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25 Neuropathic Pain Syndromes

25 Neuropathic Pain Syndromes
The Massachusetts General Hospital Handbook of Pain Management

25
Neuropathic Pain Syndromes

John D. Markman and Anne Louise Oaklander

It is evidently impossible to transmit the impression of pain by teaching, since it is only known to those who have experienced it. Moreover, we are ignorant of each type of pain before we have felt it.
—Galen (A.D. 129–199)

I. Definitions and nosology
II. Mechanisms of neuropathic pain

1. Mechanisms involving peripheral neurons

2. Mechanisms involving central neurons
III. Clinical presentations and syndromes

1. Cardinal clinical features

2. Associated clinical features
IV. Specific neuropathic pain syndromes

1. Peripheral neuropathic pain syndromes

2. Central pain syndromes
V. Diagnostic evaluation of patients with neuropathic pain

1. History

2. Examination

3. Imaging

4. Diagnostic local anesthetic nerve blocks

5. Electrophysiologic studies

6. Histologic evaluation of sensory nerves by biopsies of skin or sural nerves

7. Laboratory markers of neuropathic pain
VI. Treatment of neuropathic pain

1. Tricyclic antidepressants

2. Anticonvulsants

3. Opioids

4. Topical agents

5. Adjunctive treatments

6. Invasive options
VII. Conclusion
Selected Readings

Neuropathic pain arises from injury to the sensory nervous system. In contrast to acute pain, a beneficial response that safeguards tissue integrity, neuropathic pain is pathologic and can produce devastating disability. It occurs when an abnormal somatosensory system chronically transmits pain signals in the absence of tissue injury. Neuropathic pain syndromes can originate at any point or points along the somatosensory pathways, from the most distal nerve endings in the skin to the somatosensory cortex of the parietal lobe. The cardinal clinical feature of neuropathic pain syndromes is chronic pain associated with abnormalities of sensation.
The causes of neuropathic pain are diverse. In clinical practice, these syndromes are defined by their common symptom pattern, by their neuroanatomic localization, and sometimes by etiology. The discrepancy between the severity of the pain and the lack of objective evidence of injury or neurologic damage can make these syndromes uniquely disabling. Neuropathic syndromes are perhaps the most formidable treatment challenge for pain specialists.
I. DEFINITIONS AND NOSOLOGY
Acute pain is an adaptive response necessary for the preservation of tissue integrity. The reflexes and emotions induced make it almost impossible not to withdraw one’s finger from the flame. Loss of normal pain sensation through disease results in potentially lifethreatening tissue injuries. Chronic pain is different. It is pain that has outlived its usefulness. When pain stems from ongoing tissue damage, as in the arthritides or with tumor-related pain, it is called nociceptive pain. The persistent pain is from an intact sensory system that is registering ongoing stimulation.
In neuropathic pain, there is sustained transmission of pain signals in the absence of ongoing tissue injury. The primary injury is to the sensory nervous system. Neuropathic pain is pathologic pain. This definition is based on the location of the primary pathology, and is independent of its cause. The presence of perturbations of somatosensory function (Fig. 1) hints at the presence of neuropathic pain. Of these, by far the most common is the presence of numbness, or hypoesthesia. Patients comment that they paradoxically feel numbness, or decreased sensation, in their area of maximum pain. Pain thresholds can be lowered—hypoalgesia—or raised—hyperalgesia. Paresthesias, or a pins-and-needles sensation, are a positive sensory phenomenon suggestive of neuropathic pain. Patients sometimes use the word numbness to describe paresthesias, so the terminology can require discussion.

Figure 1. Graphic representation of perturbations of somatosensory function associated with pathologic pain states.

Some neuropathic pain patients perceive pain from an innocuous stimulus, such as light touch. This aberrant response is allodynia. Mechanical allodynia is the greatest handicap, and some patients go to extreme lengths to avoid having their neuropathic area touched (Fig. 2). Pain may be experienced from contact with clothing, bed sheet, or even a breeze. Patients with trigeminal neuralgia may not be able to shave areas of their face, and intraoral allodynic areas can interfere with eating and cause potentially dangerous weight loss or malnutrition. Some women with postherpetic neuralgia (PHN) on the torso are unable to wear a brassiere, and some patients are unable to tolerate wearing clothes over the affected area. Patients with distal painful neuropathies sometimes hang their feet over the edge of their bed to avoid the bedclothes. Many patients describe worsening of their pain in cold weather. This may reflect a component of cold allodynia. Cold allodynia interferes with walking barefoot for some, and warmth allodynia prompts some patients to carry ice bags or fans to continually cool the painful area.

Figure 2. Some patients go to extreme lengths to avoid having their neuropathic area touched. This man has postherpetic neuralgia and has cut his T-shirt in half because of allodynia.

