Neuropathic Pain : Pathophysiological Response of Nerves to Injury

”Normal,” “Inflammatory,” and “Neuropathic” Pain

Normally, pain is felt when signals originating in thinly myelinated (Aδ) and/or unmyelinated (C) nociceptive afferents reach a conscious brain. Examples are pinprick or a stubbed toe. The pain is always evoked by stimuli; spontaneous pain is not normal. The sensation felt (pain) corresponds in location, time, and quality to the stimulus (noxious) in the expected manner. This is “normal” (or nociceptive) pain.

In addition to evoking acute nociceptive pain, burns, abrasions, chemical irritations, and infections often cause more prolonged pain, both spontaneous and evoked by stimuli. Pain in response to weak, normally innocuous stimuli is “allodynia”; exaggerated pain in response to stimuli expected to be (moderately) painful is “hyperalgesia” ( ). In the case of allodynia, at least, tenderness in the “sensitized” tissue (pain) no longer corresponds to the stimulus (non-noxious). This type of pain is usually called inflammatory pain since it is typically accompanied by an immune response and mediated by pro-inflammatory molecules. It should be noted, however, that pungent substances such as capsaicin and (non-injuring) electrical shocks can provoke pain with these characteristics even though they do not damage tissue or elicit an immune response.

Neuropathic pain, like inflammatory pain, involves pathology; it is not “normal,” and it often features sensitization and allodynia and hence mismatch between stimulus (non-noxious) and response (pain). It differs, however, in that it is caused by a lesion or disease of the somatosensory nervous system itself. This distinction is not without problems. Pain from inflammation in a major nerve trunk (“neuritis”) is generally considered neuropathic. On the other hand, even minor trauma to skin, muscle, or joint always injures the terminal part of some nerve fibers. Despite the neuropathy present, however, such pain is rarely neuropathic. The reason is that except in rare cases, the minor neural injury is not the cause of the pain. Neuropathic pain is also distinguished from inflammatory pain by the frequent presence of unique sensory features such as electric shock–like sensations and hyperpathia.

Normal (nociceptive) pain and inflammatory pain are adaptive design features of the intact pain system—an alarm bell. Neuropathic pain, in contrast, reflects faulty, maladaptive functioning of a pain system that has been damaged. Consider a defective alarm system constantly producing false alarms. All three types of pain can and often do co-exist. For example, a space-occupying tumor may simultaneously apply noxious force to otherwise healthy tissue evoking nociceptive pain, trigger an inflammatory response, and directly injure nerves. The relationships among these different pain terms are illustrated in Figure 61-1 .

Sensitization

Sensitization by chemical substances, inflammation, and neuropathy may result from PNS and/or CNS processes. The classic explanation of tissue hypersensibility is the “sensitized nociceptor” hypothesis ( ). According to this hypothesis, hypersensibility is due to a reduction in the threshold of nociceptive sensory endings, such as in the skin (“peripheral sensitization”). This is probably the right explanation in the case of heat allodynia. Bradykinin and many other inflammatory mediators are known to cause thermosensitive nociceptors to respond to modest warming at temperatures normally too low to evoke pain. The result is “heat allodynia.” If the threshold falls below the ambient temperature, impulse firing and burning pain will appear to be spontaneous. Likewise, sensitized nociceptors show an exaggerated response to suprathreshold heat and mechanical stimuli, including de novo responses of previously insensitive C fibers ( ). This yields “heat and mechanical hyperalgesia.” However, the sensitized nociceptor hypothesis does not explain “tactile allodynia” i.e., pain evoked by light touch. The mechanical response thresholds of Aδ and C nociceptors rarely drop into the range that evokes tactile allodynia no matter what inflammatory mediator is applied ( ; ; ; ; ; ; , ). Rather, a considerable body of evidence indicates that tenderness to touch is signaled by low-threshold Aβ touch afferents, not sensitized nociceptors.

