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Differential Diagnosis: Nociceptive and Neuropathic Pain
Bruce Nicholson, MD

Differential Diagnosis: Nociceptive and Neuropathic Pain

Bruce Nicholson, MD

Pain, both acute and chronic, affects millions of people in the United States. Pain can be categorized along a variety of dimensions, including one of the most important divisions, nociceptive versus neuropathic pain (NP). Nociceptive pain results from activity in neural pathways secondary to actual tissue damage or potentially tissue-damaging stimuli. NP is chronic pain that is initiated by nervous system lesions or dysfunction and can be maintained by a number of different mechanisms. Three common conditions that are often associated with acute and chronic NP are painful diabetic peripheral neuropathy (DPN), painful postherpetic neuralgia (PHN), and cancer. Although estimates of DPN vary widely depending on the assessment criteria employed, as many as 50% of people with diabetes have some degree of DPN. PHN develops secondary to herpes zoster infection, and there are 600 000 to 800 000 cases of herpes zoster in the United States each year, with 9% to 24% of patients progressing to PHN. Acute or chronic NP may occur in more than 50% of patients with cancer pain. Patients with painful DPN, PHN, or cancer may present with a variety of acute or chronic NP symptoms, and it is important to distinguish these conditions from other pain syndromes so that appropriate therapy can be initiated.

(Am J Manag Care. 2006;12:S256-S262)

The International Association for the Study of Pain defines pain as "an unpleasant sensory and emotional experience associated with actual or potential tissue damage or described in terms of such damage."1 This definition recognizes pain as a subjective experience with both psychologic and sensory components. It also recognizes that tissue damage does not need to be present for pain to be experienced.

Pain has been categorized in a variety of different ways, and one division that has been particularly useful is nociceptive pain versus neuropathic pain (NP). Nociceptive pain results from activity in neural pathways caused by actual tissue damage or potentially tissue-damaging stimuli. Examples of nociceptive pain include pain after surgery, arthritis pain, mechanical low back pain, and pain associated with sports injuries.2,3 In contrast, NP is chronic pain that is initiated by nervous system lesions or dysfunction and can be maintained by a number of different mechanisms. For example, excess stimulation of nociceptive pathways or damage to inhibitory pathways can alter the balance between painful and nonpainful sensory inputs so that pain results in the absence of nociceptor stimulation.2,4,5 Thus, NP may be present without any readily demonstrable physical findings.5


NP can arise from a variety of different conditions that affect the peripheral and/or central nervous systems (Table 1).5 Disorders of the brain or spinal cord, such as multiple sclerosis, stroke, and spondylotic or posttraumatic myelopathy, can lead to NP. Peripheral nervous system disorders that may be involved in the development of NP include diseases of the spinal nerve roots, dorsal root ganglia, and peripheral nerves. Damage to peripheral nerves that occurs in association with amputation, radiculopathy, carpal tunnel syndrome, and other entrapment neuropathies can also give rise to NP.4 Abnormal sympathetic nerve activation, catecholamine release, and activation of free nerve endings or neuromas can give rise to sympathetically mediated pain.4 NP can also be associated with infectious disease, most notably human immunodeficiency virus (HIV). Cytomegalovirus, which is often present in patients with advanced HIV disease, may also cause debilitating low back pain, radicular pain, and myelopathy.4 NP is a common and important source of morbidity in patients with cancer. Such pain in cancer patients can arise from tumor-related compression of neural tissue or nervous system injury secondary to radiation or chemotherapy.4,6

The clinical features of NP are summarized in Table 2, and a number of different pathologic processes have been suggested as factors in their development and maintenance. These include insertion of ion channels into nerve fiber membranes, alterations in receptors associated with increased levels of inflammatory cytokines, sprouting of primary afferent axon terminals in the dorsal horn of the spinal cord, cross-talk between sympathetic and somatosensory afferents, reduced numbers of gamma-aminobutyric acid-containing neurons in the spinal cord, and hyperexcitability associated with increased glutamatergic neurotransmission secondary to upregulation of metabotropic glutamate receptors in the dorsal horn.3,4,7,8


Prevalence, Risk Factors, and Natural History

Diabetic peripheral neuropathy (DPN) is very common. Although prevalence estimates vary widely depending on the assessment criteria employed, as many as 50% of people with diabetes have some degree of DPN.9 The most prevalent form of DPN is distal symmetric sensorimotor polyneuropathy, which is also the most common event leading to lower limb amputation in patients with diabetes. The Rochester Diabetic Neuropathy Study reported some form of neuropathy in 60% of subjects with type 1 or type 2 diabetes, and the prevalence of polyneuropathy was 48% in this group.10 A recent report from the GOAL A1C study group indicated that 37% of a sample of 4628 patients with type 2 diabetes had neuropathy. Given that the overall prevalence of diabetes (both type 1 and type 2) in the United States is 20.8 million,11 these results suggest that as many as 7.7 million people in this country may have some degree of DPN.