II. MECHANISMS OF NEUROPATHIC PAIN
Neuropathic pain is associated with abnormalities in the nociceptive neurons that transmit and process pain messages. Identical symptoms can be produced by lesions at different levels of the neuraxis, ranging from the peripheral sensory neurons to the highest levels of cortical processing. It is unequivocal that ongoing neuropathic pain is generated by electrical hyperactivity of neurons along the pain pathways. Unfortunately, it is still unclear where the major site(s) of the electrogenesis are located in the different types of pain syndromes. The impetus for unraveling the complex mechanisms of neuropathic pain is the hope of enabling the development of new classes of medications with greater effectiveness and fewer side effects than those currently available. The following is a brief list of the mechanisms currently thought to contribute to clinical neuropathic pain syndromes. As this is an area of active research, the list is sure to be quickly outdated.
1. Mechanisms involving peripheral neurons
(i) Primary sensitization of nociceptive nerve endings
Many (if not most) nociceptors are electrically silent under normal conditions and activate only under conditions of local injury or inflammation (e.g., after burn). Nociceptors have receptors for protons, histamine, bradykinin, and many other inflammatory mediators. Activation of these receptors makes the nociceptor electrically hyperexcitable and induces it to fire after stimuli that would not normally trigger an action potential. Primary sensitization plays a critical role in acute pain by motivating individuals to protect an injured area from further use and potential worsening. It has been conjectured that sustained primary sensitization also contributes to neuropathic pain, but the experimental evidence is weak. It appears likely that peripheral sensitization is much less important for neuropathic than for nociceptive/inflammatory pain.
One area of active investigation is whether sensitivity to molecules released by effector axons contributes to neuropathic pain syndromes. For instance, injured nociceptive nerve endings can develop sensitivity to epinephrine and norepinephrine released by nearby autonomic neurons. The clinical contribution of this phenomenon to pain is not yet clear. Loss of a proportion of the axons innervating a target may alter the local environment in a way that favors abnormal signal transduction by the axons that remain.
(ii) Ectopically generated or propagated action potentials within damaged nerves
Normally, the mid axon is insensitive to the stimuli that trigger action potentials in the periphery. In the event that axons are transected by illness or injury, the molecules that transduce sensory action potentials are still inserted into the distal-most portion of the axon, which is now no longer at the periphery. Thus, damaged nerves can acquire the ability to generate ectopic action potentials that contribute to neuropathic pain. In its most florid form, palpable neuromas form. These consist of tangles of axonal sprouts that have not been able to find a distal nerve stump through which to reinnervate their target and are entrapped in connective tissue. Neuromas can be extremely sensitive to mechanical stimuli. Thus, any pressure or movement can trigger paroxysms of pain. Although some neuromas can be treated medically, some require surgical resection, with burial of the new proximal nerve stump deep in muscle, or in a deeper tissue less likely to be jostled. Occasionally, several surgeries must be performed as new painful neuromas reform.
Even in the absence of a palpable neuroma, injured painful nerves can contain distal ends of axons attempting to regenerate. Neurosurgeons trace the rate of progression of axonal regrowth after a nerve injury by mapping the location of Tinel’s sign (painful paresthesias elicited with percussion over the hypersensitive ends of regenerating axons). Occasionally, a pain syndrome that develops after a nerve injury may remit as the hypersensitive axon sprouts finally reach their end-organ target. This can take months or longer because of the slow rate of axonal growth (about 1 mm/ day at best). Axonal sprouting varies by disease pathophysiology, so this mechanism does not always play a significant role. Nonneuronal cells such as Schwann cells, macrophages, and mast cells secrete cytokines and other inflammatory mediators that may damage or sensitize axons and contribute to aberrant firing.
(iii) Abnormal electrogenesis within the sensory ganglia
The cell bodies of most sensory neurons are another site where it is possible to generate action potentials. Spontaneous potentials have been recorded from healthy neurons, and the frequency of these action potentials increases under conditions of illness and injury. Sensory neuronal cell bodies are exposed to the extraneural environment since most ganglia lack a blood–nerve barrier. Normally, they are protected from mechanical stimuli by their proximal location between the vertebrae. However, it is easy to imagine that they might get compressed under conditions of spinal osteoarthritis or other degenerative conditions.
2. Mechanisms involving central neurons
(i) Loss of input from peripheral nociceptors into the dorsal horn of the spinal cord