The radical idea that pain can be signaled by non-nociceptive low-threshold afferents comes from many observations. First and foremost is response time. If sensitized C-fiber nociceptors were to blame, there ought to be a long delay between the tactile stimulus and the pain, about a second for an inflamed finger (≈1-m conduction distance at ≈1 m/sec) and longer for an inflamed toe. One could argue that the immediate response actually experienced is due to sensitized Aδ nociceptors. However, one would then expect that each touch would evoke two volleys of pain, a rapid Aδ-fiber response and then a later C-fiber response (first and second pain). Tactile allodynia is a common, almost an everyday event, and a 1-second delay between stimulus and response could not be missed. Such delays do not occur ( ). A second argument is that sensitized nociceptors show only a small reduction in the tactile response threshold. As noted above, few if any come to respond to the light brush, touch, and air puff stimuli that evoke allodynic pain. A variety of additional observations involving afferent-selective nerve block, intraneural electrical stimulation, absence of flare, and others support the conclusion that the signal that evokes tactile allodynia is carried centrally by rapidly conducting, thickly myelinated, Aβ, low-threshold mechanoreceptive touch afferents ( ).

The existence of “Aβ pain” constitutes a revolution in our understanding of both inflammatory and neuropathic pain. Indeed, since tactile allodynia is an important cause of suffering and disability in patients with neuropathic pain, pain signaled by Aβ touch afferents may be as important as pain signaled by nociceptors. However, how can Aβ fibers, which normally evoke touch, come to evoke pain? This is due largely to altered central processing of the peripheral signal, or central sensitization ( ). Central sensitization, in contrast to peripheral sensitization, is not simply a threshold-lowering process. Indeed, in tactile allodynia there is no noticeable change in the response threshold of Aβ touch-sensitive fibers to touch stimuli. Moreover, the sensation that they evoke is not strong touch. It is pain. Rather than simply amplifying, central sensitization changes the modality of the response from touch to pain. This is accompanied by a corresponding change in the cortical areas activated ( ). A large variety of electrophysiological mechanisms have been proposed to explain this transformation. Examples include activation of previously blocked N -methyl- d -aspartate (NMDA)-type glutamate receptors, imbalance in chloride ion equilibrium, loss of inhibitory interneurons, activation of glia, and altered descending control. Mechanisms of central sensitization will not be discussed here, although the concept will be referred to frequently.

Ectopia

Neuromas, sprouts, and patches of dysmyelination are structural entities. Whether they contribute to pain depends on whether their formation is accompanied by the development of electrical hyperexcitability. In classic studies, electrophysiological recordings were made from sensory axons that terminate in an experimental nerve-end neuroma, and massive spontaneous discharge of impulses was observed. The firing was generated in the neuroma and was eliminated (transiently) by resection of the neuroma and by local anesthetic block of the nerve end. Likewise, it was enhanced by mechanically probing the neuroma ( Fig. 61-3 ; also see Fig. 61-2 ; ). Similar ectopic electrogenesis (ectopia), both spontaneous and evoked by stimuli, also occurs at mid-nerve locations such as neuromas-in-continuity, disseminated microneuromas, and sites of demyelination such as experimental entrapment neuropathies ( ). Subsequent research revealed ectopic spontaneous and evoked electrogenesis at additional pacemaker locations in injured nerves: in regenerating sprouts ( ); at sites of nerve inflammation (neuritis) ( ); in experimental diabetic polyneuropathy ( ); after viral infections ( ); after vincristine, taxol, and methylmercury intoxication ( ); and in hereditary demyelinating polyneuropathies ( ). The specific agent that causes neural injury may have some effect, but not a critical one. Pathophysiological discharge can emerge no matter how axons are injured.

