“Know your enemy and know yourself and you can fight a hundred battles without disaster.” –Sun Tzu

There is no doubt that the experience of pain transforms an individual’s life, both while it is ongoing and after the acute effects have passed. Pain alters healing, activity, social interactions and the kinesthetics of movement. Pain will always undergo some aspects of amplification and deamplification - allowing it to persist or gradually reduce over time.

While the subject of pain processing is startlingly comp lex, an understanding of the basic framework allows the clinician to design a more appropriate, individualized analgesic treatment for their patient in pain.

When contemplating the physiology of pain signaling there is a continuum between acute pain and chronic pain that defies attempts to confine these definitions to discrete time frames. Physiologists studying ‘acute pain’ define this as pain that does not actually cause damage to tissue. Clearly, this is a very different scenario from what a clinician would describe as acute pain, which very often involves surgical incisions, manipulation of deep, visceral type tissues and always, consequent inflammation. For this discussion, I will not attempt to separate acute pain processing from chronic pain processing, but rather see acute pain as phasic, and chronic pain as a progress through the entire spectrum that becomes tonic, at least for a while.

In the complexity of clinical medicine, it is not possible to predict where any given individual will land along the road of pain amplification. Many will fully recover from acute injury and return to a state indistinguishable from a non-injured counterpart (unless you were to investigate the pain map that was created on their glia). Others will manifest life-long changes and these individuals will tend to move differently and manifest accumulating dysfunction as their kinesthetics, myofascial system and nervous system find alternative methods of processing.

Simple pain begins at the site of injury, and may begin as a proportional response to the level of stimulus (the pain reported is proportional to the intensity of the injury). Peripheral nerve terminals are established in close association with resident mast cells and capillaries. These triads sense changes in pH, temperature and proteins as well as transducing high intensity mechanical stimuli. Unlike the other sensory receptors, pain receptors do not fatigue in response to repeated stimulation. Rather, with repeated stimulation, changes occur that include: increased sensitivity, budding of new receptive terminals, and recruitment of previously quiescent terminals (silent nociceptors). Likewise, when significant neuronal activity occurs (with or without local tissue damage) the associated mast cells and capillaries escalate the release of inflammatory mediators, recruit white blood cells and promote metabolic activity in the region.

Once a signal is sufficient to trigger the high-intensity receptors (pain receptors) the signal travels up the axon. The axon may be myelinated (A-delta fibers) or unmyelinated (c fibers). In the peripheral nervous system, the primary afferent will synapse in the dorsal horn of the spinal cord in lamina 1, 2, 3 or 5. Other sensory fibers synapse in similar regions (especially 3, 4 and 5), allowing interaction between signaling pathways carrying different types of sensory information.

• Local anesthetics/Na Channel blockers
• Anti-inflammatories (NSAID or steroid - local or systemic)
• Antihistamines
• Ice, heat, TRP channel modifiers
• Touch, acupuncture, laser

Before plunging into a discussion of the dorsal horn it is important to recognize some major way-points for pain signal modification along the path of axonal flow. All along the axons of peripheral nerves are ion channels, receptors and the cellular machinery for energy production and electrical gradient maintenance. Contemplating the sheer magnitude of a nerve fiber (picture a horse sensory nerve body in the DRG extending up to the spinal cord and down to the coronary band) provides an understanding of how much activity occurs along this pathway. Imagine the amount of transportation that must occur along the filaments within the axon fibers. Thus, the axonal entity is not inert, but rather subject to modification during prolonged pain states.

• Touch, acupuncture, laser
• Local anesthetics/Na channel blockers
• Ice, heat, TRP channel modifiers

Likewise, the dorsal root ganglion (DRG) holds the cell bodies for peripheral pain fibers. There is a tendency to think about these cell bodies as if they were fans in the bleachers - watching the action go by without having any impact on the outcome. Not so, as becomes immediately evident when we consider the role of the cell body. With increased activity along a nerve fiber the cell body becomes very active, synthesizing proteins and receptors, packaging them and sending them long distances along axonal filaments to be placed at nerve terminals, the dorsal horn and along the axons themselves. Ion channel populations change dramatically during chronic pain states, and all of these changes begin with the cell body in the DRG. It is also very interesting to recognize that the DRG is the region in the CNS that is least protected by the blood-brain­ barrier. Thus the cell body becomes privy to circulating proteins, drugs, inflammatory mediators and toxins that are excluded from the bulk of pain processing.

• Lidocaine (IV route)
• Anti-inflammatories (NSAID or steroid)
• Acetaminophen (centrally acting COX modification)
• Anti-Epileptics (gabapentin, pregabalin, etc.)

Returning to the dorsal horn of the spinal cord, the first order neuron devolves the electrical signal from the painful stimulus into a chemical one.  Keep in mind that ions still play a major role in this step, with calcium being required to release neurotransmitters into the cleft. The signal is carried across the cleft between first and second order neurons by diffusion of these proteins. The major players in passing this information across the synapse are glutamate and substance P. Many other proteins, receptors and ion channels contribute to the complexity of this process. When repeated stimulation occurs additional channels, proteins and receptors become active. These may serve to facilitate transfer of signals or to dampen transfer of signals. I will discuss the most relevant details in the discussion about currently available therapies directed at this aspect of pain processing.