Some conditions cause frank death of sensory neurons, with degeneration of both the central and the peripheral axons. The most common such condition is shingles, but sensory neuronopathies also occur in autoimmune disease. These conditions eliminate or reduce electrical input from the peripheral sensory neurons into the central nervous system (CNS). Peripheral input can also be lost in diseases that result in truncation of sensory axons (sensory neuropathies). Most distal axonopathies affect the central axon as well as the peripheral one and result in disconnection of the peripheral afferent neuron from its central target. A decrease in peripheral input has a marked impact on the second-order sensory neurons within the spinal and trigeminal dorsal horn, and probably on higher-order neurons as well. Trophic molecules such as nerve growth factor are synthesized in the peripheral tissues, internalized into sensory axons, and transported into the spinal cord, where they profoundly influence the gene expression of these target neurons.
In general, dorsal horn neurons that are deprived of peripheral input become electrically hyperexcitable. They fire spontaneously, and at maximal rates in response to submaximal stimuli. These mechanisms probably evolved to maintain homeostasis under circumstances of mild or moderate loss of peripheral input, but under severe conditions, they contribute to the problem rather than the solution. In its most extreme form, spontaneous activity in deafferented central sensory neurons contributes to phantom limb pain.
(ii) Ephaptic sprouting within the dorsal horn
Since neurons abhor a vacuum, when presynaptic inputs from the periphery are lost, other nearby neurons send in sprouts and begin to influence the behavior of the injured central neuron. As remaining peripheral neurons send sprouts into areas vacated by the degenerating axons, the receptive fields of these postsynaptic dorsal horn neurons expand. Stimuli from areas outside the zone of the original injury become capable of eliciting pain. A related mechanism that has been described in animals is the sprouting of peripheral neurons that normally transmit messages of light touch, onto second-order neurons that transmit pain messages. This “mixing” of signals may explain the allodynia (pain triggered by light touch) that is common in neuropathic pain. Since allodynia has also been described after lesions wholly within the brain, this aberrant sprouting may also be possible at centers higher than the dorsal horn.
(iii) Central sensitization
Prolonged pain signals arriving from peripheral nociceptors induce molecular changes within even normal dorsal horn projection neurons. There is even some evidence that these “pain memories” can last for years. The contribution of central sensitization to neuropathic pain is hard to assess, since electrical hyperexcitability is also induced by loss of peripheral neurons.
(iv) Loss of inhibitory interneurons
Primary sensory neurons influence second-order neurons not only by direct synapses but also indirectly via inhibitory interneurons. These interneurons, which often use gamma-aminobutyric acid (GABA) or glycine as neurotransmitters, are excited by synapses from peripheral sensory neurons, and then form pre- and postsynaptic inhibitory synapses on second-order projection neurons. Since the indirect synaptic pathway involving interneurons is slightly slower than the direct synaptic pathway, the indirect pathway helps bring action potentials of the second-order neurons to a rapid halt. These inhibitory circuits also limit the number of second-order neurons excited by a single primary afferent. There is evidence that these interneurons preferentially die under conditions associated with the development of neuropathic pain. Administration of oral or intrathecal baclofen is an attempt to restore a more normal “inhibitory tone” within the dorsal horn (and potentially higher centers as well).
(iv) Mechanisms at higher centers
Much less is known about the more rostral mechanisms of pain. Functional imaging studies have shown that pain is processed in widespread areas of the brain. Ascending pathways from the lateral spinothalamic tract send collaterals to the periacqueductal nuclei of the brain stem before synapsing within the thalamus. Thalamic output radiates widely to the post-central gyrus and anterior cingulate gyrus, as well as other areas of the brain. Central neuropathic pain, originally associated exclusively with the thalamus, has been demonstrated after lesions affecting any part of the central nociceptive pathways. The ventral and posterior portions of the thalamus are particularly involved in pain processing, and electrical hyperexcitability has been demonstrated during recordings from patients with neuropathic pain.
Functional imaging has confirmed that sprouting of neighboring intact neurons into areas vacated by the death of neurons accounts for some of the bizarre features observed in some patients with neuropathic pain. This has best been studied in patients with phantom pain after loss of an innervated body part. For instance, some patients can induce pain in an amputated arm by stroking around their mouth. On the cortical somatosensory homunculus, the mouth area is immediately adjacent to the region that normally receives input from the hand. When innervation from the hand is lost, incoming sensory axons that normally subserve the mouth may sprout into empty synapses within the hand cortex. The finding of these types of phenomena early after injury has suggested that there may be unmasking of normally present but functionally silent synapses.
III. CLINICAL PRESENTATIONS AND SYNDROMES
1. Cardinal clinical features
The clinical spectrum of neuropathic pain ranges from barely noticeable to severely disabling. Certain clinical features are present in many neuropathic pain patients regardless of etiology, mechanism of injury, and location of nerve injury. These features are:

