Overview
Definitions
- Pain:
- According to the International Association for the Study of Pain (IASP), pain is “an unpleasant sensory and emotional experience associated with actual or potential tissue damage, or described in terms of such damage.”
- Mental suffering or distress
- Nociception:
- Noxious (or toxic) stimulus or stimulus that can become noxious with prolonged exposure
- Process through which peripheral pain receptors transmit information about current (or potential) tissue damage centrally as pain
- Nociceptor: receptor in end organ that detects biochemical changes associated with current or potential tissue damage
- Hyperalgesia: exaggerated response to noxious stimuli
- Allodynia: sensation of pain in response to an innocuous stimulus
Types of pain
- Physiologic (acute) pain
- Pathologic (chronic) pain
- Nociceptive:
- Pain in response to actual or potentially harmful stimuli
- Often described as aching, localized
- Aggravated by movement
- Neuropathic:
- Nerve injury or impairment that is associated with allodynia
- Often described as radiating, shooting
- Independent of movement
| Physiologic change | Acute pain | Chronic pain |
|---|---|---|
| Vital signs | May vary consistently with degree of pain severity | No or minimal change |
| Purpose of pain | Useful | Inhibits function and not useful |
| Central sensitization | Short term; improves with healing of injury | Remains present despite absence of ongoing injury |
| Neuropathic pain | Increases likelihood of chronic pain when present in acute phase | Common etiology of chronic pain |
| Nociceptive pain | Often found during acute pain state | Commonly presents with some neuropathic pain |
Differences in types of pain and their common etiologies
CRPS
CRPS
Complex regional pain syndrome (CRPS) is a chronic regional neuropathic pain condition characterized by excruciating pain (out of proportion to apparent tissue damage or inciting trauma), paresthesia, allodynia, temperature abnormalities, skin discoloration, edema, reduced range of motion, and bone demineralization.
Complex Regional Pain Syndrome (CRPS):
complex regional pain syndrome
Complex Regional Pain Syndrome
Complex regional pain syndrome (CRPS) is a chronic regional neuropathic pain condition characterized by excruciating pain (out of proportion to apparent tissue damage or inciting trauma), paresthesia, allodynia, temperature abnormalities, skin discoloration, edema, reduced range of motion, and bone demineralization.
Complex Regional Pain Syndrome (CRPS)
Embryology
- 7 weeks: development of free nerve endings
- 18 weeks: hormonal stress responses to pain
- 23–30 weeks: thalamic projections into the somatosensory cortex
- 26 weeks: hemodynamic and behavioral reactions to painful stimuli
Function of pain
- Adaptive measures to minimize and avoid further tissue damage
- Evoked responses:
- Withdrawal from noxious stimulus (e.g., spinal reflexes)
- Anticipatory movements (e.g., movement of the arms to protect the eyes and face, bracing before imminent impact)
Anatomy and Physiology of Pain Pathways
Phases
- Transduction
- Transmission
- Modulation
- Central perception
Nociception process
- Thermal, mechanical, or chemical stimuli of noxious intensity comes into contact with a tissue.
- Injured tissue releases inflammatory mediators, including:
- Globulin
- Protein kinases
- Arachidonic acid
- Histamine
- Nerve growth factor (NGF)
- Substance P (SP)
- Calcitonin gene–related peptide (CGRP)
- These mediators stimulate transducer channels (similar to voltage-gated channels) → initiation of receptor potentials (transduction)
- Receptor potentials evoke action potentials in sensory nerve fibers.
- Action potentials are carried as afferent signals via sensory nerve fibers to the dorsal root ganglia and dorsal horn of the spinal cord Spinal cord The spinal cord is the major conduction pathway connecting the brain to the body; it is part of the CNS. In cross section, the spinal cord is divided into an H-shaped area of gray matter (consisting of synapsing neuronal cell bodies) and a surrounding area of white matter (consisting of ascending and descending tracts of myelinated axons). Spinal Cord (transmission).
