Pain physiology with an eye towards understanding endogenous and exogenous pharmacophysiology (Proceedings)

Part 1: Pain Processing

"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 as well as after the acute effects have passed. Pain alters healing, activity, social interactions and the kinesthetics of movement.

While the subject of pain processing is startlingly complex, 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 progress through the entire spectrum.

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. Others will experience 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.

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.

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.

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.

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.

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 seratonin and norepinepherine. The hypothalamus releases endorphin and initiates a cascade of opioid- dependent inhibitory mechanisms.

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. Pain signals 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'.

From this discussion of pain processing we will move onto the patho- physiological changes that may occur when the system is over-used or damaged. However, I'd like to step away for a moment and recognize 'bystander' systems that become implicated during pain states.

Muscle and fascia live alongside the neurologic framework and become implicated in changes that occur. With excessive neuronal activity associated muscles spasm and enter into an 'energy crisis'. An initial sustained release of calcium due to muscle splinting and activation results in sustained sarcomere contracture. 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.

Part 2: Tapping into the Body's Pharmacy

In the past when I have been asked to give a lecture on the pharmacology of pain medications I have gone through a laundry list of the available options. This having been elegantly accomplished many times by now, I have decided that it would be more consistent with the physiological framework to describe the various ways we have of interfering with pain signaling in sequence. If you would like a very accurate and concise list of the drugs, I would recommend the paper 'Chronic Pain in Dogs and Cats' by Sheila Robertson at www.ivis.org .

Periphery The triad of elements making up nerve ending are all modifiable.

Nerve endings in the periphery are blocked with a laundry list of sodium channel blockers(lidocaine, bupivacaine, etc) that block a particular subtype of sodium channels known as tetrodo-toxin sensitive channels. These drugs are relatively indiscriminate about which types of nerves that are blocked (bupivacaine and ropivacaine may slightly favor sensory), although the kinetics of drug penetration tends to favor blockade of thinner, less myelinated and less deeply bundled nerves. Sensory fibers carrying pain, heat and touch sensations are readily altered while thick, myelinated motor fibers are slower to affect.

As with the local anesthestics, a wide variety of nerve endings are present in the periphery and not only pain fibers are affected by interventions. Stimulating heat or cold-sensing receptors, touch sensing receptors, etc sends competing signals to the dorsal horn of the spinal cord. These stimuli decrease the amount of afferent stimuli reaching being received. This is one method by which heat, cold, touch, massage, and acupuncture play a role at the nerve endings. This particular aspect of descending inhibition was targeting by early pain pioneers Melzak and Wall in their 'gate theory'.

Finally, the mast cells and capillaries are critical. Local release of inflammatory mediators set an avalanche of events into action. Interventions at this level include peripherally acting anti-inflammatories such as non-steroidal drugs (NSAIDs) and steroids. Cooling, photodynamic treatments such as low-level laser therapy and acupuncture also are likely to have direct affects on both decreasing inflammation and improving lymphatic and capillary drainage from the region of the triad.

Axon

The most effective way to interfere with electrical signaling is to interfere with sodium channels, so here we see the return of the local anesthetics.

When used along a major axon use of local anesthetics is generally termed 'regional anesthesia' and this is clearly a hallmark of food animal practice. However, a huge resurgence has occurred across all types of human and veterinary species with fantastic new applications. The advantage to targeting the axon with local anesthetics is that it avoids placing drug right at the site of the injury. Both the biology of injured tissue (acidic, edematous, etc) and the pharmacology of the local anesthetics (pH sensitive, anti-inflammatory, painful on injection, nerve damage with repeated administration) provide interactions that are avoided by placing drug remote to the injury. A disadvantage to using a local anesthetic along the axon is that, although the signal is blocked from entering the dorsal horn, the activity continues and the peripheral site of injury. Therefore the release of inflammatory mediators, the uptake of these mediators into the bloodstream and passing of the signal to the DRG still occurs. Therefore the interference into the pain processing is not as complete as once thought when a regional technique is used.

Some of the exciting advances in regional techniques have come about through improved accuracy of drug placement. Nerve stimulation is a fantastic method for verifying needle placement. An excellent review by Luis Campoy titled: Fundamentals of Regional Anesthesia using Nerve Stimulation in the Dog can be found on www.ivis.org .

Ultrasound guidance is a second improved technique for ascertaining block placement. Finally, the improvement of indwelling diffusion catheters for local anesthetics has provided a mechanism for increasing the possible duration of analgesia provided by these techniques. Diffusion catheters may be placed for regional desensitization (along major axons) or peripheral diffusion (within the surgery site at the level of the nerve terminals).

Finally, Low Level Laser Therapy plays an important role at the axonal level. Pain signaling has been shown to decrease with photodynamic therapy, and one of the proposed mechanisms is disruption of axonal flow due to disruption of flow along the filaments within axons.