Ongoing (or stimulus-independent) pain described as “burning,” “aching,” “crushing,” or “gnawing”

Stimulus-evoked pain (allodynia), especially to mechanical stimuli

Lancinating pains described as brief severe jolts of pain, sometimes called electrical or lightning pains, which can be spontaneous or stimulus evoked
To some extent, these features are common to almost every clinical pain syndrome. Patients with painful neuropathies may complain most of ongoing pain in the feet, whereas allodynia may be the major concern of a patient with PHN. Trigeminal neuralgia is known for severe lancinating pains, which can be provoked by an allodynic stimulus to a trigger zone on the face. However, questioning will reveal that most patients have also experienced the other cardinal features of neuropathic pain at some time during their illness.
Most of us have transiently experienced mechanical and thermal allodynia after sunburn. Patients with mechanical allodynia go to great lengths to avoid having the affected area touched by other people, bedclothes, or clothing. The allodynia might be so severe as to result in disuse of the affected area. Severe sensory abnormalities frequently occur without visible signs of damage, so patients often find it difficult to convince others of the severity of their disability.
2. Associated clinical features
Although they are not always present, other types of neural damage can occur in these patients. Since different types of neurons are mingled together within the central and peripheral nervous systems, damage the nociceptive pathway can affect other systems as well. Patients with damage to motor pathways can have abnormalities of muscle tone, bulk, and strength. The presence of objective motor signs can be helpful in making the diagnosis of neuropathic, rather than nociceptive, pain. It can be helpful to look for occult motor involvement, for instance, with electromyographic (EMG) examination, if the cause of a patient’s pain remains obscure. Increased tone in the affected area is suggestive of a central lesion, such as from stroke, whereas peripheral lesions, such as compressive radiculopathies or nerve injuries, can reduce tone. Sometimes, only minor motor symptoms, such as a tendency to muscle cramps, are present. Of course, disuse of a painful limb can lead to secondary motor changes as well. Occasionally, the motor damage is primary, and the pain is produced by abnormal muscle tone, as in the focal, segmental, or generalized dystonic syndromes.
Autonomic abnormalities are not rare in neuropathic pain syndromes, and they have inspired much confusion and speculation as to their role in the primary pathogenesis of the pain [e.g., sympathetically maintained pain, complex regional pain syndrome I (CRPS-I)]. Fortunately, it is now better appreciated that most neural structures contain autonomic as well as somatic neurons, and that these autonomic fibers are vulnerable to damage by the same lesions that damage the somatic pathways. For instance, a nerve injury that produces CRPS is likely to disrupt the sympathetic fibers that regulate vascular tone that course within the same nerve. Damage to these axons produces changes in color and temperature in the affected tissues, and it can cause swelling due to abnormal leakage of intravascular fluid. Similarly, the growth of skin, hair, nails, and other cutaneous structures can become abnormal if innervation is disrupted.
Patients with painful neuropathies frequently have autonomic damage as well. All such patients should be queried about symptoms such as orthostatic hypotension, impotence, delayed gastric emptying, abnormal sweating and/or thermoregulation, and difficulties with elimination. Occasionally, cardiac arrhythmias are present that require medical or surgical treatment.
IV. SPECIFIC NEUROPATHIC PAIN SYNDROMES
1. Peripheral neuropathic pain syndromes
(i) Painful polyneuropathies
The majority of neuropathic pain syndromes affect the peripheral nerves, at least at their onset. Because peripheral nerves contain motor and autonomic fibers, pain is often accompanied by changes in the functions subserved by these components during the course of the syndrome. Motor symptoms typically include weakness and affect the distal muscles, often the extensor groups. Sensory disturbance is confirmed on examination by loss of pinprick, temperature, and vibratory perception. Painful peripheral neuropathies may be classified by etiology, distribution, and pathology. The diagnostic workup includes a thorough history to ascertain the cause, including questions regarding systemic illnesses, nutritional deficiencies, family history, and potential injury.
Painful sensory neuropathies can be associated with systemic disorders such as diabetes mellitus, alcohol abuse, amyloidosis, rheumatoid arthritis, malignant cancers such as oat cell carcinoma, and benign monoclonal gammopathies (IgG, IgA, and IgM). The chronicity of the specific disease process is an important factor. Most inherited neuropathies, such as the hereditary motor and sensory neuropathies, and neurofibromatosis are less commonly associated with neuropathic pain because of their predilection for non-nociceptive neurons. Fabry’s disease is a painful inherited sensory neuropathy associated with loss of almost all nociceptive nerve endings in the skin. Some painful small-fiber neuropathies of unknown cause (idiopathic) are present in multiple family members and undoubtedly have genetic causes that await investigation. Other acquired neuropathies are those related to toxin and drug exposure, some of which produce painful neuropathies.
The distribution of neuropathies can be generalized and symmetrical, asymmetrical, multifocal, or focal. The symmetrical generalized polyneuropathies commonly affect sensory and motor modalities in a distal-to-proximal gradient. Neuronal dysfunction is first reported in the extremities, the distal portions of the longest axons. So the earliest symptoms of axonal neuropathy are those of the autonomic and small-fiber sensory modalities. Loss or alteration of pain and temperature perception due to injury to the unmyelinated or thinly myelinated axons can herald more global deficits.
Diabetic neuropathy affects up to 15% of the 5 million patients with diabetes mellitus. It may be the most common peripheral polyneuropathy in the United States. Pain can be due to damage at many levels of the nervous system, but the small nerve fibers are disproportionately affected. The symmetrical, small-fiber neuropathy associated with diabetes mellitus presents with “burning feet” and autonomic features of impaired thermoregulation and sweat production. Neuropathy and vascular insufficiency are the main risk factors for diabetic foot ulcers and amputation.
In patients with painful diabetic polyneuropathy, pathologic studies demonstrate loss of both myelinated and unmyelinated fibers. Demyelination can be present as well. Endoneurial vascular damage, insufficient neurotrophic support, and autoimmune inflammation may all contribute. Diabetes mellitus is associated with other types of peripheral neuropathies, including proximal motor neuropathies (diabetic amyotrophy), autonomic neuropathies, vulnerability to compressive lesions, acute painful neuropathies from nerve ischemia, hypoglycemic neuropathy, treatment-induced neuropathy, and distal motor neuropathies.
Patients with multifocal neuropathies (mononeuropathy multiplex) usually develop focal loss of function in several peripheral nerves. The pathologic basis of these syndromes is usually ischemic with infarction of the vasa nervorum. Prognosis for recovery is favorable if the underlying cause of the infarction can be addressed. Systemic lupus erythematosus, rheumatoid arthritis, cholesterol emboli, and polyarteritis nodosa as well as diabetes mellitus can cause this pattern.
(ii) Painful mononeuropathies
Isolated focal peripheral nerve lesions are most commonly caused by trauma. Although accidents are the most common cause, iatrogenic injuries due to surgery or needlestick are a close second. Since a proportion of accidents occur on the job, or from participation in sports, these patients are likely to be young, in their most productive years, and they are often male. Nerve injuries may not be diagnosed at the time of the initial accident, since they are not visible on radiographs, and medical attention usually focuses on more obvious injuries. Nerve lesions affecting predominantly sensory neurons and producing pain as the major symptom are less likely to be diagnosed than those that produce frank motor deficit as well. Such delays in diagnosis are unfortunate, as some peripheral nerve injuries benefit from early surgical nerve repair. Furthermore, failure to diagnose a nerve injury can result in repeated surgeries if the pain is erroneously attributed to other causes.