In all these cases the discharge is “ectopic” because it originates away from the normal location of sensory impulse generation, the peripheral sensory ending. As expected, activity generated ectopically drives spinal and higher-order neurons in the CNS in the normal way. This has been confirmed by electrical recording, imaging, and the use of activity markers ( ). Note that the terms “ectopic” and “ectopia” do not imply that the abnormal discharge necessarily arises spontaneously. Discharge evoked by the application of stimuli at locations where impulse initiation does not normally occur, at the wrist in carpal tunel syndrome, for example, is also ectopic. With one known exception, heat ( ; ), natural non-traumatic stimuli applied at a mid-nerve location do not evoke impulse discharge or refered sensation. In the presence of neuropathy, however, they frequently do. Nerve injury triggers a fundamental change in the midportion of axons that renders them locally hyperexcitable and capable of ectopic electrogenesis.

Firing Rates and Patterns

Spontaneous ectopic discharge occurs in both myelinated (A) and unmyelinated (C) fibers, although with certain differences. Activity in A fibers tends to commence earlier, is found in a higher proportion of neurons at its peak, and is characterized by higher firing rates and more bursting than is activity in C fibers ( Fig. 61-4 ). In A fibers the ectopia is usually rhythmic; that is, there is a fixed interval between subsequent impulses within a train (usually 65–35 msec, which translates to an instantaneous discharge rate of 15–30 Hz). In many fibers the impulse train is interrupted by silent pauses, which results in a bursting, on–off pattern (“interrupted autorhythmicity”; see Fig. 61-3 ). The remaining A fibers, as well as most C fibers, fire in a slow, irregular pattern (0.1–10 Hz; ). Spike patterning, particularly bursting, can have an effect on post-synaptic neurons over and above the average firing rate by virtue of temporal summation of excitatory post-synaptic potentials during bursts ( ).

Different afferent types differ in their tendency to develop spontaneous firing or to become ectopically mechanosensitive. However, it is difficult to identify in which functional types ectopia preferentially develops. The problem is that axotomy disconnects the receptor ending from the rest of the axon. Heroic efforts are required to preserve information about the original receptor type over the many hours or days that elapse before ectopic firing begins. Partial information has been obtained from conduction velocity, from the ability to follow tetanic stimuli (the “marking method”), by comparing recordings from dorsal versus ventral roots, and from examination of cutaneous nerves versus nerves serving muscle, viscera, and other tissues. Injured sensory axons are much more likely than injured motor axons to generate spontaneous ectopic activity. Aβ and Aδ afferents are represented roughly in proportion to their numbers in the nerve. Interestingly, although injured cutaneous afferents frequently show ectopic mechanosensitivity without spontaneous firing, muscle afferents are more likely to fire spontaneously, at least after distal axotomy ( ). Perhaps this is because muscle nerves normally contain many tonic and slowly adapting afferent fiber types (muscle spindle afferents, proprioceptors). Neuroma end-bulbs and sprouts tend to develop the same sensitivities that they had before injury, presumably because of fiber type–specific gene expression at the level of the cell soma ( ).

Neurolysis As a Therapeutic Strategy

Since neuromas are an important source of painful ectopia, it seems logical that surgical resection or neurolysis should bring relief. Unfortunately, shortly after neuroma resection the same pathophysiological processes that caused pacemaker activity in the first place are re-engaged at the freshly cut nerve end, perhaps even in intensified form as a result of priming. Surgical mobilization of a neuroma to a site with a reduced likelihood of mechanical compression, however, may provide long-term relief in cases in which mechanosensitivity rather than spontaneous firing is the main problem (Campbell 2007). Different nerves behave differently. An incision for thoracotomy, for example, which frequently damages intercostal nerves, is much more likely than a comparable incision in the abdomen to be followed by neuropathic scar pain. For reasons that are not entirely clear, destruction of the tooth pulp in root canal treatment or tooth extraction does not commonly induce a painful neuroma. The same seems to be true of the intrinsic innervation of long bones. In hip replacement surgery, the femur is cut across and a prosthetic joint and bone cement are introduced into the bone marrow chamber. Yet despite the massive destruction of intrinsic bone afferent axons, the development of chronic neuropathic pain is infrequent. This suggests that pain relief might be achieved in patients with osteoarthritis by intrinsic denervation of the epiphyseal end of the bone, just as in dental root canal treatment ( ).

