Medicosnext
PREFACE
Pain has a myriad of concepts, and no one really welcomes pain and always tries to dispose of it as soon as possible. This is understandable, as pain is unpleasant and irksome, but the unpleasantness of pain is what it makes it so effective and an essential part of life. Pain is protective in nature; it warns you of danger and helps you from further damage or prevent any impending mishap. It makes you move differently, think differently, and behave differently, which also makes it crucial for healing. Hence, pain is a friend.
All pain experiences are rather normal and an excellent, though unpleasant, response to what your brain judges to be a threatening situation. If a problem exists in your musculoskeletal, neurological, immune system, etc., it will not hurt if your brain thinks you are not in danger; it will hurt if your brain thinks you are in danger.
Pain is weird. Occasionally, the pain systems act peculiarly, e.g. bleeding in the toe doesn’t hurt until you notice blood at the injury site. Also, the pain system sometimes fails in some life-threatening condition like cancer, where patients do not feel the pain like what the conditions suggest it to be, which is the reason why it often goes undetected.
There are numerous myths, misunderstandings, and unnecessary fears about pain. Most people, including health care professionals, do not have a modern understanding of pain. This is really frustrating, because understanding the concept of pain helps us tackle it effectively. However, medical professionals are instead frightening the layman in the name of pain. Therefore, people are always apprehensive when they are in a state of pain. Understanding the anatomy and physiology of pain, which is very facile, changes the way people think about pain, reduces its threat values, and ameliorates its management. Finally, pain shouldn’t be annihilated, it should be better acknowledged and used as a guide towards positive changes in order to confront its prime cause(s).
INTRODUCTION
The International Association of Study of Pain (IASP) defines pain as “an unpleasant sensory and emotional experience associated with actual or potential tissue damage, or described in terms of such damage.” Further, “Pain is a complex unpleasant phenomenon composed of sensory experiences that include time, space, intensity, emotion, cognition, and motivation. It is the unique undesirable circumstance that is uniquely experienced by each individual, and it cannot be adequately defined, identified, or measured by an observer (Pathophysiology of Pain, Prof. J. Hanacek, MD, PhD).
Pain is derived from the Latin word poena, which means punishment or penalty. The American Pain Society and the Joint Commission on Accreditation of Healthcare Organizations (JCAHO) have declared pain as the fifth vital sign.
There are three hierarchical levels at which an individual experiences pain, and it usually produces a complex picture of pain.
a) Sensory – discriminative (associated with location, intensity, quality, temporal, and spatial aspects of pain)
b) Motivational – affective (determines the individual’s approach and avoidance behavior like depression, anxiety, etc.)
c) Cognitive – evaluative (includes thoughts concerning the cause and significance of pain, which help to block or modulate the perception of pain)
NOCICEPTION
Nociception is the sensory processes of detecting tissue damage. Nociceptors are unspecialized, free, unmyelinated nerve endings that convert a variety of stimuli into nerve impulses, which the brain interprets to produce the sensation of pain. A diverse group of receptors are stimulated in this process. Though pain and nociception are believed to be the same, they are not the same entity. It is quite possible to experience pain without nociception, and vice versa; nociception can occur without any pain being experienced. Nociceptors are excited not only by physical trauma (such as pressure energy) to the tissue, but also by the consequent release of a multitude of chemical mediators during the phase of transduction. This information is further transduced into an electrical signal, which is transmitted along the primary neuron to the dorsal horn of the spinal cord. The signal is transduced into quantal release of chemical neurotransmitters, which transmits the signal across the synaptic cleft to the second order neuron.
The nervous system for nociception that alerts the brain to noxious sensory stimuli is separate from the nervous system that informs the brain of innocuous sensory stimuli. The nerve cell bodies are located in the dorsal root ganglia, or for the trigeminal nerve, in the trigeminal ganglia, and they send one nerve fiber branch to the periphery and another into the spinal cord, or brainstem.
Chemical or mechanical stimuli that activate the nociceptors result in nerve signals that are perceived as pain by the brain. Research and understanding of the basic mechanism of nociception and pain perceptions provides a rationale for therapeutic interventions and potential new targets for drug development.
Cutaneous Nociceptors
These are unlike other sensory receptors in that they are free nerve endings and respond to highly intense stimuli, i.e. those likely to cause injury to the tissue. The stimuli detected may be chemical, thermal, or mechanical, hence they are also known as polymodal nociceptors.
Deep tissue Nociceptors
These are located in the deep structures, such as joints, bones, muscles, and viscera. Compared to their cutaneous counterparts, their receptive fields are much larger, and pain experienced is more diffuse in nature. Moreover, visceral pain can also be referred to distant parts of the body, as is the cause with cardiac pain referred to the left arm. This may be due to the primary afferent neurons from the heart entering the dorsal root entry zone at the same level as those cutaneous nociceptors which serve the left arm. As the brain can make no distinction between the two, it interprets the pain as coming from the superficial structure. The same mechanism is behind diaphragmatic pain being experienced in the shoulder tip.
Visceral organs do not have any Aδ nerve innervation, but the C fibers carrying the pain information from the visceral organ converge on the same area of the spinal cord (substantia gelatinosa) where somatic nerve fibers from the periphery converge, and the brain localizes the pain sensation as if it were originating from the somatic peripheral area instead of the visceral organ. Thus, pain from internal organs is perceived at a location that is not the source of the pain; hence it is known as referred pain.
