Chapter 3 Neurophysiology of Pain from Landmine Injury

Many factors contribute to pain after landmine injury. In preclinical models, both tissue injury and nerve injury are able, within a few tens of minutes, to initiate a cascade of processes that may culminate in persistent pain [1–3]. Initially mechanical and thermal activation of nociceptors appear at the site of damage, and are quickly followed by inflammatory activation [1,3]. Ectopic and perhaps ephaptic activity can quickly add to the neuronal chaos [4]. These processes become the source of high-intensity, long-duration impulses and this intense nociceptive barrage leads almost immediately to changes in the dorsal horn of the spinal cord, particularly in the second-order transmission cells [5–8]. Experimental inflammation activates gene expression in the dorsal horn within 20 minutes [2]. Ligating the isolated rat sciatic nerve within hours leads to novel gene expression in the dorsal horn and to swelling and inflammation in the nerve itself [9]. In virtually every instance of landmine injury, sufficient time elapses before initial care so that the patient must be viewed as already being in a subacute phase of pain and thus is no longer suitable for “acute” or “preemptive” intervention. The concept of “preemptive” analgesia for later medical procedures, such as stump revision or re-amputation, may be applicable. Yet even then, patients already have well-established “wind-up” or “sensitization” processes that are mediated through multiple mechanisms. Because treatment with any form of analgesic is rarely begun within hours if not days after the initial trauma, virtually every mechanism recognized to generate subacute and “chronic” pain in preclinical models and clinical practice has ample time to develop in the patient. As time passes after any injury, additional sources of persistent pain may occur as a result of active pathophysiological processes (such as infection or ischemia) and of adaptations in the peripheral and central nervous system that produce sensitization. This sensitization may be manifest as perceptions of pain triggered by stimuli that normally are not painful (allodynia). For example, an amputee may avoid even the light contact of any garment (and certainly of any prosthesis) due to mechanical allodynia of the residual limb. These irritating changes may involve only the territory of the affected nerve, but they may also extend to surrounding tissue. Peripheral neural sensitization and central synaptic plasticity with sensitization are expected physiological processes contributing to neuroma pain, residual limb pain (allodynia/hyperalgesia), and phantom limb sensation/pain [10]. They occur in response to nociceptive stimulation of high intensity, long duration, or both, or to peripheral nerve lesions (i.e., section, crush, stricture) [11,12]. Postamputation pain is common after amputation for occlusive arterial disease. In such instances, patients suffer from pain before amputation (ischemic pain, neuropathic pain, postoperative pain from previous surgeries, and so on). In contrast, landmine victims are generally younger and pain-free before the injury. In such persons, additional risk factors include psychological trauma, blood loss with hypovolemia and hypoperfusion of vasa nervorum, and peripheral nerve lesions. Sensitization can occur at multiple sites in the peripheral and central nervous system. Neuroma pain is likely an expression of the distal, local sensitization of cut nerve ends “regenerating” into painful, mechanically sensitive masses of scar and damaged nerve [13]. Residual limb pain is likely a reflection of plasticity and “wind-up” in the central nervous system, especially involving changes at N-methyl-d-aspartate (NMDA) and non-NMDA type receptors on transmission cells [14,15]. Phantom limb phenomena probably involve pathological activity along the entire neuroaxis, but especially reflecting changes in the cortex [16,17]. Landmine victims usually experience both nociceptive and neuropathic pain for some hours or days before surgical amputation. Both pains sensitize nociceptors and central nociceptive neurons of projection. Sensitization of the nociceptors is normally caused by the components of the inflammatory “soup”[18], including substances released by injured cells (H+, K+, arachidonic acid), plasma (bradykinin), blood cells (histamine, serotonin, opioids), sympathetic nerves (adenosine, neuropeptide Y, enkephalins, norepinephrine), and somatic nerves (substance P, calcitonin gene-related peptide [CGRP], nerve growth factor, excitatory amino acids, etc.). Excitatory substances sensitize or activate nociceptors, which become spontaneously active and develop exaggerated responses to painful and nonpainful stimuli. They also awaken silent nociceptors and promote a phenotypic shift of low-threshold fibers to nociceptive-like