Veterinary Anesthesiologist & Integrative Pain Management Specialist, Mistralvet.com
A thorough review of pain physiology markedly lubricates the conversation around the mechanisms of analgesia—both pharmacologic and non-pharmacologic.
In this short lecture on the topic we will quickly cover the major contributors of pain physiology, and how treatments address these subcategories in the generation (or treatment) of pain.
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 tetrodotoxin 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 anesthetics, 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 targeted by early pain pioneers Melzak and Wall in their ‘gate theory.’ Thermotherapy (ice/cold) also chemically inhibit pain signals through their effect on TrP channels in peripheral sensory nerves.
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 antiinflammatories such as nonsteroidal drugs (NSAIDs) and steroids. A large laundry list of nutritional supplements act as antioxidants and have some effect and reducing inflammation (Boswellia, Curcumin, etc.). Cooling, photodynamic treatments such as low-level laser therapy and acupuncture also are likely to have direct effects on both decreasing inflammation and improving lymphatic and capillary drainage from the region of the triad.
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 the 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 at 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 and/or ultrasound are fantastic methods 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.
Photobiomodulation (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. Furthermore, cytochrome c activity is amplified, which provides a pro-metabolic, immune-modulatory effect.
Likewise, using sound for biomodulation with shock wave therapy has been shown to improve tissue healing and reduce pain in tendon, bone and skin injuries.
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 subtypes are slowly switched to tetrodotoxin resistant types (not responsive to traditional sodium channel blockers). Likewise, calcium channels are upregulated and different subtypes emerge. Cyclooxygenase 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, carbamazepine, zonisamide and lamotrigine target high-use sodium channels. Gabapentin and pregabalin 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 promotility effects on the gastrointestinal 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.
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 presynaptic and postsynaptic membranes. Three major examples of these ligand-receptor pairs are opioids (mu, kappa and delta receptors), serotonin (5HT), and norepinephrine (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 messaging. GABA is an important messenger at the dorsal horn that unfortunately has had mixed results when targeted for pain modulation. For example, benzodiazepines are GABA agonists, but have a variable effect on pain perception ranging from antinociceptive to pronociceptive 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. Dogs have an extremely effective first pass metabolism of narcotic drugs, and the only oral narcotic that has shown any levels in the plasma of dogs is codeine.
Tramadol has been utilized as an alternative to opioids because of its oral bioavailability in humans. It is an opioid-like drug with about 10–20% of the efficacy of morphine at mu receptors (in people - likely very minimal opioid effects in dogs). Its effectiveness is improved via additional effects on the noradrenergic and serotonergic systems in humans. In dogs, there is controversy about the efficacy or oral tramadol, although parenteral tramadol has been shown to be analgesic. Like tramadol, drugs commonly regarded as ‘antianxiety’ medications generally target noradrenergic and serotonergic systems in the brain and spinal cord. Amitriptyline and imipramine are common examples in veterinary medicine.
Specific alpha-two agonist drugs such as dexmedetomidine, 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 some difficulty for post-placement assessment.
Brain Stem and Cortex
Serotonin, norepinephrine 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 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 (such as pentoxifylline), 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.
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, NSAIDs, and many supplements 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 sequala 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. Fascia is recently recognized as having proprioceptive and sensory capacity, and also plays a major role in both the generation of pain, and the treatment of pain and proprioceptive deficits by physical medicine modalities.
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.
Bone and Joint
Clearly, the more physiologically functional 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 glycosaminoglycan 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 some potential harm for damaging cartilage (Depo-Medrol®), although other studies (especially in horses) have shown a cartilage sparing effect of triamcinolone when combined with HA. These injections may have an important role to provide comfort in end-stage joints and facilitate physical therapy. Biologicals such as PRP or stem cells may also improve joint comfort, although more research is needed in these areas. Using local anesthetics in joints has recently come under fire, as changes in cartilage healing have been found with infusions of bupivacaine directly into joints.
Nutritional supplements directed at cartilage and joint function include fatty acids, soy and avocado insaponifiables, glucosamine, chondroitin, MSM, elk-velvet antler, green-lipped mussel, milk-based products such as Duralactin®, Myristol, herbals such as dandelion, Boswellia, turmeric, etc. Many of these products have merit, some more validated than others. Omega-three fatty acids (50 mg/kg EPA+ DHA) have the highest level of evidence, and are therefore commonly recommended. There are many supplements available, and while they may be helpful, they may also serve to direct money and energy away from validated therapies. Those of animal origin have other concerns, such as disease transmission and ethical harvesting. Whenever possible, it is recommended to favor products from companies that are pursuing scientific validation for their products. Consider avoiding glucosamine/chondroitin containing products in spinal cord until further evidence is found that it won’t inhibit central nerve healing.