Neural Mechanism of Pain
Peripheral Mechanism
Sensory Neurons (Primary afferent neuron)
These are the fibers conveying the information of the peripheral milieu to the central nervous system.
Aδ and C fiber are the nociceptors that are responsible for pain perception. C fibers are small diameter, unmyelinated nerves that conduct the nerve impulse slowly at the rate of 2m/sec i.e. 72 km/hr and respond polymodally to thermal, mechanical, and chemical stimuli. The pain experienced via C fibers is slow, dull, long lasting (protopathic pain). Aδ fibers are larger diameter, lightly myelinated nerves that conduct nerve impulses faster at the rate of 20 m/sec i.e. 72 km/hr, and responds to mechanical and mechanothermal stimuli. The pain experienced via Aδ is sharp, shooting, fast pain (epicritic pain).
Peripheral activation of the nociceptors is modulated by a number of chemical substances, which are released when there is cellular damage. These mediators influence the degree of nerve activity, and hence, the intensity of the pain sensation. Repeated stimulation typically causes sensitization of peripheral nerve fibers, causing lowering of pain thresholds and spontaneous pain, a mechanism that can be experienced as cutaneous hypersensitivity, like in the case of sunburn. In addition, local release of chemicals, such as substance P, causes vasodilation and swelling, as well as release of histamine from the mast cells, further increasing vasodilation. This complex chemical signaling protects the injured area by producing behaviors that keep that area away from mechanical or other stimuli. Promotion of healing and protection against infection are aided by the increased blood flow and inflammation, which is the protective function of pain.
Central Mechanism
Centrally, spinothalamic pathway and trigeminal pathway are the major routes for the transmission of pain and normal temperature information from the body and face to the brain. Visceral organs have only C fiber, and hence there is no reflex action due to visceral organic pain.
Spinothalamic Pathway
The nerve fibers from the dorsal root ganglia enter the spinal cord via dorsal root and send 1-2 branches up and down the spinal cord via dorsolateral tract of Lissauer before entering the gray matter, where they make contact with nerve cells in Rexed lamina I (marginal zone) and lamina II (substantia gelatinosa). The Aδ fibers innervate the cells in the marginal zone, and the C fibers innervate mainly the cells in the substantia gelatinosa layer of the spinal cord. These nerve cells in turn innervate the cells in the nucleus propius, another area of the spinal cord gray matter, which send nerve fibers across the spinal midline and ascend in the anterolateral part of the spinal white matter through the medulla and pons and innervate thalamus.
Trigeminal Pathway
Noxious stimuli from the face are transmitted in the nerve fibers originating from the nerve cells in the trigeminal ganglion as well as cranial nuclei VII, IX, and X. The nerve fibers enter the brainstem and descend to the medulla, where they innervate a subdivision of the trigeminal nuclear complex. From here, the nerve fibers from these cells cross the neural midline and ascend to innervate the thalamic nerve cells on the contralateral side.
The area of the thalamus that receives the pain information from the spinal cord and trigeminal nuclei is also the area that receives information about normal sensory stimuli, such as touch and pressure. From this area, nerve fibers are sent to the surface layer of the somatosensory cortical area.
Pain Transmission
Nociceptive signal that are damaging or potentially damaging to the normal tissue follows the pathway from the periphery to the brain. Transmission of pain occurs by four processes, as follows:
A) Transduction
B) Transmission
C) Modulation
D) Perception
Transduction: It is the process by which noxious stimuli are converted to electrical signals in the nociceptors. Nociceptors readily respond to different noxious modalities like thermal, mechanical, or chemical stimuli. Nociceptive afferent fibers are typically pseudounipolar neurons with a peripheral and central terminal. Peripheral release of neurotransmitter leads to the classic axonal reflex that leads to redness, swelling, and tenderness.
Transmission: The second stage of processing of noxious signals, where information from the periphery is relayed to the spinal cord, then to the thalamus, and finally to the cortex. Noxious information is transferred mainly via two different types of primary afferent nociceptive neurons that conduct at different velocities. The afferent fibers then synapse on a second order neuron in the superficial layer of the spinal cord. This second order neuron will send its axon across the midline and form the ascending spinothalamic tract that leads to the thalamus, where it further synapses with the third order cells that finally projects to the sensory cortex. One of the most important neurotransmitter for pain is glutamate, which can interact with both N-methyl-D-aspartate (NMDA) and non NMDA excitatory amino acid receptors. Another neurotransmitter responsible for pain is substance P, which interacts with the tachykinin receptor family.
Modulation: The third and critically important aspect of processing of noxious stimuli, where the nervous system, in response to noxious stimuli, can be changed and allows noxious signals to be received at the dorsal horn of the spinal cord to be selectively inhibited, so that the transmission of the signal to higher centers is modified. An endogenous modulation of pain consists of intermediate neurons within the superficial layers of the spinal cord, and descending neural tracts can inhibit transmission of the pain signal. Endogenous and exogenous opioids can act on the presynaptic terminal of the primary afferent nociceptor and indirectly block the voltage gated calcium channel, as well as opening potassium channels. This results in the inhibition of pain neurotransmitter release from the primary afferent fibers, causing analgesia.
Perception: Eventually, the signal traverses from the thalamus to the somatosensory areas of the cerebral cortex in the post central gyrus and superior wall of the sylvian fissure. Fibers are also projected to the limbic system at the anterior cingulate gyrus and insula, which are associated with emotional aspect of pain perception.