Cell Body (in the DRG)

Therapies directed at the cell body generally fall into the chronic pain category. Increased expression of a variety of ion channels and receptors accompany chronic pain states. Opioid receptors are synthesized, packaged and sent to peripheral locations. Sodium channel sub-types are slowly switched to tetrodo-toxin resistant types (not-responsive to traditional sodium channel blockers). Likewise, calcium channels are upregulated and different sub-types emerge. Cyclo-oxygenase subtypes increase (COX 2 specifically) in the cell body and terminals.

Therefore, the cell body in the DRG is an important target for transcriptionally directed therapies. NSAIDs play some of their pain-relieving role here and both the centrally acting and peripherally acting NSAIDS probably have some access to the DRG. Steroids work in this location both by interfering with COX and also by causing transcriptional changes. Acetaminophen serves a COX 3 modifying role in the DRG and dorsal horn, although it does not serve as an anti-inflammatory in peripheral tissues.

Anti-epileptic drugs often target high-use receptor subtypes of sodium and calcium channels. Drugs such as Phenytoin, Carbemazepin, Zoneisamide and Lamotrigene target high-use sodium channels. Gabapentin and Pregablin target calcium channel expression.

Although most of the cell body therapies are directed at chronic changes, it has recently been recognized that the cell body is highly involved in the effect of low-concentration systemic lidocaine administered via constant rate infusion (Lidocaine CRI). While this method has become increasing popular due to analgesia and pro-motility effects on the gastro-intestinal system, the mechanism of action has been unclear as it has been shown that the doses are too low to justify a blocking effect on peripheral tissues, and the drug is excluded from the central nervous system by the blood-brain barrier. Meclizine is an orally-available sodium channel blocker of the same class as lidocaine and can sometimes be useful in pain states that respond to lidocaine infusions.

Dorsal Horn

An entire graduate course can be filled with treatments directed at decreasing pain signaling through the dorsal horn. We have already discussed descending inhibition from activation of non-pain sensory fibers sending competitive signals through lamina 1-5 in the axon section. We have discussed several of the transcriptionally mediated changes to ion channels above in the cell body section. The bulk of the cell body discussion plays out in the dorsal horn, which is, after all, an extension from the cell body.

Glutamate and substance P are major players in synaptic conductance; however, their roles are too diverse throughout the body to serve as good specific targets for pain therapy. The major receptors for glutamate are AMPA, NMDA and metabotropic glutamate receptors. The NMDA receptor tends to remain quiescent in the dorsal horn (it is much more active in the brain as it serves an important role in learning). It becomes activated only when enough activity passes through the synapse to dislodge a Mg ion that occupies the pore. However, 'sustained activity' to a nerve is really only 10-15 minutes or less, once again pointing out some different perceptions between physiologists and clinicians (who tend to see chronic stimulation as occurring over weeks to months). Once activated this receptor massively amplifies calcium handling and glutamate receptor activation - like a supercharger for a pain stimulus. Thus, it is a great target. Ketamine, Amantadine, dextromethorphan and methadone have NMDA antagonist effects.

Inhibitory receptors are also routinely expressed at both the pre-synaptic and post-synaptic membranes. Three major examples of these ligand-receptor pairs are opioids (Mu Kappa and Delta receptors), seratonin (5HT), and Norepinepherine (Alpha-2 receptors). When bound to the channel these ligands activate second messenger systems that modify channel kinetics- hyperpolarizing membranes, closing ion channels and interfering with cellular messenging. GABA is an important messenger at the dorsal horn that unfortunately has had mixed results when targeted for pain modulation. For example, benzodiazapines are GABA agonists, but have a variable effect on pain perception ranging from anti-nociceptive to pro-nociceptive in different studies and at different drug concentrations.

Opioid agonists (morphine, meperidine, hydromorphone, oxymorphone, fentanyl) and partial agonists (butorphanol, buprenorphine, nalbuphine) bind to receptors that are repleat through all levels of the pain processing system. Opioid receptors work via channels (as mentioned above) as well as stimulating inhibitory interneurons. The number of recognized receptor subtypes continues to expand, shedding some light on some important differences in individual responses to different opioids. In general, agonists tend to provide more potent analgesia than partial agonists. It is important to note, however, that opioids may bind to either inhibitory linked g-proteins (decreasing pain signaling) or excitatory linked g-proteins. With chronic administration the excitatory-linked receptors are increasingly manufactured- leading to tolerance and forms of dysphoria or excitement. Several opioids have been shown to directly stimulate glial activation (see section below). So, while opioids are the cornerstone of acute pain management, they express increasing limitations in the treatment of chronic conditions. Tramadol is an opioid-like drug with about 10-20% of the efficacy of morphine at mu receptors. It's effectiveness is improved via additional effects on the noradrenergic and seratonergic systems.