Microneurography in Humans

The method of percutaneous microneurography has extended observations on ectopia to awake humans, including those with neuropathic pain. It remains a research rather than a diagnostic tool, however, because of its technical difficulty and intrinsic risk. Practitioners have been justifiably reluctant to insert microelectrodes into already problematic nerves. Nonetheless, enough studies have appeared to make it clear that ectopic hyperexcitability occurs in patients as in nerve-injured animals and that it is a fundamental contributor to many clinical neuropathic pain conditions.

Not long after the first observations in animals, carried out a pioneering study in which they documented ongoing firing in the peroneal nerve in a lower extremity amputee who had ongoing phantom foot pain. Percussion of the neuroma evoked stabbing pain (the Tinel sign) and an intense burst of spike activity. The evoked bursts and the evoked pain were eliminated by local anesthetic block of the neuroma. Interestingly, however, much of the ongoing discharge persisted. The DRG is the most likely source of this persistent activity, but direct evidence of this in humans is still lacking. Subsequent microneurographic studies documented a direct relationship between ectopia and pain in a variety of other neuropathic conditions (e.g., ). For example, painful dysesthesia triggered by straight-leg lifting in a patient with radiculopathy (Lasegue’s sign) was accompanied by evoked ectopic bursts recorded in the sural nerve. The ectopic source was the injured spinal root or DRG ( ).

More recent studies have used the “marking method” to resolve activity in individual C fibers. The results provide evidence that the ongoing, often burning pain characteristic of many peripheral neuropathies is due to spontaneous discharge in C-fiber nociceptors ( ). Multiplet and burst firing, afterdischarge, and other interesting peculiarities of ectopia in animal models (below) have also been seen in patients, thus further strengthening the clinical relevance of the experimental models ( ). Other lines of evidence support these electrophysiological data. For example, pain is evoked by the application of substances known from animal preparations to excite ectopic pacemaker sites, including K ⁺ channel blockers and adrenergic agonists ( ). Likewise, blockers of ectopia such as local, regional, and systemic anesthetics suppress neuropathic pain ( ). Even the most severe pain, such as occurs in complex regional pain syndrome (CRPS), is reliably stopped by peripheral nerve or brachial plexus block, thereby permitting physiotherapy, albeit only for the duration of the block.

Animal Models of Spontaneous Pain

The foregoing observations leave little doubt that spontaneous ectopic discharge is a primary driver of spontaneous pain in humans. Spontaneous ectopia also occurs in neuropathy models in animals. Although this implies that the animals also experience spontaneous pain, proving it is not trivial. This issue is important because animal models are essential for screening novel analgesic drugs. This topic is discussed in more detail in Chapter 62 .

Spontaneously emitted behaviors such as vocalization, abnormal posture and gait, and unprovoked paw lifting occurs in neuropathy models and have been put forward as potential markers of spontaneous pain. However, follow-up study has failed to provide convincing support for this conjecture ( , Urban et al 2011). Instinctive behavioral biomarkers of spontaneous pain may not even exist in prey species such as mice and rats since they would signal vulnerability to predators and natural selection is likely to have excluded them. Convincing evidence for spontaneous pain is available from a conditioning paradigm in which animals were trained to show place preference for a chamber in which they were provided with analgesia ( ).

Autotomy behavior in the neuroma model provides another option ( ). This behavior has been validated as a biomarker of spontaneous neuropathic pain (anesthesia dolorosa) via a number of approaches ( ). For example, it is reduced by appropriate drugs, it is associated with prominent ectopia, augmenting the ectopia augments the autotomy, and suppressing it suppresses autotomy ( ). Recently, it has been shown that a gene variant that predisposes to autotomy in rodents is associated with neuropathic pain in humans ( ). Two other end points proposed recently also offer some hope: the coding of facial expressions in mice ( ) and a new procedure for tracking ultrasonic calls ( ).