Adding to the complexity, recognize that there are likely more than just two nerve-endings at the synaptic cleft being stimulated in our discussion. The signal is likely to also pass to interneurons, rapid projecting neurons and glial receptors that live in the same immediate neighborhood. The glial system and other support cells (mast cells, resident macrophages, etc) have recently been recognized as potent and active contributors to pain signaling. Likewise, interneurons can serve in inhibitory, excitatory and recruiting functions.

• Narcotics (opioids)
• Serotonin/ norepinephrine modifiers
• NMDA antagonists
• Alpha-two modifiers
• Cannabinoids
• Centrally acting anti-inflammatories (NSAIDS, steroids, acetaminophen)

After neurotransmitters diffuse across the cleft they bind to specific receptors (such as AMPA and NK1 respectively) which in turn initiate electrical depolarization of the second order neuron. This second order neuron, or projection neuron, will carry the signal up to the brain-stem. The spino-cervico-thalamic tract is one of the major paths for somatic pain signaling in domestic animals and it crosses midline in the cervical region - arriving in the thalamus with minimal synaptic modification. The spinoreticular tract is the second important pathway for pain signaling, especially important in carrying deep or visceral pain. It tends to undergo extensive branching and synaptic modification as it ascends both sides of the spinal cord. This difference in ascending tracts helps to explain some of the physiologic and pharmacological differences between somatic and visceral pain. Interestingly, the spinoreticular tract also sends some signals directly through the limbic system - giving a structural reason for the common experience that visceral pain lends a greater sense of misery than superficial somatic pain.

• Spinally administered drugs

Once pain a pain signal has arrived in the thalamus or reticular system it is distributed to a variety of regions in the cortex, limbic system, midbrain, etc. The nucleus raphe magnus (NRM) and nucleus reticularis gigantocellularis in the medulla receive signaling and provide descending inhibition utilizing serotonin and norepinephrine. The hypothalamus releases endorphin and initiates a cascade of opioid- dependent inhibitory mechanisms.

• Narcotics (opioids)
• Serotonin/norepinephrine modifiers NMDA antagonists
• Alpha-two modifiers
• Cannabinoids
• Anxiety modifiers (environment, sedatives)
• Centrally acting anti-inflammatories (NSAIDS, steroids, acetaminophen)
• Acupuncture, massage, exercise

The mechanistic explanation of pain signaling that has emerged around the first synaptic transfer (dorsal horn of the spinal cord) does not translate easily to the complexity found in the CNS. Pain signals synapse in the limbic system, allowing emotional state and memory to affect processing. They synapse in regions that alter autonomic activity, thereby increasing or decreasing physiological functions, levels of consciousness, etc. The milieu of output from the CNS, is therefore less distinct. This is frustrating as a scientist, but perhaps more fascinating as a clinician as it allows entry of concepts such as ‘quality of life’ and ‘comfort’.

In particular, the glial network of the spine and CNS has been gathering significant respect as a long-term modifier of pain. The glial cells become activated by activity within the synapse, and rapidly spread this excitement (non-synaptically) from cell to cell, across midline, and facilitating the intensity of the signal. These changes may persists far longer than the wind-up that occurs in the nerves, and can contribute to conditions such as neuropathic pain, opioid tolerance and addiction, and reduced healing within the nervous system.

• NMDA antagonists
• Opioid antagonists
• Glial antagonists
• Acupuncture, exercise

Muscle and fascia live alongside the neurological framework and become implicated in changes that occur. With excessive neuronal activity associated muscles spasm and enter an ‘energy crisis’. An initial sustained release of calcium due to muscle splinting and activation results in sustained sarcoma recontracture. Increased metabolic rate of these muscle groups is compounded by local ischemia due to the contracted state of the muscle inhibiting local blood flow. Energy in the form of ATP is required to move intracellular calcium back into the sarcoplasmic reticulum at the end of the contraction, which is no longer possible in the sarcomeres anoxic state, thus the high intracellular calcium remains, sustaining the contraction.

In addition to be painful of their own right, chronic muscle contraction (trigger points) contribute to changes in movement and put additional strain on joints and/or spinal segments served by the contracted muscle bellies. Over time this ‘myofascial restriction’ help to create co-morbid conditions that accumulate into a multi-faceted pain experience. Furthermore, in our non­speaking patients, a knowledge of these patterns can create a standard ‘pain map’ that helps us to identify the likely sources of pain, or at least implicate typically­ associated groups (shoulder/neck and iliopsoas/caudal lumbar).

• Acupuncture with trigger-point deactivation
• Local anesthetics
• PRP-regenerative medicine
• Exercise/ motion/stretching
• Massage
• Heat/ice
• Laser/ shock-wave