- From there, the signal is transmitted up the spinal cord Spinal cord The spinal cord is the major conduction pathway connecting the brain to the body; it is part of the CNS. In cross section, the spinal cord is divided into an H-shaped area of gray matter (consisting of synapsing neuronal cell bodies) and a surrounding area of white matter (consisting of ascending and descending tracts of myelinated axons). Spinal Cord to the brain stem Brain Stem The brain stem is a stalk-like structure that connects the cerebrum with the spinal cord and consists of the midbrain, pons, and medulla oblongata. It also plays a critical role in the control of cardiovascular and respiratory function, consciousness, and the sleep-wake cycle. Brain Stem and thalamus Thalamus The thalamus is a large, ovoid structure in the dorsal part of the diencephalon that is located between the cerebral cortex and midbrain. It consists of several interconnected nuclei of grey matter separated by the laminae of white matter. The thalamus is the main conductor of information that passes between the cerebral cortex and the periphery, spinal cord, or brain stem. Thalamus, where significant processing (modulation) may occur.
- The signal finally reaches the somatosensory cortex (central perception). The biopsychosocial interpretation of the painful experience also involves:
- Amygdala: involved in the emotional and affective response to pain and pain modulation
- Hypothalamus Hypothalamus The hypothalamus is a collection of various nuclei within the diencephalon in the center of the brain. The hypothalamus plays a vital role in endocrine regulation as the primary regulator of the pituitary gland, and it is the major point of integration between the central nervous and endocrine systems. Hypothalamus: involved in the neuroendocrine corticotropin response to pain
- Periaqueductal gray matter Gray matter Region of central nervous system that appears darker in color than the other type, white matter. It is composed of neuronal cell bodies; neuropil; glial cells and capillaries but few myelinated nerve fibers. Cerebral Cortex: key center for pain modulation, involved in aversive and defensive pain behaviors
- Basal ganglia Basal Ganglia Basal ganglia are a group of subcortical nuclear agglomerations involved in movement, and are located deep to the cerebral hemispheres. Basal ganglia include the striatum (caudate nucleus and putamen), globus pallidus, substantia nigra, and subthalamic nucleus. Basal Ganglia: involved in the cognitive, affective, and discriminative (ability to localize sensory input) aspects of pain perception
- Cerebral cortex Cerebral cortex The cerebral cortex is the largest and most developed part of the human brain and CNS. Occupying the upper part of the cranial cavity, the cerebral cortex has 4 lobes and is divided into 2 hemispheres that are joined centrally by the corpus callosum. Cerebral Cortex: ultimate site of pain perception, potential for conscious activation of descending pathways for pain modulation
Modulation of pain
- Pain signals are modulated (reduced transmission from nociceptive afferents) by endogenous opioid peptides (e.g., endorphins, dynorphins, enkephalins) in the:
- Spinal cord
- Dorsal root ganglia
- Midbrain periaqueductal gray (PAG)
- This mechanism occurs in the “descending” (“inhibitory”) pathways.
- Mechanisms of action of endogenous opioid peptides:
- Activation of mu, kappa, and delta opioid receptors → decreased presynaptic Ca2+ influx → decreased release of glutamate and SP
- Increased K+ conductance in dorsal horn neurons
- Other modulators include:
- Norepinephrine (NE)
- Glycine
- GABA
Diagram showing the pathway of pain transduction, transmission, modulation, and central perception
Image by Lecturio.Types of afferent nerve fibers
Type A fibers:
- Large and myelinated → fast-conducting
- A-alpha: primary receptors of the muscle spindle and Golgi tendon organ
- A-beta:
- Afferent axon with the largest diameter
- Secondary receptors of the muscle spindle that contribute to cutaneous mechanoreceptors.
- Perceive light touch and/or moving stimuli
- A-delta:
- Free nerve endings that conduct stimuli related to pressure and temperature.
- Conduction speed approximately 20 m/sec
- A-gamma: motor neurons that control the intrinsic activation of the muscle spindle.
Type B fibers:
- Midsized, thinly myelinated fibers
- Responsible for autonomic information
Type C fibers:
- Unmyelinated nociceptor slow fibers
- Conduction speed approximately 2 m/sec
- Respond to combinations of thermal, mechanical, and chemical stimuli
Rexed laminae
- Organized somatosensory and motor map laid out in the spinal cord Spinal cord The spinal cord is the major conduction pathway connecting the brain to the body; it is part of the CNS. In cross section, the spinal cord is divided into an H-shaped area of gray matter (consisting of synapsing neuronal cell bodies) and a surrounding area of white matter (consisting of ascending and descending tracts of myelinated axons). Spinal Cord (primarily the dorsal horn) of each spinal segment
- Different types of sensory nerves (and some motor, laminae VI–IX) and the corresponding information they carry are organized so as to synapse Synapse The junction between 2 neurons is called a synapse. The synapse allows a neuron to pass an electrical or chemical signal to another neuron or target effector cell. Synapses and Neurotransmission in specific territories in the dorsal horn known as laminae.