Mechanosensitivity: Hot Spots, Trigger Points, and the Tinel Sign

Exploring the surface of an injured nerve with a fine probe reveals clusters of tiny mechanosensitive “hot spots.” They do not occur in normal nerves. Such probing excites silent axons and also accelerates discharge in already active ones ( Fig. 61-2 A and B). Spontaneous and evoked discharges almost certainly arise from the same cellular locus and pacemaker process ( ). Mechanosensitivity underlies the Tinel sign, the often stabbing or electric shock–like dysesthesia evoked by percussion of neuromas, along nerves in painful diabetic neuropathy, and in carpal tunnel syndrome, and it is responsible for the shooting leg pain in sciatica ( ). Like normal mechanosensitive endings, hot spots typically respond either with a short spike burst at the onset and/or release of a stimulus or with sustained firing for the duration of application of the force (rapid and slow adaptation). Interestingly, however, in some hot spots firing persists beyond the end of the stimulus (“mechanical afterdischarge,” Fig. 61-6 A). In effect, the brief stimulus triggers a period of spontaneous firing. This clearly abnormal pattern accounts for the frequent persistence of evoked sensation in neuropathy ( ). Locations where nerves run adjacent to tendons and bone (e.g., the carpal tunnel) or where small nerve branches cross tough fascial planes are particularly at risk for sustaining focal trauma and developing ectopic mechanosensitivity. Pain evoked at such trigger points by local palpation, weight bearing, and untoward movements may represent a neuropathic contribution to chronic musculoskeletal pain, perhaps including fibromyalgia.

Ectopia and Tactile Allodynia

Tactile allodynia, unlike hyperalgesia and tender points, is probably not a result of excessive mechanosensitivity of nociceptive sensory endings for reasons noted above (under Sensitization ). Even though tender collateral sprouts and intradermal disseminated microneuromas may well contribute, the major cause of tactile allodynia is thought to be spike activity in Aβ touch afferents processed by sensitized spinal cord circuitry. Here too, however, spontaneous ectopia in the periphery plays a crucial role: it induces and maintains the central sensitization. Thus, tactile allodynia results from pathophysiology in the PNS and in the CNS. Note that the sensory effect of spontaneous ectopia in Aβ fibers is also exacerbated by central sensitization, thereby adding to the spontaneous pain. Finally, central sensitization may amplify the sensory consequences of spontaneous and evoked activity in at least some types of nociceptors ( ).

In Figure 61-7 the sequence of events believed to underlie the tactile allodynia in neuropathy is illustrated by using the spinal nerve ligation model of neuropathic pain ( ). In this model the L5 (or L5–6) spinal nerve is cut; about half the afferents in the sciatic nerve are severed and the hindpaw is partially denervated. Cutting the nerve creates two permanent sources of spontaneous ectopic activity, the L5 spinal nerve-end neuroma and the L5 DRG. “Uninjured” nociceptors in the L4 segment may also contribute. This activity drives central pain pathways and also triggers central sensitization, hence augmenting spontaneous pain and inducing allodynia.

Corresponding observations have been made in patients. For example, observed that when a focal source of ectopia from an old scar was identified and blocked with local anesthetic, not only was the focal pain temporarily eliminated but also the widespread allodynia that the patient suffered. The same principle is also relevant to conditions such as migraine and visceral and musculoskeletal pain ( ). The focal impulse source dynamically maintains central sensitization. Remove it and hypersensibility fades, usually within minutes or at most a few hours.