Patients without a history of trauma or surgery usually have internal entrapment, compression, or nerve ischemia. Chronic nerve entrapment injury can be associated with rheumatic disease, diabetes mellitus, uremia, repetitive use, or malnutrition, or can occur in otherwise healthy individuals.
The hallmark of nerve injuries is that the pain is primarily in the distribution of a particular peripheral nerve or branch. The most useful aid to diagnosis is to ask the patient to outline on their body the area of worst pain. Often, this corresponds to the innervation territory of a specific nerve or branch. However, the clinical picture can be confusing since the pain can spread widely, outside traditional nerve territories. Most often, this is because C fibers trifurcate within the substantia gelatinosa on entry to the spinal cord. They send collateral axons approximately two segments up and down the cord, so that lesions of single nerves can be expected to produce more-widespread effects. Additionally, loss of afferent input into the spinal cord causes ectopic axonal sprouting that serves to enlarge the receptive fields of spinal pain-processing neurons. Interestingly, a few of these patients develop bilateral pain with contralateral pain in the area immediately opposite the nerve injury.
A common focal neuropathy is carpal tunnel syndrome. This causes pain, and in severe cases weakness, of the medianinnervated thumb and forefinger. Another common entrapment lesion is meralgia paresthetica. This presents as intermittent pain along the anterior thigh. It is caused by entrapment of branches of the lateral femoral cutaneous nerve as they pass beneath the inguinal ligament. It can be worsened by obesity or pregnancy. Saphenous nerve injury may produce pain in the knee joint and/or medial surface of the lower leg in the setting of prior knee surgery or arthroscopy. Virtually any nerve, branch, or twig containing sensory neurons can be entrapped with resultant neuropathic pain.
Clinicians should evaluate these patients with the aid of a handbook that demonstrates the individual nerve territories. Stewart’s textbook Focal Peripheral Neuropathies is an invaluable resource for diagnosing these syndromes. Occasionally, it is helpful to refer patients with difficult-to-diagnose syndromes for evaluation by a neurologist or neurosurgeon with subspecialty training in peripheral nerve injury.
(iii) Painful neuronopathies
Painful neuronopathies are injuries that are centered on the neuronal cell body. For somatosensory neurons, these are in the dorsal root ganglia, and in the trigeminal (Gasserian) ganglion for axons innervating the face. Sensory neuronopathies can occur from shingles, as paraneoplastic syndromes, and as part of Sjögren’s syndrome. In two thirds of patients with paraneoplastic syndromes, the sensory neuronopathy precedes the discovery of the malignancy. An important clue that points to a neuronal rather than an axonal process is that the first manifestations may not involve the neurons with the longest axons (in the feet) as is usual with axonopathies. The onset is usually rapid and associated with burning dysesthesias or paresthesias. Areflexia may ultimately result from this syndrome because of loss of the afferent limb of the monosynaptic reflex.
With over 850,000 cases in the United States annually, acute herpes zoster is by far the most common sensory neuronopathy. Both herpes zoster and PHN disproportionately affect the elderly. Fifty percent of patients over age 60 with zoster will experience PHN. Suppression of cell-mediated immunity often associated with advancing age or concurrent medical illness permits latent varicella-zoster virus (VZV) to erupt into shingles. The dermatomal distribution and vesicular rash are the clinical signatures of VZV reactivation in the dorsal root ganglia. The thoracic segments are the most commonly affected. The next most common site is the ophthalmic division of the trigeminal nerve. The pain is described as burning, often associated with itching and volleys of lancinating pain. The diagnosis of PHN requires the persistence of pain 3 months after the initial rash. Over time, the distribution of pain symptoms can widen to involve adjacent dermatomes.
Shingles causes neuropathic pain syndromes affecting every area of the body including the limbs and genitals. These areas are vulnerable to motor and autonomic abnormalities as well, and adjunctive therapies may be needed. PHN is rarely present after shingles with an absent or inapparent rash (zoster sin herpete ).
Acute zoster produces a mixed inflammatory/nociceptive and neuropathic pain syndrome that is present in the peripheral nerves, dorsal root ganglia, and spinal cord. Early treatment with antiviral medications (acyclovir, famciclovir, or valacyclovir) shortens and lessens the symptoms of zoster and decreases by about one half the likelihood of progressing to PHN. Antiviral therapy should be used in virtually all shingles patients, and it should be instituted as soon as possible. Early and aggressive pain control with tricyclics and opiates is also helpful in decreasing the likelihood of long-term PHN.
Clearance of myelin debris can take more than 1 year within the CNS, but the inflammation of acute zoster eventually subsides in most patients. Those left with PHN experience neuropathic pain. PHN is an excellent model of neuropathic pain and has been the subject of many research studies. Evidence from psychophysical studies and examination of nerve endings within skin biopsies suggests that in many cases there is severe loss of cutaneous innervation, especially nociceptive innervation, in PHN-affected skin.
(iv) Amputation
Pain often remains a major problem following amputation. Although best described after limb amputation, these syndromes can occur after a wide variety of amputations, including mastectomy and removal of visceral organs such as the rectum. Several different mechanisms can cause pain in these patients. Stump pain is pain perceived proximal to the site of amputation. It can have several causes, including skin breakdown or infection, vascular insufficiency, excess pressure by a prosthesis, or mechanical causes. Sectioned nerves can form painful neuromas.
Phantom pain, in contrast, is perceived distal to the site of the amputation. The most important initial question to ask amputees complaining of pain is whether the pain is proximal or distal to the amputation. Pain is only one of many phantom sensations that can be experienced by amputees. Patients in pain before their amputation (e.g., from infection or injury) may experience precise “memories” of their earlier pain. Although incompletely understood, these phantom sensations are thought to result from spontaneous electrical activity in central sensory neurons that are deprived of their normal afferent input.
2. Central pain syndromes
Neuropathic pain of central origin was originally described after thalamic injury, but these syndromes may occur from lesions in various locations throughout the CNS. Virtually any type of lesion including demyelinating, vascular, infectious, inflammatory, and trauma can produce pain. With central lesions, the onset of pain can be delayed by weeks, months, and occasionally years after a temporally well-defined insult such as a stroke. This may reflect the slower rate of degeneration within the CNS than the peripheral nervous system.
The painful somatic territory typically localizes to the corresponding central pain pathway, as in the thalamic pain syndrome characterized by Dejerine and Roussey. In those cases, the entire contralateral hemibody may be involved in the pain syndrome, or merely a portion of it. In virtually every case of central pain, the spinothalamic pathways are implicated. Out of the absence or disruption of sensory input to the CNS, pain attributable to “deafferentation” emerges. The challenging aspect of central pain syndromes is not usually diagnosis, since these patients often have a constellation of neurologic symptoms associated with their primary disorder. Management seems to be even more difficult than for patients with peripheral neuropathic pain syndromes. Phantom sensations in numb regions are described.
(i) Post-stroke pain
Up to 6% of all strokes are associated with chronic pain that limits rehabilitation and contributes to the development of poststroke depression. The most common description is that of “burning,” which is remarkably similar to accounts by patients with multiple sclerosis, post-cordotomy dysesthesia, and syringomyelia. The neuropathic features of pain in post-stroke syndromes have several characteristic features:

The region of most intense pain encompasses only a portion of the total territory of sensory deficits.

Functional recovery is poorest in the regions of most severe pain.

The modalities of thermal perception and sensation to pinprick are more commonly affected than light touch.
(ii) Trigeminal neuralgia
Most commonly, neuralgias arise from lesions of the peripheral nerve; however, clinically similar syndromes develop with lesions of the cranial nerve nuclei and outflow tracts as a result of ischemic lesions. The peak onset of trigeminal neuralgia is in patients over 50 years old. The syndrome is marked by brief paroxysms of lancinating pain, usually in the territory of the second and third divisions of the trigeminal nerve. Light mechanical stimuli often trigger the pain. New onset of this syndrome in a younger adult (under 30 years) suggests multiple sclerosis. Older adults should be imaged to screen for compression by tumors or aneurysms. Glossopharyngeal neuralgia, which is caused by lesions affecting the somatosensory component of the IXth cranial nerve, shares similar jolts of pain but in the region of the throat or behind the angle of the jaw. These syndromes are also described in Chapter 29.
(iii) Spinal cord syndromes
Spinal cord syndromes are most often associated with trauma and demyelinating diseases such as multiple sclerosis. Chronic pain due to dysesthetic phantom limb, and visceral sensations occur in more than one third of patients with spinal cord injury, and 10% of these patients characterize their pain as severely disabling. The pain is classified as (a) peripheral segmental, (b) central cord, (c) visceral, and (d) mechanical. Spinal fractures can also produce pain by compressing the remaining neural structures.
In more than half of the patients, the onset is within 6 months of the initial injury. It is variously described as “burning,” “shooting,” and “crushing.” The most common level of injury associated with pain is the cauda equina, followed by central cord injuries. Syringomyelia and syringobulbia as a delayed consequence of trauma or congenital malformation can interrupt central nociceptive afferents and produce neuropathic symptoms that affect a segment of the body. Since the spinothalamic pathways cross in the midline of the spinal cord near the site of entry to the cord, pain is the most common and earliest symptom of these syndromes.
(iv) Multiple sclerosis
Neuropathic pain is frequently associated with multiple sclerosis and is a significant cause of disability. The locations of plaques most commonly implicated are in the cervical spinal cord involving nociceptive afferents. Demyelination of the cervical and thoracic cords is common in multiple sclerosis and can produce lancinating pain in radicular distribution, or episodes of burning pain. Other sites where plaques produce neuropathic symptoms are in the radicular region at the dorsal root entry zone and the cranial nerves (see section IV, 2, ii).
V. DIAGNOSTIC EVALUATION OF PATIENTS WITH NEUROPATHIC PAIN
1. History
Neuropathic pain is a clinical syndrome, not a specific diagnosis. For this reason, the history is the most helpful diagnostic tool. The success of the evaluation rests on the clinician’s ability and willingness to validate and evaluate the patient’s pain. It is paramount to establish the underlying cause of the neuropathic pain at the outset of treatment, since the cause of some syndromes is reversible and further progression of disability can be prevented. The pain assessment integrates the following pain data points: onset, location, temporal profile, pain quality, pace of progression, severity and associated disability, aggravating and alleviating factors, response to past treatments, habits, and coping skills.
2. Examination
The general medical examination and the musculoskeletal examination provide important information about the pain condition. Features such as skin integrity, temperature, and the presence of edema or discoloration are important clues about the level of nervous system involvement and the severity of the condition. The positioning of an extremity or use of clothing to protect a limb from physical contact reveals much about the patient’s complaint. As with all components of the examination, the absence of findings does not disprove the presence of a pain condition.
The neurologic sensory examination can be normal or abnormal in the context of chronic pain. The abnormalities of sensory nervous system dysfunction do not usually fit neatly into discrete modalities such as pinprick or temperature sensation. One defining feature of neuropathic pain is the concurrence of distinct abnormal sensory perceptions. For this reason, it is critical to test several different modalities in a given territory.
A second important consideration is specific testing for positive sensory phenomena such as allodynia and hyperalgesia. Allow patients to describe the sensory experience using their own terms. It is often useful to have the patient use markers to map the region of abnormality or discomfort. The sensory exam must be clearly explained to the patient. Normal areas should be examined first to establish a baseline, and to educate the patient about the testing process. The patient should be queried first as to whether the sensation is normal or abnormal. Subsequent questions are used to establish the presence and characteristics of the pain. As always, the behavior accompanying the patient’s answers provides helpful context in which to interpret any findings. Sensory losses such as diminished pinprick sensation are routinely noted in patients with painful lesions of the sensory nervous system.
When the pain history suggests neuropathic features, it is important to also evaluate positive sensory signs including allodynia, hyperpathia, and hyperalgesia. These findings are the most specific for neuropathic pain syndromes. Allodynia can be tested mechanically by brushing the affected area with a cotton swab and with a thermal stimulus such as a cool metal reflex hammer or tuning fork. In contrast, to test hyperalgesia, a normally painful stimulus is applied, and an exaggerated pain response is consistent with a positive result. Motor deficits are often associated with neuropathic findings. Specifically, alterations in tone, strength, and endurance should be documented. In the case of central pain syndromes, these signs can be dramatic.
As with the evaluation of any patient with chronic pain, psychological assessment is important. Unrelieved pain often contributes to or unmasks psychiatric disorders such as depression, anxiety, panic disorder, and post-traumatic stress disorder. History taking should include an inventory of mood symptoms and consideration of affective signs of a behavioral problem. Many patients with chronic neuropathic pain need evaluation and treatment for depression at some time during the disease.
3. Imaging
Magnetic resonance (MR) or computed tomographic (CT) imaging is the gold standard for localization of cranial and spinal cord lesions causing central pain syndromes. Increased T2-weighted signal persists in the thalamus of a patient who has a neuropathic pain syndrome from a stroke. Computed axial tomography (CAT) of the head often reveals a hypodense neuroanatomic correlate. For radicular syndromes, CT myelography is the most sensitive imaging modality for bone impingement on nerve roots. MR imaging of the spinal cord is valuable when the examination and history are suggestive of a sensory level and an inflammatory cord lesion is likely or edema, secondary to compression, is suspected.
4. Diagnostic local anesthetic nerve blocks
Nerve blocks are useful diagnostic tools although only rarely indicated for management of chronic neuropathic pain. Temporary relief of pain from a local anesthetic injection near a particular nerve often helps to localize injury to a particular nerve or nerve segment in mononeuropathies and entrapments. Nerve block therapy is not curative and should not be used with this intent.
5. Electrophysiologic studies
Nerve conduction studies and EMG provide physiologic information about the sensory and motor components of peripheral nerves. Most neuropathic pain syndromes are mediated by smalldiameter C fibers, which are not evaluated by these tests so their value in the evaluation of neuropathic pain syndromes is limited. It is important to note that the sensory nerve action potentials (SNAP) can have normal amplitudes in patients with neuropathic syndromes of radicular origin, because the causative lesion is proximal to the dorsal root ganglion. The neuropathic features of acute radicular pain in patients with acute inflammatory demyelinating polyneuropathy (Guillain-Barré) produce the characteristic pattern of demyelination in the compound muscle action potential (CMAP)—namely, slowing of conduction velocities, prolongation of the distal motor latencies, conduction block, and temporal dispersion.