- There are 10 laminae, designated I–X:
- Lamina I: receives and relays noxious and thermal stimuli
- Lamina II: receives and relays noxious and nonnoxious physical stimuli and is involved in pain modulation
- Lamina III: receives and relays physical stimuli related to light touch and proprioception
- Lamina IV: receives and relays nonnoxious physical stimuli
- Lamina V: receives and relays noxious stimuli and is involved in pain modulation
- Lamina VI: receives and relays information involved in spinal reflexes and proprioception
- Lamina VII: receives and relays information related to visceral function and noxious stimuli
- Lamina VIII: receives and relays information related to modulation of voluntary movement
- Lamina IX: receives and relays information related to motor control (gross muscle contraction)
- Lamina X: centrally located (central gray commissure); where sensory and motor neurons cross before ascending/descending and where some degree of interneuronal cross-talk (modulation) takes place
- There are also associated nuclei that are beyond the scope of this discussion.
- Under physiologic conditions, sensory and motor information (and associated modulation) is transmitted within and among the laminae in a highly organized and predictable fashion.
- Under pathologic conditions (e.g., persistent nociceptive input, neurologic damage), there can be an abnormal rearrangement of sensory inputs that contributes to the development of central sensitization and other manifestations of chronic pain:
- Nociceptive neural inputs land in laminae devoted to nonnoxious or motor stimuli.
- Nonnoxious or motor inputs land in laminae devoted to nociceptive stimuli.
- Leads to abnormal pain perception to normally nonnoxious stimuli or movements:
- Allodynia
- Hypersensitivity
- Hyperalgesia
- Paresthesia/dysesthesia
- Development of neuropathic pain in an area devoid of nerve damage
- Expansion of the receptive field beyond the normal territory of a peripheral nerve
- Spontaneous pain in the absence of noxious stimuli or tissue damage
- Abnormal interneuronal reflexes may develop:
- Muscle activation or joint movement (motor stimuli, proprioceptive stimuli) triggers painful stimuli.
- Painful stimuli may trigger abnormal motor activity (e.g., hypertonicity, muscle spasm).
- Painful stimuli may trigger autonomic or enteric phenomena and vice versa. For example:
- Nausea in response to painful stimulus
- Sweating and/or piloerection in response to painful stimulus
- Vasoconstriction in an area of painful stimulus (i.e., CRPS CRPS Complex regional pain syndrome (CRPS) is a chronic regional neuropathic pain condition characterized by excruciating pain (out of proportion to apparent tissue damage or inciting trauma), paresthesia, allodynia, temperature abnormalities, skin discoloration, edema, reduced range of motion, and bone demineralization. Complex Regional Pain Syndrome (CRPS))
Cross section of the spinal cord Spinal cord The spinal cord is the major conduction pathway connecting the brain to the body; it is part of the CNS. In cross section, the spinal cord is divided into an H-shaped area of gray matter (consisting of synapsing neuronal cell bodies) and a surrounding area of white matter (consisting of ascending and descending tracts of myelinated axons). Spinal Cord showing the rexed laminae (left) and associated nuclei (right)
Image by Lecturio.Ascending and descending pain pathways
Ascending pathway of pain:
- Nociceptors:
- Receptors in the periphery respond to heat, intense cold, mechanical distortion, changes in pH, and chemical irritants (e.g., ADP, bradykinin, serotonin, histamine)
- Afferent nerve conduction → 1st-order neuron
- Neuron cell bodies:
- The cell bodies of 1st-order neurons are located in the dorsal horn and dorsal root ganglia of the spinal gray matter Gray matter Region of central nervous system that appears darker in color than the other type, white matter. It is composed of neuronal cell bodies; neuropil; glial cells and capillaries but few myelinated nerve fibers. Cerebral Cortex (or trigeminal ganglia)
- Glutamate, SP, and CGRP are the main neurotransmitters released by primary afferents
- 2nd-order neuron:
- After synapsing in the spinal cord Spinal cord The spinal cord is the major conduction pathway connecting the brain to the body; it is part of the CNS. In cross section, the spinal cord is divided into an H-shaped area of gray matter (consisting of synapsing neuronal cell bodies) and a surrounding area of white matter (consisting of ascending and descending tracts of myelinated axons). Spinal Cord, the 1st-order neurons project to 2nd-order neurons
- 2nd-order neurons cross the midline at the anterior white commissure
- These neurons then ascend to the thalamus Thalamus The thalamus is a large, ovoid structure in the dorsal part of the diencephalon that is located between the cerebral cortex and midbrain. It consists of several interconnected nuclei of grey matter separated by the laminae of white matter. The thalamus is the main conductor of information that passes between the cerebral cortex and the periphery, spinal cord, or brain stem. Thalamus via the contralateral spinothalamic tract, carrying both pain and temperature sensations.