Exacerbation of Ectopia by Temperature and by Chemical Mediators

Cold intolerance and cold allodynia are common symptoms in neuropathy; people who live in cold climates suffer in particular during the winter ( ). On the other hand, in some conditions, notably CRPS, patients may obtain relief by wrapping the painful limb in a cold, wet towel. This difference might reflect which primary afferents are involved ( ). Ectopic activity in C fibers tends to be excited by cooling and suppressed by warming. Collateral sprouts (which derive mostly from C fibers) and many intradermal disseminated microneuroma endings are therefore expected to be hypersensitive to cold and to provoke pain when the skin is cooled. In contrast, ectopia in A fibers is enhanced by warming, whereas cooling suppresses it. If the pain in CRPS were primarily due to Aβ fibers, this could explain why cooling provides some relief in this condition. As discussed below, the abnormal sensitivity of injured axons reflects altered regulation and trafficking of ion channels and receptors, including thermoresponsive transient receptor potential (TRP) channels. This varies with fiber type ( ).

In addition to temperature, metabolic stress and a wide array of chemical factors can also depolarize sensory neurons and directly excite discharge at ectopic pacemaker sites in neuropathy. All these factors can also sensitize pacemaker sites and make them hyper-responsive to mechanical and other stimuli. Examples include tissue ischemia and hypoxia, changes in blood gases, elevated blood glucose, altered ion concentrations, and numerous endogenous neuroactive substances, including catecholamines, adenosine triphosphate (ATP), nitric oxide, peptides, cytokines, small lipids, neurotrophins, histamine, bradykinin, prostaglandins, TNF-α, and many other pro-inflammatory mediators ( ). New mediators continue to appear regularly, which suggests that the current inventory is far from complete. The chemical milieu of afferent neurons is a major factor in ectopia and neuropathic pain, but only if ectopic pacemaker capability has developed first.

Systemic and Focal Inflammation (“Neuritis”)

In Guillain-Barré syndrome (GBS) and related inflammatory polyneuropathies, nerves suffer widespread myelin destruction and axonopathy as a result of autoimmune attack. This causes paralysis and sensory loss. However, as in other forms of neuropathy, these negative symptoms are often accompanied by dysesthesias and ongoing pain ( ). Membrane remodeling and pain behavior have been documented in the animal model of GBS (experimental allergic neuritis), and ectopic hyperexcitability is probably present in this model ( ). There is direct electrophysiological evidence that ectopic hyperexcitability occurs at sites of focal nerve inflammation. In the chronic constriction injury model of neuropathic pain, for example, chromic gut ligatures are applied loosely to the sciatic nerve. This causes local inflammation and nerve swelling, which partially strangles the nerve ( ). Variants of this model include focal constriction of trigeminal nerve branches and compression of dorsal root and trigeminal ganglia ( ). Such injury causes frank destruction of many axons, focal demyelination of others, and the release of inflammatory mediators.

Peripheral nerve injury also triggers an inflammatory reaction in associated ganglia, including activation of intrinsic glial cells and attraction of invasive immune cells. An inflammatory milieu contributes to the development of ectopic firing at both the nerve injury site and the ganglia, with consequent spontaneous pain and hypersensibility ( ). The animal constriction and compression models emulate the many clinical conditions that feature focal neuropathy exacerbated by inflammation. Among these are carpal tunnel syndrome, disc herniation with sciatica, and solid tumors that press on nerves. Indeed, a contribution of inflammation in conditions involving neural trauma may be the rule rather than the exception.

There is also tentative evidence that inflammatory mediators might be able to act on mid-nerve fibers directly without concurrent (structural) neuropathy. Specifically, it has been reported that when TNF-α or complete Freund’s adjuvant is applied to the surface of healthy nerves or DRGs, a focus of spontaneous firing and mechanosensitivity may emerge rapidly ( ). By inference, in systemic and focal inflammatory and toxic neuropathies in which there is minimal concurrent nerve trauma, widespread pain might result from the direct action of inflammatory mediators on midaxon and intraganglionic receptors.