Additional epidemiologic study results indicate that the prevalence of DPN increases with both age and duration of disease.12 Results from the Diabetes Control and Complications Trial showed further that hyperglycemia is a significant risk factor for the development of DPN in patients with type 1 diabetes. This large-scale, long-term trial demonstrated that tight glycemic control decreased the appearance of neuropathy by 69% over a mean follow-up period of 6.5 years.13

Although the severity of the neuropathy in DPN may fluctuate, painful symptoms tend to persist for years. Review of the natural history of the disease also suggests that DPN-associated pain tends to worsen in most patients over long-term follow-up, although severe pain can also occur early in the course of the disease.14

Classification of DPN

DPN can be classified as acute or chronic. Acute DPN is an uncommon transient condition that affects the lower limbs and is distressing and occasionally incapacitating. This acute condition occurs in the context of either poor glycemic control or a rapid improvement in control. Chronic DPN is defined by pain symptoms that have been present for at least 6 months.15

Symptoms of Painful DPN

Diabetic neuropathy has been used to describe a large number of diffuse and focal neuropathic syndromes that result from damage to peripheral somatic or autonomic nerve fibers (Table 3). These syndromes include distal, symmetric sensorimotor polyneuropathy, autonomic neuropathy, symmetric proximal lower limb motor neuropathy (amyotrophy), cranial neuropathy, radiculopathy/plexopathy, entrapment neuropathy, and asymmetric lower limb motor neuropathy.16

Distal symmetric sensorimotor polyneuropathy, the most common form of DPN, has an insidious onset. In most people, the most distal extremities (the toes) are the first part of the body to be affected. Symptoms in patients with symmetric sensorimotor polyneuropathy may be described as either negative (eg, loss of feeling) or positive (eg, burning pain or muscular weakness).15 Loss of small unmyelinated fibers in these patients may predispose them to injury and foot ulceration.16 Patients with DPN may also experience carpal tunnel syndrome, or meralgia paresthetica, and/or pain in the distribution of the lateral femoral cutaneous nerve. Symptoms of DPN may be exacerbated at night, and they may prevent sleep, resulting in secondary fatigue, irritability, and myofascial dysfunction.4

Many patients with distal symmetric sensorimotor polyneuropathy are asymptomatic in early stages of the disease, and careful physical examination and sensory testing may be necessary to detect the syndrome. In the Rochester Diabetic Neuropathy Study, about 48% of the subjects evaluated had evidence of polyneuropathy, but only 15% were symptomatic.10 Similarly, results from 7892 patients in the GOAL A1C study indicated physician-diagnosed neuropathy in 18% of patients versus 30% who demonstrated mild-to-moderate neuropathy, and an additional 7% with severe neuropathy demonstrated by monofilament testing.17

Clinical diagnosis of DPN, particularly in patients with sensorimotor polyneuropathy, may be difficult, because symptoms are variable, ranging from a complete absence of pain with disease perhaps reflected only by an insensitive foot ulcer to very severe pain. Sensory symptoms and signs of DPN are more common than motor symptom but the latter may include reduced ankle reflexes and/or minimal distal muscle weakness.18


Herpes zoster is caused by a reactivation of the varicella zoster virus (VZV), the primary infection that causes chicken pox in children.19 After the chicken pox infection, VZV remains dormant in sensory ganglia throughout the body. Reactivation is more common in older individuals and in those with compromised immune systems. Reactivation results in the rash commonly referred to as shingles, which is accompanied by acute pain. Pain that persists for extended intervals after the rash has subsided is postherpetic neuralgia (PHN).19 Although definitions for PHN vary, the one set forth by the American Academy of Neurology is pain that persists for more than 3 months after resolution of the rash.20

The etiology of PHN is not completely understood; however, it has been shown that patients with this condition have damage to sensory nerves, dorsal root ganglia, and spinal dorsal horn.21 It is thought that viral particles spread to these sites after reactivation, and that this is accompanied by inflammation, immune response, hemorrhage, and damage to peripheral sensory neurons and their processes.22 It is also known that VZV infection can invade the spinal cord and central nervous system blood vessels, causing a wide range of serious neurologic symptoms.23


Review of results from epidemiologic studies indicates that there may be as many as 1 million cases of herpes zoster in the United States each year. It has also been estimated that between 9% and 24% of these patients will develop PHN.4 The risk of PHN secondary to herpes zoster infection increases progressively with age. It has been estimated that PHN follows herpes zoster infection in 2% of people older than 40 years of age, 21% of those 40 to 60 years old, and in 40% of those older than 60.24 Age-associated decline in immune system function explains the association between older age and greater risk of herpes zoster, although the explanation for the greater risk of PHN in older herpes zoster patients is not understood. Patients who have diseases or who are receiving treatments that compromise the immune system are also at increased risk for herpes zoster infection and PHN. It has been noted that the incidence of herpes zoster is up to 15 times higher in HIV-positive people than in those without HIV infection, and that the risk for this condition is also elevated in patients with Hodgkin's disease, non-Hodgkin's lymphoma, and leukemia, as well as those undergoing bone marrow or solid organ transplantation.14,21

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