- Thalamus:
- From the thalamus Thalamus The thalamus is a large, ovoid structure in the dorsal part of the diencephalon that is located between the cerebral cortex and midbrain. It consists of several interconnected nuclei of grey matter separated by the laminae of white matter. The thalamus is the main conductor of information that passes between the cerebral cortex and the periphery, spinal cord, or brain stem. Thalamus, the stimulus is sent to the somatosensory cerebral cortex via fibers in the posterior limb of the internal capsule
- Other thalamic neurons project to areas of the cortex associated with emotional responses (e.g., cingulate gyrus Cingulate gyrus One of the convolutions on the medial surface of the cerebral hemispheres. It surrounds the rostral part of the brain and corpus callosum and forms part of the limbic system. Limbic System, insular cortex)
Descending pathway of pain:
The hypothalamus and cortical regions process painful stimuli and signal for the release of inhibitory mediators and hormones Hormones Hormones are messenger molecules that are synthesized in one part of the body and move through the bloodstream to exert specific regulatory effects on another part of the body. Hormones play critical roles in coordinating cellular activities throughout the body in response to the constant changes in both the internal and external environments. Hormones: Overview (e.g., opioid peptides, norepinephrine, glycine, and GABA) that make pain suppression more effective → pain modulation
Visceral Pain
Characteristics
- Poorly localized
- Unpleasant
- Associated with nausea and autonomic symptoms
Nociception process
- Nociceptors in the walls of the viscera are sensitive to distention and
inflammation
Inflammation
Inflammation is a complex set of responses to infection and injury involving leukocytes as the principal cellular mediators in the body's defense against pathogenic organisms. Inflammation is also seen as a response to tissue injury in the process of wound healing. The 5 cardinal signs of inflammation are pain, heat, redness, swelling, and loss of function.
Inflammation of the organ → receptor and action potentials are evoked:
- Pain shifts in intensity when produced in peristaltic structures (e.g., intestines).
- Pain may be sharp upon contraction and dull upon relaxation.
- The action potentials are carried by afferent fibers via sympathetic and parasympathetic nerves of the myenteric plexus.
- The signal is transmitted to the neural bodies in the dorsal (and cranial) nerve ganglia → signal continues to the dorsal horn of the spinal cord Spinal cord The spinal cord is the major conduction pathway connecting the brain to the body; it is part of the CNS. In cross section, the spinal cord is divided into an H-shaped area of gray matter (consisting of synapsing neuronal cell bodies) and a surrounding area of white matter (consisting of ascending and descending tracts of myelinated axons). Spinal Cord.
- Convergence-projection theory: visceral afferent fibers converge with somatic afferent fibers on the same neural bodies in the dorsal horn → the signal is sent through the spinal cord Spinal cord The spinal cord is the major conduction pathway connecting the brain to the body; it is part of the CNS. In cross section, the spinal cord is divided into an H-shaped area of gray matter (consisting of synapsing neuronal cell bodies) and a surrounding area of white matter (consisting of ascending and descending tracts of myelinated axons). Spinal Cord to the thalamus Thalamus The thalamus is a large, ovoid structure in the dorsal part of the diencephalon that is located between the cerebral cortex and midbrain. It consists of several interconnected nuclei of grey matter separated by the laminae of white matter. The thalamus is the main conductor of information that passes between the cerebral cortex and the periphery, spinal cord, or brain stem. Thalamus and the somatosensory cortex.
- Pain is perceived to come from the somatic structure corresponding to the somatic fibers that converged with the visceral fibers (referred pain).