Comprehensive evaluation of sensory function can be performed by administering well-characterized stimuli of known intensity and recording the patient’s perceptions. This type of testing, termed quantitative sensory testing, is described in Chapter 7. These psychophysical evaluations are commonly used in research labs studying pain and analgesia in humans and animals. Although of some use in clinical practice, considerable expertise, as well as computerized thermal stimulators, are required for a full evaluation. Screening with a pin or nylon von Frey probes can be useful to screen for loss of protective sensation in a diabetes clinic, for instance.
6. Histologic evaluation of sensory nerves by biopsies of skin or sural nerves
Modern histologic examination, especially with quantitation, joins electrophysiologic recording as the most comprehensive way of investigating neuropathic pain. Removal of a segment of the sural nerve for light and electron microscopic analysis has shown loss of all types of axons in patients with painful polyneuropathies of varying causes. However, sural nerve biopsies cannot be repeated, are not useful for lesions that spare the sural nerve, and are quite invasive (occasionally causing neuromas, infections, and other clinical problems). For these reasons, they are largely being replaced by histologic examination of sensory nerve endings by punch biopsies of skin from the affected area, or the removal of epidermis only from induced skin blisters.
Immunohistochemical markers against PGP9.5 allow preferential visualization of the nerve endings as they course through the skin. In the epidermis, which is exclusively innervated by free nociceptive nerve endings, quantitation of the density of nerve endings is feasible. Skin biopsy studies have almost universally shown that chronic neuropathic pain is associated with profound loss of nociceptive nerve endings from painful areas of the skin.
7. Laboratory markers of neuropathic pain
There are currently no diagnostic tests specific and sensitive for neuropathic pain. At present, equivalence between symptoms and cellular mechanisms has not been established. Diagnostic evaluation is important to identify potentially reversible causes of neuropathic pain syndromes. For some of these entities, prevention of ongoing injury is paramount, as in the case of diabetic polyneuropathy, where tight glucose control can minimize disease progression. There is a role for serum titers of VZV in cases of suspected PHN in which the presentation is uncharacteristic. In the case of mononeuropathy multiplex, evaluation of markers for connective tissue disease may be helpful. In polyradiculopathy, where sensory symptoms are accompanied by weakness and areflexia at multiple levels, cerebrospinal fluid (CSF) protein and lymphocyte counts contribute to the diagnosis of acute inflammatory demyelinating polyneuropathy (Guillain-Barré). In chronic sensory neuronopathies without a clear diagnosis, evaluation for paraneoplastic antibodies and basic screening for evidence of tumor may be indicated. Where a sensory level is detected on neurologic examination, CSF samples may show evidence of inflammation and may be cultured to help identify an organism.
VI. TREATMENT OF NEUROPATHIC PAIN
Medical treatment is first-line therapy for neuropathic pain syndromes. It is the character of the prominent pain symptoms that drives therapeutic decision making, and the efficacy of drugs against neuropathic pain has been discovered serendipitously through clinical observation, usually after the drugs have been marketed for other indications. While pain researchers and pharmaceutical companies search for new ligands with molecular specificity, most of the effective treatments in current clinical use have activity at multiple sites within the pain pathways.
The good news is that multiple medications have proven effective against neuropathic pain in blinded, placebo-controlled clinical trials. The bad news is that none of these medications is effective in all patients, and we do not yet know how to predict who will be improved by which medication. Because of these limitations, it is often necessary to try several different medications before identifying the optimal agent and dosage for a particular patient. This sequential process should be explained to the patient to ensure that expectations for the extent and timing of relief are appropriate.
In general, the medication, or class of medications, judged most likely to be effective should be tried first, raised to an adequate level, and monitored for efficacy and side effects. Only if the primary analgesic is ineffective at the maximally tolerated dose should it be discontinued and replaced with a second agent. The four major classes of medications for treating neuropathic pain syndromes are tricyclic antidepressants (TCAs), anticonvulsants, opioid analgesics, and topical agents.
1. Tricyclic antidepressants
Historically, the TCAs have been the mainstay of medical therapy for neuropathic pain. They are well studied and widely prescribed. There is strong evidence of efficacy in diabetic neuropathy and PHN. Initially, the tricyclic antidepressants were thought to be most effective for persistent ongoing pain. More recent studies demonstrate their efficacy for lancinating pain and allodynia as well. Despite this, patients rarely obtain complete relief and frequently are unable to tolerate the side effects of TCAs.
The TCAs increase serotonergic and noradrenergic activity by interfering with their removal from the synaptic cleft. They have substantial sodium channel blocking activity and affect many other transmitters and receptors as well. Imipramine, amitriptyline, nortriptyline, and clomipramine are balanced in their reuptake of serotonin and norepinephrine, whereas desipramine is more selective for norepinephrine and tends to be associated with fewer side effects (see Chapter 11, table 1). In fact, affinity for histaminergic, cholinergic, and adrenergic receptors varies with each agent. This spectrum of receptor affinities accounts for the variability of analgesia and side effects described by patients. Caution is needed in patients with cardiovascular disease and closed-angle glaucoma. A full description of these drugs can be found in Chapter 11 and in Appendix VIII.
Starting doses range from 10 to 25 mg, usually given at bedtime. Choosing the initial dose depends on the patient’s age and concerns about side effects. Elderly patients or those on complicated regimens should begin at the lowest dose. Tolerability and degree of relief guide the process of weekly dose escalation in 10- to 25-mg increments. It is important to proceed slowly in the early phase of titration as the anticholinergic side effects (constipation and dry mouth) may prompt susceptible patients to discontinue the medication prematurely. Most patients experience pain relief in the range of 30 to 100 mg/day. If at the upper end of this range significant relief is not attained, other therapies should be tried. Occasional patients require doses from 150 to 250 mg/day.
2. Anticonvulsants
A full description of these drugs can be found in Chapter 10.
(i) Sodium channel blockers
First-generation sodium channel blocking anticonvulsant drugs, such as carbamazepine and phenytoin, have long been the preferred drugs for the treatment of lancinating pain. This parsing of treatment by symptom has not been supported by more recent trials. The most effective use of these first-generation agents is in trigeminal neuralgia where carbamazepine markedly reduces pain in approximately 75% of patients. Significant pain relief for patients with diabetic neuropathy has been demonstrated in controlled trials, but second-generation anticonvulsants (e.g., gabapentin) are favored because their side effects are more tolerable. Regardless of the diagnosis, the analgesic dose response varies greatly among patients.
The initial dosage for sustained-release carbamazepine in adults is 200 mg once daily. After a 1-week period to allow induction of hepatic enzymes, slow titration to a daily dose of approximately 400 mg twice daily should follow. The therapeutic range is usually between 800 and 1200 mg/day. For the central syndromes, carbamazepine has been more extensively studied. If effective, it is usually in the dosage range used for treatment of seizures. Blood count and liver and renal function must be monitored.
