 2
sensory receptors capable of transducing and encoding transmission, with the spinothalamic tract being the primary
noxious stimuli. They are particularly abundant in areas like nociceptive pathway. These additional pathways contribute to
the fingertips, hands, periosteum, and face. the cognitive, motivational, and affective aspects of pain
processing.
Nociceptors can be specific to particular types of pain
modalities, responding solely to mechanical or thermal Slow pain is transmitted to various areas of the cerebral
stimuli, or polymodal, responding to mechanical, thermal, and cortex, including the anterior cingulate cortex, insular cortex,
chemical stimuli. When activated by noxious stimuli, primary somatosensory (S1), secondary somatosensory (S2),
nociceptors initiate a cascade of events leading to the and prefrontal cortex. These signals, particularly those
generation of action potentials. This activation occurs through reaching areas outside the cortical centers such as the reticular
the opening of ion channels present on the nociceptor formation, serve to arouse rather than provide sensory
terminals, acting as molecular transducers. These ion discrimination of pain.
channels, including transient receptor potential (TRP), acid-
sensing ion channels (ASIC), and purinergic receptors, allow In the case of facial nociceptive transmission, nerve fibers
the influx of sodium (Na+) and calcium (Ca2+) ions, leading carry inputs from the ipsilateral portion of the face to the
to depolarization and the generation of action potentials. subnucleus caudalis in the spinal trigeminal nucleus, located in
the lateral medulla of the brainstem. From there, the signal
Overall, transduction represents the initial step in the pain travels to the contralateral thalamus via the anterior
processing pathway, converting external noxious stimuli into trigeminothalamic tract before reaching the brain areas,
electrical signals that propagate along nerve fibers, ultimately similar to nociceptive transmission from other parts of the
leading to the perception of pain in the brain. Understanding body.
this process is crucial for elucidating the mechanisms
underlying pain sensation and developing targeted therapeutic Modulation:
interventions.
Modulation is a pivotal process in pain processing where pain
Conduction: signals undergo modification, either by suppression or
enhancement of pain input signals.
Conduction involves the relay of nociceptive electrical signals
from the peripheral tissues to the spinal cord. The primary One crucial mechanism of modulation is descending
afferent neurons responsible for this transmission are pseudo- inhibition, a top-down modulation of afferent inputs occurring
unipolar, possessing both peripheral and central branches, with at the dorsal horn of the spinal cord. This pathway originates
cell bodies located in the dorsal root ganglia (DRG). The primarily from the rostroventral medulla (RVM),
peripheral branch terminates in various tissues and organs, periaqueductal gray matter (PAG), medullary reticular nuclei
detecting different sensory modalities, while the central of the gigantocellular complex, and the locus coeruleus.
branch transmits impulses to the spinal cord via the dorsal
horns. The rostroventral medulla (RVM) serves as a major relay for
descending modulation of pain transmission in the spinal cord.
The electrical signals generated by nociceptors travel along The raphespinal tract, originating from the raphe magnus
nerve fibers to the DRG and then terminate in the dorsal horn nucleus of the RVM, is a primary descending inhibitory tract.
of the spinal cord, where they synapse with second-order Additionally, the periaqueductal gray matter (PAG) receives
neurons. Glutamate, acting as a neurotransmitter, is released inputs from various cortical areas and ascending fibers via the
from the presynaptic neuron and binds to AMPA receptors on spinoparabrachial tract. The PAG exerts opioid-mediated
the postsynaptic neuron in the substantia gelatinosa of inhibition of nociception in the dorsal horn of the spinal cord
Rolando. Substance P may also be released, especially in cases by activating the RVM.
of excessive pain.
The RVM, along with the PAG, also receives signals from the
From the dorsal horn, the signal is transmitted via the lateral thalamus, parabrachial nucleus, and locus coeruleus. It sends
spinothalamic tract (neospinothalamic or paleospinothalamic serotonergic and noradrenergic projections to the dorsal horn
tract), crossing to the opposite side of the spinal cord and of the spinal cord, leading to the inhibition of nociceptive
ascending to the thalamus before reaching the cerebral cortex. signals either directly or via the activation of spinal
Other pathways, such as the spinoreticular, interneurons.
spinomesencephalic, spinohypothalamic, and
spinoparabrachial tracts, are also involved in pain signal It's noteworthy that serotonin (5-HT) plays a dual role in
descending modulation, acting via different receptor subtypes.
Uva Clinical | Understanding Pain Physiology: Foundations for Effective Chronic Pain Management (Part 1) 3
Serotonin is involved in both facilitation and inhibition, Descendng inhibitory pathways also play a role in modulating
depending on the specific receptors engaged. For instance, 5- pain transmission at the gate. Stress-induced analgesia, where
HT2 and 5-HT3 receptors are associated with descending pain is suppressed until after a stressful episode has passed, is
facilitation, whereas 5-HT7 and 5-HT2A receptors are linked explained by this theory. Additionally, the analgesic effects of
to descending inhibition. However, serotonin is generally treatments like transcutaneous electrical nerve stimulation
considered to have a predominantly facilitatory effect rather (TENS) are attributed to their ability to influence the gate
than inhibitory. control system.