Like tramadol, drugs commonly regarded as 'anti-anxiety' medications generally target noradrenegic and seratonergic systems in the brain and spinal cord. Amitriptyline and Imipramine are common examples in veterinary medicine. The more specific alpha-two agonist drugs such as dex-medetomidine, romifidine and xylazine also cause a tremendous amount of sedation, making them very useful for acute pain therapy in individuals who would benefit from sedation but less useful in the management of chronic or ongoing pain.

Before leaving the topic of the dorsal horn, a more direct way to maximize drug effects in this location (or to have drug effects in the case of drugs that cannot penetrate the blood-brain barrier) is to administer the drugs by epidural or spinal routes. The most common drugs used in this way are opioids, local anesthetics, alpha-two agonists and ketamine. Epidural catheters may be placed for long-term administration of drugs through this route. Finally, mild electrical stimulus applied to the spinal cord dramatically reduces some forms of neuropathic pain. Spinal cord stimulators are available for this purpose, although application in non-speaking populations poses difficulty in post-placement assessment.

Brain stem and cortex

Seratonin, norepinepherine and endorphins/opioids are the most well-understood modulators of pain processing in the brain. In addition, psychological state has a profound influence on pain processing. So, in addition to the generally recognized analgesic drugs, anxiolysis becomes a critical feature in modifying pain messages in the higher centers. Acepromazine is a profound anxiolytic that has a solid place in pain management despite the fact that it is not independently analgesic. However, natural forms of anxiolysis are probably far superior and include touch, companionship, being at home, reduction of stressful inputs, etc. Acupuncture studies using functional MRI have shown reduced activation of brain areas commonly associated with stress.

Glia

Glia are constitutively active support cells that can be upregulated to perform immune functions in the central nervous system. They are activated by transmitter over-flow from the synaptic cleft as well as specific compounds (fractaline) released by active neurons. Astrocytes communicate among one another of great distances by non-synaptic gap-junctions and in turn activate microglia through the release of glutamate, cytokines and other proteins. Opioids can directly stimulate glial activation as well. In addition to some less common therapies, Centrally acting NSAIDs slow glial activation. Glial activation secondary to opioid use can be slowed or prevented by co-treatment with NMDA antagonists, gabapentin, or low-dose opioid antagonists. Much information has yet to be gained as the glial component has only been reported in the last 5 years.

Immune system

Already covered at each step in pain processing, the immune system is implicitly linked to even the most acute pain signaling. Systemic reductions in inflammation with steroids or NSAIDs can reduce tissue damage, to both the nervous system and the other collateral systems (musculoskeletal, myofascial). Acupuncture provides immune modulation both systemically and regionally. Cooling and gentle massage have regional effects on immune function.

Muscle and connective tissue

Muscle and connective tissue sequella are inevitable with any sort of amplified pain processing, both through guarding of the painful region as well as bystander activation from neuronal and glial amplification. Systemic muscle relaxants such as methocarbamol may aide in reducing muscle tension. Specific regional techniques to reduce muscle tension are generally superior and include: acupuncture, low-level laser therapy, ultrasounds therapy, transcutaneous electrical stimulation, massage and physical therapy. Caution is advised when adding these modalities to your practice as there is significantly less regulation of these affiliated professions. Verify an appropriate evidence-based training or go through validated training programs yourself.

Botulinum toxin has become more readily available since it entered the beauty supply market. Local application to regions of prolonged muscle spasm cause long-term relaxation. Furthermore, direct analgesic effects have been postulated that occur through a separate mechanism that muscle relaxation. Caution is required, however, because very little evaluation has occurred in veterinary species.

Bone and joint

Clearly, the most physiologically function a body region, the less pain and accommodation will need to occur. Definitive surgical correction should always be pursued when available. Additionally, many methods are available to augment bone and joint function. Inflammation is a key component to the demise of cartilage, and anti-inflammatory products are irreplaceable in this setting. Other products that may have an impact in reducing joint inflammation are glycosamino-glycan products such as adequan. While the presence of articular cartilage may improve the effect of GAGs, there is also evidence that decreased inflammatory mediators (such as IL-1) follow treatment and may help joint comfort even when little normal cartilage remains. Intra-articular administration of Hyaluronic acid takes this approach to a more direct level. Intra-articular steroids have great potential for harm in joints with viable cartilage, but may have an important role in comfort in end-stage joints.

Nutritional supplements directed at cartilage and joint function include fatty acids, soy and avocado insupponofiables, glycosmine, chondroitin, MSM, elk-velvet antler, mild-based products such as duralactin, myristol, etc. Many of these products have merit, some more validated than others. For instance, the fatty-acid repleat diet J/D has very compelling data that has helped to give rise to the concept of neutrogenomics. However, prescribing other of these products may also serve to direct money and energy away from validated therapies. Therefore, they may be tried with the comfort of knowing they are unlikely to cause harm, but with an eye to not placing them in a superior position to more strongly validated therapies.