(ii) Gabapentin
The relatively benign side-effect profile of gabapentin (Neurontin) is propelling it to a first-option treatment for neuropathic pain in spite of the fact that it is not approved by the U.S. Food and Drug Administration for this indication. Unlike earlier anticonvulsants, gabapentin causes few drug–drug interactions and less CNS dysfunction. Tolerability allows for the high-dose therapy that is often necessary for significant pain relief. With no need to monitor levels or enzymes, this drug is relatively easy to use. Gabapentin has a broad range of effectiveness for sensory and affective pain qualities in the treatment of PHN and diabetic neuropathy.
The starting dose for gabapentin is 300 mg nightly, or 100 mg nightly in older patients. The regimen is gradually increased every 3 to 7 days to approach a dose of approximately 900 mg three times daily. Most responders report significant relief in the dose range of 2,100 mg to 3,600 mg daily. Dizziness and mild sedation are common. Edema of the extremities is the most frequent specific side effect.
3. Opioids
Although traditionally opioids have been avoided in the treatment of neuropathic pain, in patients who do not respond to nonopioid adjuvant therapy, opioids are an important alternative. These agents may offer the most disabled patients relief when all other drugs and modalities have been ineffective. The basis of the traditional avoidance of opioids was twofold: (a) the belief that they were not effective and (b) the fear of addiction. The efficacy of opioids in chronic neuropathic pain has been demonstrated prospectively in several blinded placebo-controlled trials. Unfortunately, they are not helpful for all patients, and often a trial is necessary to determine efficacy. The risk of addiction is a real though exaggerated concern. Patients with chronic pain rarely develop opiate addiction, except when there is a prior history. The use of opioids in chronic nonmalignant pain is discussed in detail in Chapter 30.
4. Topical agents
The introduction of topical therapies in the form of patches, creams, and gels is a promising advance in the treatment of peripheral polyneuropathies and PHN. These are applied to painful skin and act locally at the peripheral sites of pain generation. The absence of systemic side effects and drug interactions make these treatments an important option. Capsaicin, a substance P depleter occurring in chili peppers, has had limited adoption because of its intolerable side effect, a local burning sensation. Lidoderm, a topical formulation of 5% lidocaine, has proved safe and effective in early, well-designed trials in patients with neuropathic pain. Lidocaine gels, ointments, or sprays can be helpful for patients with pain affecting mucous membranes, allowing them to engage in specific activities such as chewing, defecation, sexual activity, or use of tampons or pads during menstrual periods. Because systemic absorption can occur, serum levels may need to be monitored.
5. Adjunctive treatments
The chronicity of neuropathic pain states creates significant disability. An interdisciplinary approach to the care of these patients should address the psychosocial burdens and functional impact of living with chronic pain. Supportive psychotherapy can be helpful to patient and family alike. Behavioral therapy encourages safely increasing physical activity. Cognitive approaches foster ways of thinking about pain that are less negative and self-defeating. Physical and occupational therapies address the loss of strength, decreased range of motion, and abnormal muscle tone. Physical and occupational therapies maximize functional gains and minimize secondary problems associated with disuse. For example, interventions such as placing a cardboard box under the covers of a patient with allodynia of the feet can prevent a secondary sleep disorder.
6. Invasive options
(i) Neuraxial catheter treatments and stimulators
Invasive methods of pain treatment should be considered for the management of neuropathic pain states refractory to medical therapy. The most common interventions are epidural and intrathecal drug delivery systems and dorsal column spinal cord stimulators. In general, these techniques require a long-term commitment on the part of the patient and pain specialist and consideration of possible, but infrequent, surgical complications. Infusion pumps of morphine, hydromorphone, and baclofen have all shown analgesic benefit in several case series, but the variety and range of implantation techniques, drugs, and protocols for infusions have precluded conclusive validation with outcome studies. In patients with opioid-responsive pain, infusion pumps may offer a long-term, alternative route of administration that minimizes dose-limiting side effects.
Spinal cord stimulation over the dorsal pathways has been shown to be effective for diverse chronic pain states over the past 30 years. The evidence supporting the use of dorsal column stimulators is not limited to neuropathic pain states and the mechanism of pain relief is not well understood. Chronic precentral and central motor cortex electrical stimulation, for post-stroke pain and deafferentation syndromes are used in the most advanced centers. Recent technical advances have been promising, but further clinical studies are needed. Peripheral stimulation of individual injured peripheral nerves is a technique with success rates significantly higher than most other medical and surgical options.
(ii) Decompressive neurosurgery
Select patients with well-defined lesions may benefit from surgical exploration and decompression. This is well accepted for patients with carpal tunnel syndrome, but unfortunately underutilized for patients with similar problems elsewhere in the body. The relatively benign nature of these procedures, which do not involve cutting or injuring the involved nerves, must be emphasized. Pain relief after lysis of connective tissue bands compressing peripheral nerves has been described at multiple locations in the body.
(iii) Ablative neurosurgery
These procedures are performed far less frequently now than in the past. In most cases, this is good, because cutting nerves does not usually relieve the pain, but in a very few instances, these options ought to be considered. These procedures should be performed only by those with subspecialty training in neurosurgical management of pain. Patients in whom these procedures are probably underutilized include those with advanced disease and limited life expectancy. For them, the risks of inadvertent damage to motor or autonomic pathways may be acceptable to achieve good pain control for their remaining time. Transection of the pain pathways of the spinal cord can be performed by a skilled neurosurgeon percutaneously under fluoroscopic guidance. Cutting nerves that innervate areas of neuropathic pain, while a seemingly attractive option, has been shown through a century of clinical practice to be generally ineffective, and it can in fact worsen neuropathic pain. Unfortunately, one still sees patients treated with neurectomies who present with severe and complex neuropathic pain syndromes.
VII. CONCLUSION
Whereas neuropathic pain was considered a distinct entity associated with specific diagnoses such as diabetic peripheral neuropathy, PHN, and trigeminal neuralgia, it is now considered an integral part of many chronic pain syndromes, including CRPS, cancer pain, and even low back pain (under certain conditions). It is certainly the most challenging type of pain we treat in the pain clinic, and the most difficult to understand. It is a prominent focus of attention for clinicians and researchers who together are attempting to unravel its mechanisms and improve the specificity and efficacy of its treatments. Neuropathic pain is ubiquitous in pain practice and worthy of an intensive effort to help its unfortunate victims and to overcome the shortcomings in its treatment.
SELECTED READINGS

1.
Backonja MM, Galer BS. Pain assessment and evaluation of patients who have neuropathic pain. Neurol Clin 1998;16:775–790.

2.
Devinsky O, Feldmann E. Examination of the cranial and peripheral nerves. New York: Churchill Livingstone, 1988.

3.
Galer BS. Painful polyneuropathy. Neurol Clin 1998;16:791–812.

4.
Hans G, Davar G. Recent advances in the pharmacology of nerveinjury pain. Neurol Clin 1998;16:951–966.

5.
Stewart JD, ed. Focal peripheral neuropathies, 3rd ed. Philadelphia: Lippincott Williams & Wilkins, 2000.

6.
Dejerine J, Roussey G. Le syndrome thalamique. Rev Neurol 1906; 14:521–532.

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