Handling Pathologic Pain
You have asked... what is the best strategy for addressing abnormal pain in my patients?The expert says...The physiologic processes underlying the experience of pain are complex, and nociceptive input is extensively modulated before the final conscious experience of pain. Acute pain is usually brief, resolving, if adequate analgesia is provided, as tissue heals. The goal of any analgesic protocol should be to avoid development of chronic pain states, including peripheral and central sensitization.
Abnormal PainAbnormal pain states can result from peripheral sensitization, central sensitization, or neuropathic pain. They frequently include symptoms of hyperalgesia and allodynia.1 Abnormal pain states are challenging to treat because they develop through a variety of complex mechanisms.2-5
Neuropathic PainNeuropathic pain occurs when a lesion or disease affects the central or peripheral nervous system; it can manifest as numbness, spontaneous burning, or lacinating pain. Examples of neuropathic pain include diabetic or postherpetic neuropathy and multiple sclerosis in humans, interstitial cystitis in cats and humans, and pain that develops subsequent to nerve trauma, such as a crushing injury or limb amputation.1-3
With neuropathic pain, nerve injury causes activated glial cells and astrocytes to release cytokines, prostaglandins, and glutamate that activate NMDA receptors and cause sprouting of the central and peripheral ends of damaged fibers. Nerve injury also leads to an increase in the number of spontaneously active Na+ channels in the periphery, dorsal root ganglion, and dorsal horn. The result is an increase in spontaneous generation of action potentials and cross-excitement of inactive neurons. In addition, low-threshold A beta (tactile), motor, and sympathetic neurons may activate sensory afferents, resulting in allodynia.2-8
Peripheral HypersensitivityWith tissue trauma and inflammation, nociceptors on peripheral terminals of C-fiber neurons become sensitized or directly stimulated by many inflammatory mediators, including prosta-glandins and leukotrienes. This stimulation leads to further excitation of nerve fibers and activation of normally silent nociceptors. The result is a decrease in the threshold for activation of nociceptors and an increased magnitude and duration of response to a nociceptive stimulus at the site of injury (primary hyperalgesia). Another result is the perception of low-intensity, subthreshold mechanical stimuli as painful (allodynia).
Peripheral sensitization frequently leads to central sensitization and hyperalgesia in the surrounding uninjured tissue (secondary hyperalgesia) because it causes sustained nociceptive input into the dorsal horn. Prevention of inflammation-induced peripheral hypersensitivity and subsequent central hypersensitivity is the rationale for use of corticosteroids and nonsteroidal antiinflammatory drugs.2-4,6,7
Central SensitizationWhen glutamate is released from primary afferent neurons in the dorsal horn in response to an acute noxious stimulus, it briefly activates AMPA and kainate receptors on second order neurons, resulting in brief activation of central nociceptive pathways. Glutamate also binds to NMDA receptors on second-order neurons, but sustained depolarization of the neuronal membrane is required to remove the Mg2+ block of the ion channel of the NMDA receptor, allowing its activation.
If repetitive and high-frequency stimulation of C fibers occurs, as from inflammation, neuropathic pain, osteoarthritis, or other sources of sustained nociceptive input, release of glutamate and concurrent release of substance P and other excitatory neurotransmitters is prolonged. This release causes sustained activation of AMPA receptors; prolonged, slow membrane depolarization; removal of the Mg2+block; and activation of NMDA receptors.2-5
Other factors probably involved in the development of central sensitization include loss of tonic inhibition from neurotransmitters such as GABA and glycine and loss of descending inhibition.
Wind-Up PainNMDA receptor activation results in a large influx of Ca2+ ions into the second-order neuron that activates cellular second messengers (eg, protein kinases), causing early gene induction, altered protein synthesis, changes in neurotransmitter receptor density, and enhanced glutamate release from primary afferent neurons. Na+ and Ca2+ channels and NMDA and AMPA receptors on second-order neurons are activated, and the resulting increased frequency of firing and increased magnitude and duration of response to subsequent afferent input is termed wind-up.