- For example:
- Pain in MI MI MI is ischemia and death of an area of myocardial tissue due to insufficient blood flow and oxygenation, usually from thrombus formation on a ruptured atherosclerotic plaque in the epicardial arteries. Clinical presentation is most commonly with chest pain, but women and patients with diabetes may have atypical symptoms. Myocardial Infarction is referred to the left upper limb.
- Pain due to ureteral distention is referred to the corresponding testicle in men.
- There may also be motor/sudomotor manifestations in somatic structures related to the corresponding spinal segment mediated by spinal interneurons.
- In the osteopathic literature, this manifestation is referred to as facilitation or a viscerosomatic reflex.
- Example: muscle spasm, fascial restriction in the paraspinal musculature at a spinal level corresponding to visceral dysfunction
- For example:
Diagram illustrating the convergence-projection theory of visceral pain
Image by Lecturio.Peripheral versus Central Sensitization
Peripheral sensitization
- Results from persistent or repetitive peripheral nociception (traditional inflammation Inflammation Inflammation is a complex set of responses to infection and injury involving leukocytes as the principal cellular mediators in the body's defense against pathogenic organisms. Inflammation is also seen as a response to tissue injury in the process of wound healing. The 5 cardinal signs of inflammation are pain, heat, redness, swelling, and loss of function. Inflammation) or nerve injury
- Hyperstimulation or damage to the 1st-order neuron alters the electrical traits and elaboration of neurotransmitters (e.g., SP, CGRP, NGF).
- The
inflammation
Inflammation
Inflammation is a complex set of responses to infection and injury involving leukocytes as the principal cellular mediators in the body's defense against pathogenic organisms. Inflammation is also seen as a response to tissue injury in the process of wound healing. The 5 cardinal signs of inflammation are pain, heat, redness, swelling, and loss of function.
Inflammation and the initial injury combine to create an enhanced pain sensation and perpetuates the pain response:
- Neuropathic pain may develop in an area devoid of nerve injury.
- May manifest with hypersensitivity, hyperalgesia, allodynia.
Central sensitization
- Phenomenon thought to occur centrally, perhaps at the level of the rexed laminae
- Generally a progression from peripheral sensitization but may also be produced without any known peripheral stimulus or a CNS insult.
- Segmental central sensitization: neuroplastic changes that occur in response to a physical injury that cause constant activation of the pain pathway (i.e., progression from central sensitization)
- Suprasegmental central sensitization: neuroplastic changes in brain sites of the pain pathway with or without known injuries (from CNS injury).
- Often occurs in the setting of CNS insults (e.g., stroke, spinal cord Spinal cord The spinal cord is the major conduction pathway connecting the brain to the body; it is part of the CNS. In cross section, the spinal cord is divided into an H-shaped area of gray matter (consisting of synapsing neuronal cell bodies) and a surrounding area of white matter (consisting of ascending and descending tracts of myelinated axons). Spinal Cord injury)
- Often associated with psychiatric conditions:
- Anxiety disorders
- Mood disorders (e.g., depression)
- Sleep disorders
- Somatization disorder
- May occur as a primary disorder (e.g., fibromyalgia Fibromyalgia Fibromyalgia is a chronic pain syndrome characterized by widespread body pain, chronic fatigue, mood disturbance, and cognitive disturbance. It also presents with other comorbid symptoms such as migraine headaches, depression, sleep disturbance, and irritable bowel syndrome. Fibromyalgia)
Mechanisms of peripheral and central pain sensitization
Image by Lecturio.The Gate Control Theory of Pain
- A physiologic sensory “gate” exists at the level of the dorsal horn in any given spinal segment (or cranial nerve nucleus).
- Only so much sensory information can get through the gate at any given time.
- Preferential passage through the gate is granted to incoming sensory signals conducted by larger, more heavily myelinated, faster-conducting nerve fibers.
- An open gate is a dorsal horn receiving isolated noxious (painful) stimulus.
- A closed gate is a dorsal horn receiving simultaneous physical (nonnoxious) physical stimuli.
- Incoming pain signals are largely conducted by A-delta (relatively slow-conducting) and type C (slow-conducting) fibers, while A-alpha and A-beta (fast-conducting) fibers carry nonnoxious physical stimuli (e.g., movement, vibration, pressure, temperature, electrical stimulation).
- This distinction becomes very important when painful (noxious) and other physical stimuli (nonnoxious) are simultaneously applied in the receptive field of a peripheral nerve.