Descending Facilitation: Descending facilitation or augmentation of pain signals can

occur at the gate under conditions favoring its opening.
Descending facilitation is another crucial aspect of pain Overall, modulation of pain is thought to occur via the gate
modulation, originating from supraspinal areas and relaying at control system, with various factors such as mental state,
the rostroventral medulla (RVM). Unlike descending exercise, or stress influencing its activity. Understanding this
inhibition, which suppresses pain signals, descending theory provides a framework for understanding how different
facilitation enhances nociceptive transmission. sensations and interventions can impact pain perception and
offers insights for pain management strategies.
The RVM plays a central role in descending facilitation,
exhibiting bidirectional activity. It can either inhibit or Perception:
facilitate nociceptive signals, depending on the activity of
specific neuronal populations within it. Evidence suggests that Perception, the culmination of pain processing, occurs as the
the RVM contains distinct "ON" and "OFF" cells. Opioids, cerebral cortex interprets input signals. This intricate process
commonly used for pain management, exert their analgesic involves multiple brain regions and is influenced by various
effects by inhibiting the activity of "ON" cells and activating factors such as context, past experiences, and expectations.
"OFF" cells, leading to pain relief. Beyond sensory input, pain perception encompasses
emotional, motivational, and cognitive components, each
The balance between descending inhibition and facilitation is processed in different areas of the cerebral cortex, including
crucial for maintaining normal pain processing. Disruption of limbic structures, the anterior cingulate gyrus, prefrontal
this balance, such as an excessive facilitatory activity or a cortex, and insular cortex.
decrease in inhibitory activity, can contribute significantly to
the development and persistence of chronic pain states. These components contribute to the suffering experienced
Understanding the mechanisms underlying descending alongside sensory perception and manifest as behavioral or
facilitation is essential for developing targeted therapeutic psychological responses. This understanding underscores the
strategies to restore this balance and alleviate chronic pain. subjective nature of pain, explaining why individuals may
experience pain differently.
The Gate Control Theory of Pain:
Emotional states profoundly influence pain perception,
The Gate Control Theory of Pain, proposed by Ronald enabling the use of non-pharmacological methods like
Melzack and Patrick Wall in 1965, provides insights into distraction, behavioral therapy, or placebos in pain
certain pain processes. Essentially, the theory suggests that management. The cortical regions responsible for processing
thick myelinated Aβ nerve fibers, responsible for transmitting the subjective aspects of pain form what is known as the
touch sensations, have an inhibitory effect on pain signals neuromatrix. Major components of the neuromatrix include
conveyed by C and Aδ nerve fibers. This inhibition occurs at the anterior cingulate cortex (ACC), insular cortex (IC),
the level of the dorsal horn of the spinal cord, particularly in primary and secondary somatosensory cortices (S1 and S2),
the substantia gelatinosa, which serves as the "gate" for pain prefrontal cortices, and the thalamus. These areas collectively
signals. contribute to the subjective experience of pain and play a
crucial role in pain modulation and management strategies.
According to the theory, the synapses of unmyelinated C
fibers, thin myelinated Aδ fibers, and thick myelinated Aβ Conclusion:
fibers converge at the substantia gelatinosa. The Aβ fibers
indirectly close the gate by activating interneurons in the In conclusion, chronic pain presents a significant health
substantia gelatinosa, thus inhibiting the transmission of pain burden worldwide, affecting individuals' well-being, quality of
signals. Conversely, the C fibers can open the gate, increasing life, and productivity. Despite advancements in pain research,
synaptic transmission and enhancing pain perception. effective management of chronic pain remains a challenge.

Uva Clinical | Understanding Pain Physiology: Foundations for Effective Chronic Pain Management (Part 1) 4
Understanding the physiology of pain serves as a cornerstone 5. How can multidisciplinary pain management approaches
for improving diagnosis and treatment strategies. improve outcomes for individuals with chronic pain?
6. What are some potential pharmacological and non-
This review has explored various aspects of pain physiology, pharmacological interventions for managing chronic
including the definition and classification of pain, pain pain?
processing pathways, modulation mechanisms, and pain 7. How does the subjective nature of pain experiences
perception. Pain is a complex phenomenon involving sensory, contribute to the challenges of treating chronic pain?
emotional, cognitive, and social components, influenced by 8. What are some current research developments in the field
individual characteristics and experiences. of pain physiology and chronic pain management?
9. How do individual differences, such as genetics and
The Gate Control Theory of Pain elucidates how different psychosocial factors, influence chronic pain experiences
nerve fibers interact to modulate pain signals, offering insights and treatment outcomes?
into pain relief strategies such as massage and transcutaneous 10. What are the ethical considerations in pain management,
electrical nerve stimulation (TENS). Furthermore, perception, particularly regarding opioid use and access to care for
the interpretation of pain signals by the cerebral cortex, individuals with chronic pain?
involves multiple brain regions and subjective factors,
emphasizing the need for personalized pain management
approaches.
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