Wind-up is a form of neuroplasticity that lasts for minutes; however, ongoing noxious afferent input for hours or days leads to sustained changes in the spinal cord (ie, central sensitization) that result in expansion of receptor field size, an increase in the magnitude and duration of response to a threshold stimulus, and an overall reduction in threshold. As a result, nonnoxious stimuli now activate neurons that transmit nociceptive information.2-5
Treatment & PreventionNMDA Receptor AntagonistsThe importance of NMDA receptors in wind-up, central sensitization, and neuropathic pain has led to the use of NMDA receptor antagonists to prevent and treat these conditions. Ketamine, memantine, amantidine, methadone, and dextromethorphan show promise for reducing these conditions in humans, although adequate dosing is often prevented by unpleasant side effects, including sedation and ataxia.6,8 Although some studies demonstrate clinical efficacy of ketamine, amantidine, and methadone in animals, most treatment recommendations are based on extrapolation from human medicine or anecdotal reports in a few veterinary patients.5,9
Antiepileptic DrugsBoth Na+ and Ca2+ channels have also been targeted. The antiepileptic drugs gabapentin and pregabalin act at the alpha-2-delta subunit of voltage-gated calcium channels to reduce glutamate release and inhibit hyperalgesia and allodynia. Antiepileptic drugs that block Na+ channels, such as phenytoin, carbamazepine, and lamotrigine, also inhibit glutamate release and have been effective in treating neuropathic pain in people. Topiramate blocks Na+ channels but also potentiates the inhibitory action of GABA and may block glutamate release.6-8 Clinical efficacy studies in animals are lacking.9
Other MedicationsAgents that block the reuptake of norepinephrine or serotonin, such as tramadol, tricyclic antidepressants, selective serotonin reuptake inhibitors, or serotonin-norepinephrine reuptake inhibitors, can be beneficial by facilitating descending inhibition. Tricyclic antidepressants also block Na+ channels and NMDA receptors. Baclofen, often used as a muscle relaxant,provides analgesia in people by activating inhibitory GABAB receptors.6-8 Tramadol has shown efficacy in clinical studies in veterinary patients, but similar studies in regard to antidepressants are lacking.9
Mexiletine, an oral Na+ channel blocker used to treat cardiac arrhythmias, has shown some efficacy in treating diabetic neuropathy. However, this agent has a narrow therapeutic window and causes unacceptable adverse affects at plasma levels that result in analgesia.8
Local AnestheticsLocal anesthetics block Na+ channels and are frequently used in regional analgesia techniques. Local anesthetics reduce intraoperative anesthetic requirements, postoperative opioid requirements, and the development of sensitized pain states.7-9
Intravenous lidocaine has shown benefit in the treatment of diabetic and postherpetic neuropathy, central pain, and sciatic pain; 5% lidocaine patches have successfully relieved pain in postherpetic neuropathy in humans.6-8 In addition, intravenous lidocaine has provided intraoperative MAC reduction and postoperative analgesia in dogs.9
A Multimodal ApproachAbnormal pain states result from complex anatomic and physiologic changes occurring in the peripheral and central nervous systems. Drugs that inhibit NMDA receptor activation, decrease glutamate release, increase GABA release, or facilitate descending inhibition, have shown promise as adjuncts in the treatment of abnormal pain.2-9
Glossary of TermsAllodynia: Perception of pain in response to a stimulus that is not normally painful
Central sensitization: An increase in excitability of neurons within the central nervous system as a result of sustained noxious input to the spinal cord, which initiates changes in gene expression and transmitter receptor density
Hyperalgesia: Increased responsiveness of nociceptive neurons to their normal or subthreshold afferent input
Neuropathic pain: Pain arising as a direct consequence of a lesion or disease affecting the central or peripheral nervous systems
Nociceptive input: A noxious stimulus capable of activating peripheral nociceptors
Peripheral sensitization: A reduction in threshold and increase in responsiveness of peripheral ends of nociceptors due to action of inflammatory chemicals or mediators released around the site of tissue damage/inflammation
Wind-up pain:A form of short-term spinal neuroplasticity occurring with NMDA receptor activation and leading to increased frequency of firing and increased magnitude and duration of response to subsequent stimuli
HANDLING PATHOLOGIC PAIN • C.M. Egger
References
International Association for the Study of Pain: iasp-pain.org2. Sensitization of pain pathways in the spinal cord: Cellular mechanisms. Baranauskas G, Nistri A. Progr Neurobiol 54:349-365, 1998.3. Central neuroplasticity and pathological pain. Melzack R, Coderre TJ, Katz J, Vaccarino AL. Ann N Y Acad Sci 933:157-174, 2001.4. Mechanisms of neuropathic pain. Yaksh TL, Sorkin LS. Curr Med Chem Central Nervous System Agents 5:129-140, 2005.
Prevention of central sensitization and pain by N-methyl-D-aspartate receptor antagonists. Pozzi A, Muir WW, Traverso F. JAVMA 228:53-60, 2006.6. Recent advances in the pharmacological management of pain. Guindon J, Walczak JS, Beaulieu P. Drugs 67:2121-2133, 2007.7. Preventing the development of chronic pain after orthopaedic surgery with preventive multimodal analgesic techniques. Reuben SS, Buvanendran A. J Bone Joint Surg Am 89:1343-1358, 2007.8. Pharmacological management of neuropathic pain. McLeane G. CNS Drugs 17:1031-1043, 2003.
ResourceVeterinary Anesthesia and Analgesia Support Group: vasg.org