fibers. Inhibitory substances counteract sensitization and promote resolution of hyperalgesia parallel to wound healing. Division, crush, or constriction of a peripheral nerve [10] evokes a distinct spectrum of anatomic, neurochemical, and electrophysiological responses. The proximal end of a divided nerve degenerates, and approximately 15% of the neurons die. At the cut end of the nerve, regeneration leads to formation of a neuroma that contains relatively more C fibers than the normal nerve. At the site of a nerve lesion, unmyelinated fibers (as well as Aδ fibers) degenerate and regenerate, pain being related more closely to Aδ changes [19]. Abnormal contacts develop between all types of fibers in the neuroma [20]. Spontaneous and abnormal discharges originate at the site of injury [21] and in the dorsal root ganglion (DRG) [22]. Exaggerated responses are observed after mechanical or thermal stimulation of the nociceptors. Neurochemical consequences are prompted by the afferent barrage as alterations of the axoplasmic transport. There is also a hyper-responsiveness to catecholamines in the residual limb, which may explain complex regional pain syndrome (CRPS)-like activity sometimes seen in the residual limb [23–25]. It is debatable whether one can properly make a diagnosis of CRPS, as postamputation pain fails criterion 4 of the commonly accepted diagnostic scheme. Postamputation sympathetic dysfunction certainly occurs, but the clinical and pathophysiological significance of this observation is unknown. Many patients with this syndrome—as well as those with burning phantom pain—experience temporary relief of symptoms after sympathetic blockade. When such blocks permit a patient to undergo active physical or occupational therapy, the patient may experience long-term benefits. Central sensitization concerning spinal nociceptive neurons is well known. Excessive release of neuropeptides (substance P, CGRP, pituitary adenylate cyclase-activating polypeptide, vertical infraclavicular brachial plexus [VIP]) and excitatory amino acids (glutamate, aspartate) by nociceptive sensitized afferents leads to wind-up of spinal neurons, which exhibit an extended receptive field and exaggerated responses. Wind-up itself leads to sensitization [26], and thereafter to potentiation of synaptic efficacy [27], which is the basis for memory traces. Glutamate plays a pivotal role in the electrophysiological and biochemical changes occurring in spinal neurons [28]. α-Amino-3-hydroxy-5-methyl-4-isoxazoleproprionate (AMPA) receptor activation promotes depolarization, which relieves Mg++ block of NMDA receptors and allows an increase in intracellular Ca++ concentration. Metabotropic m-Glu R1 receptor activation, in conjunction with neurokinin receptor activation, further increases Ca++ levels and activates protein kinase C (PKC). Ca++ increase generates diffusible messengers, such as nitric oxide, and activates prostaglandin and kinase cascades. Ca++, CaMK, PKC, and cyclic guanosine monophosphate (c-GMP)-dependent kinase allow early and late gene expression. Opioid peptides (enkephalin and dynorphin), substance P, and galanin messengers RNAs are increased in the spinal cord, whereas CGRP and cholecystokinin (CCK) messenger RNAs are decreased [29,30]. These changes mean that during the early phase of sensitization, compensatory antihyperalgesic mechanisms are at work. NMDA receptor antagonists, and especially those acting as channel blockers (i.e., Mg++, dextromethorphan, memantine, ketamine), are effective in reducing secondary hyperalgesia resulting from excessive nociceptive stimulation [28], but exhibit less effect upon established synaptic potentiation. Opioids are effective in relieving nociceptive pain because of the decrease of CCK and the overexpression of opioid receptors [31]. Collateral sprouting of unaffected Aδ and C terminals extends into deafferented regions of the dorsal horn, whereas intact Aβ afferents exhibit only a negligible sprouting [32]. In the dorsal spinal horn, dynorphine immunoreactivity increases [33]. CCK receptors are increased, as well as AMPA receptors [34], whereas α2 adrenergic receptors are decreased, as are µ-opioid receptors [5]. In the DRG, Gap-43, VIP, neuropeptide Y, and galanin mRNAs increase, whereas CGRP and substance P mRNAs decrease in the early days after injury [2]. Later, large Aβ cells become able to express substance P and contribute to allodynia [6]. In the dorsal horn, the level of gamma-aminobutyric acid (GABA) increases [7], as do those of CCK and galanine. Opioid receptors [5] and α2 adrenoreceptors are likewise increased [9], as are glutamate receptors [8]. In addition to the peripheral and spinal mechanisms of sensitization and reorganization that underlie long-term pain after severe trauma, higher brain activities also undergo substantial adaptation after such injury. Mapping of the sensory