- Nonnoxious physical stimuli (conducted by faster, larger, more heavily myelinated fibers) are given preferential passage through the gate, lessening or eliminating the incoming pain (noxious) stimulus.
- Humans unknowingly apply this concept on a daily basis to relieve trivial noxious insults. For example:
- Scratching (nonnoxious physical stimulus) a mosquito bite (noxious chemical stimulus) to relieve the itch (pain)
- Rubbing (nonnoxious physical stimulus) the elbow (“funny bone Bone Bone is a compact type of hardened connective tissue composed of bone cells, membranes, an extracellular mineralized matrix, and central bone marrow. The 2 primary types of bone are compact and spongy. Structure of Bones”) after bumping it on a door frame (noxious physical stimulus) to relieve the pain
- The “pain team” purposefully applies this concept to treat pain nonpharmacologically:
- Massage
- Physiotherapy
- Peripheral nerve stimulation
- Spinal cord stimulation
Clinical Relevance
- Chronic pain: pain that extends beyond the expected period of healing (> 3 months), with an underlying pathology that is insufficient to explain the presence or extent of the pain. Chronic pain can disrupt sleep Sleep Sleep is a reversible phase of diminished responsiveness, motor activity, and metabolism. This process is a complex and dynamic phenomenon, occurring in 4-5 cycles a night, and generally divided into non-rapid eye movement (NREM) sleep and REM sleep stages. Physiology of Sleep, daily activities, and psychosocial function. Chronic pain is commonly seen in individuals with malignancies and requires a very personalized management approach.
- Pain management Pain Management Pain is defined as an unpleasant sensory and emotional experience associated with actual or potential tissue damage. Pain is a subjective experience. Acute pain lasts < 3 months and typically has a specific, identifiable cause. Pain Management: Today, medical professionals have myriad—both pharmacologic and nonpharmacologic—options to alleviate pain. The specific management strategy followed depends on the type of pain and the individual’s circumstances, perspective, and underlying condition.
- Complex regional pain syndrome ( CRPS CRPS Complex regional pain syndrome (CRPS) is a chronic regional neuropathic pain condition characterized by excruciating pain (out of proportion to apparent tissue damage or inciting trauma), paresthesia, allodynia, temperature abnormalities, skin discoloration, edema, reduced range of motion, and bone demineralization. Complex Regional Pain Syndrome (CRPS)): condition characterized by excruciating pain that is out of proportion to the inciting event and is accompanied by allodynia, temperature abnormalities, skin Skin The skin, also referred to as the integumentary system, is the largest organ of the body. The skin is primarily composed of the epidermis (outer layer) and dermis (deep layer). The epidermis is primarily composed of keratinocytes that undergo rapid turnover, while the dermis contains dense layers of connective tissue. Structure and Function of the Skin discoloration, and edema Edema Edema is a condition in which excess serous fluid accumulates in the body cavity or interstitial space of connective tissues. Edema is a symptom observed in several medical conditions. It can be categorized into 2 types, namely, peripheral (in the extremities) and internal (in an organ or body cavity). Edema, among other findings. This syndrome affects women more often than men and is often incited by trauma. Diagnosis is clinical, supported by the Budapest Consensus. Complex regional pain syndrome is closely related to litigation of work-related issues, requiring special care by the physician.
References
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- Barrett, K. E., Barman, S. M., Boitano, S., Reckelhoff, J. F. (2017). Somatosensory neurotransmission: touch, pain, & temperature. In: Ganong’s Medical Physiology Examination & Board Review. McGraw-Hill Education. http://accessmedicine.mhmedical.com/content.aspx?aid=1142554554
- House, S. A. (2021). Pain. In: Kellerman, R. D., Rakel, D. P. (Eds.), Conn’s Current Therapy. Elsevier, pp. 32–39.
- Proch, R. (2019). Fibromyalgia as a biopsychosocial model for the intersections of physical and emotional pain. DeckerMed Medicine. Retrieved October 10, 2021, from https://doi.org/10.2310/PSYCH.13071
- Ross, E. (2018). Pain syndromes other than headache. DeckerMed Medicine. Retrieved October 11, 2021, from https://doi.org/10.2310/PSYCH.6177
- Mendell, L.M. (2014). Constructing and deconstructing the gate theory of pain. Pain 155:210–216. https://doi.org/10.1016/j.pain.2013.12.010