homunculus by means of current, sophisticated approaches to brain imaging has clearly revealed marked alterations in patients after chronic pain of any origin. In patients with phantom limb sensations, this reorganization is even greater [16,17,35]. The amplitude of cerebral potentials (recorded in advance of conscious processing of sensory information) is increased in patients with chronic pain, consistent with an additional, cortical mechanism for increased sensitivity to painful stimuli. The exaggerated responses to painful stimulation are site-specific, in that patients with jaw pain, for example, are unusually sensitive to stimulation of the jaw but not to other sites. There are most likely changes in many parts of the brain aside from the sensory areas, including changes in the prefrontal cortex, anterior cingulate, and perhaps even efferent areas such as the hypothalamus. Studies during the past two decades have contributed a great deal to the understanding of symptoms in patients after landmine injury, particularly those who are left with painful stumps or phantoms. Yet, just as identical neurochemical or pathological changes do not uniformly produce pain in every patient, each phantom sensation need not be equated with a painful symptom. Virtually every adult amputee experiences phantom sensations in which the limb feels present, both in shape and, to some extent, in response to control. These sensations are so vivid for many new amputees that they have attempted to get out of bed and walk away soon after their injury. Although abundant animal studies document abnormalities that are structural (e.g., budding), functional (e.g., crossed or “ephaptic” synapse formation), and biochemical, such studies are virtually unavailable in humans. Clinical neurophysiological testing has detected a consistent decrease in blood flow in the residual limb before the onset of burning or tingling symptoms of phantom pain. In all cases studied to date (over 50), cramping phantom pain is invariably preceded by an increase in muscle tension in the residual limb. Patients with burning and shocking or shooting phantom pain do not show elevated muscle tension. An important aspect of sensitization is the occurrence of severe or prolonged pain after stimuli that normally would give rise to only mild or moderate pain (hyperalgesia). For example, bumping a toe that previously was stubbed commonly gives rise to pain that is exaggerated and prolonged in comparison with what would follow after stubbing an intact toe. The landmine victim who has an ongoing infection in the residual limb, which may have been partially amputated during the initial injury, thus experiences a confluence of sensitizing mechanisms in the peripheral and central nervous system. In such a person these processes can be a significant part of the disability, such as mild irritation from a poorly fitted prosthesis being experienced as unacceptably painful. Central sensitization may also account for the clinical observation of pain referred to the phantom from a visceral organ (e.g., the bladder), stump osteoma, hip arthrosis, or other source of pathology involving adjoining dermatomes. An example of a treatment-aggravated (iatrogenic) problem is the pain associated with tourniquets applied in the field to the damaged limb. Many hours or days may elapse before the tourniquet is released, once again producing pain from a combination of ischemia, tissue injury, and treatment-related crush injury to the nerve. Later in a patient's course, repeated local trauma from a poorly fitted prosthesis or improper use of crutches that press against the brachial plexus can produce local irritation and neuropathic pain. In sum, the combination of peripheral, spinal, and cerebral sensitization after brief, severe trauma occurs whether or not this trauma amputates a limb. The result is that subsequent stimuli to the damaged area, even those that are relatively innocuous, may provoke disproportionate sensory responses, including pain. For example, infection at a previously traumatized site commonly causes much more pain than if the site were previously intact. Subsequent amputation, particularly if delayed after hours or days of field conditions that may include early infection, may place the patient at risk for pain of disabling severity and duration. In such a patient, even after severe pain has subsided, subsequent mild insults, such as a poorly fitted prosthetic or a minor contusion, can lead to major setbacks from severe pain, often experienced as an exacerbation of phantom pain. In addition to these evoked phenomena, the clinical situation is often defined by the presence of spontaneous phantom sensation and pain. Careful examination and differential diagnosis are thus mandatory to distinguish the contributions of separate pathophysiological processes to the global report of phantom pain.