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LYRICA® (pregabalin)
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Diabetic Peripheral Neuropathy
and Postherpetic Neuralgia
Pfizer Inc
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Contents
Introduction
Section 1: Overview of Neuropathic Pain
1
Section 2: Diabetic Peripheral Neuropathy
27
Section 3: Postherpetic Neuralgia
56
Module Summary
76
Glossary
82
Bibliography
86
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Introduction
The information contained in this training module is for your educational purposes
only. This training piece is designed to provide you with information you need on
the product, the disease, and the competitive environment. It is not to be used in
detailing or distributed to any third parties.
Pain is a symptom that occurs in a multitude of disorders. There are various types
of pain, including nociceptive pain (which arises in response to injury of somatic or
visceral tissues through the excitation of nociceptors), and neuropathic pain. The
International Association for the Study of Pain (IASP) defines neuropathic pain as
pain that is initiated or caused by a primary lesion or dysfunction in the nervous
system.
Painful diabetic peripheral neuropathy (pDPN) and postherpetic neuralgia (PHN) are
2 of the most common neuropathic pain conditions. They have multiple complex
mechanisms resulting in a variety of symptoms. pDPN and PHN are debilitating and
costly. Approximately 23.6 million people in the United States have diabetes. It is
estimated that 60% to 70% of this population has diabetic neuropathy. One in 4 of
these patients are affected by pDPN, and 9 out of 10 patients with pDPN report
moderate or severe pain. LYRICA® (pregabalin) is FDA-approved for the
treatment of neuropathic pain associated with diabetic peripheral neuropathy (DPN).
The 12-month prevalence of shingles or herpes zoster in the United States is
approximately 1 million people. Of that number, an estimated 10% to 20% will
develop PHN. Although the number of people who continue to experience pain
decreases steadily over the 12-month period after the initial outbreak, 4% to 22% of
all PHN patients will continue to feel pain more than 1 year after the incident.
This module provides a description of neuropathic pain in general, to give an overall
context, and then focuses on DPN and PHN:
• Section 1 discusses the classification of pain, the mechanisms of neuropathic
pain, its comorbidities, and its diagnosis
• Section 2 provides an overview of diabetes, followed by a description of the
epidemiology of DPN, the pathogenesis of pDPN, the clinical course and
characteristics of pDPN, its diagnosis, and the healthcare providers who care for
patients with pDPN
• Section 3 provides an overview of herpes zoster infection, then discusses the
epidemiology of PHN, its pathogenesis, its clinical course and characteristics, its
diagnosis, and the healthcare providers who care for patients with PHN
The module concludes with a summary and glossary of medical terms.
Module Introduction
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i
Section 1: Overview of Neuropathic Pain
Objectives
Describe the different classifications of pain
Identify the causes and types of neuropathic pain
Describe the mechanisms of neuropathic pain
Identify and describe key comorbidities of neuropathic pain
Describe the diagnosis of neuropathic pain
Pain is a complex concept. One of the most intriguing types of pain is neuropathic
pain. Neuropathic pain represents a broad array of disorders, each of which is
associated with a variety of pain mechanisms and a multitude of signs and
symptoms.
In order to understand DPN and PHN, 2 specific types of neuropathic pain, it is
essential to understand the most common mechanisms and symptoms associated
with neuropathic pain in general.
Section 1: Overview of Neuropathic Pain
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1
Describe the different classifications of pain
Classification of Pain
Pain can be classified in a number of different ways, including according to:
• anatomic location
• body system/location
• central nervous system (CNS)
• peripheral nervous system (PNS)
• underlying cause
• frequency
• intensity
• duration and time course
It is important to note that pain is not always easily classified into just one category
and that pain may sometimes be classified simultaneously into different categories.
In spite of these difficulties, it is critical that physicians classify pain, as it allows them
to:
• accurately describe the pain being experienced by their patients
• design appropriate treatment regimens for patients
• ensure that management will be effective
Two of the most common differentiations in types of pain are:
• acute versus chronic pain
• nociceptive versus neuropathic pain
Click on the icon to view a video that provides an overview of the
different types of pain.
Acute Versus Chronic Pain
Acute and chronic pain are 2 distinct types of pain. It is important to recognize that
although the duration of pain is a primary difference between acute and chronic pain,
chronic pain is not simply a temporal extension of acute pain. While both types of
pain may be similar in intensity, they usually differ in a variety of other factors.
Section 1: Overview of Neuropathic Pain
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Describe the different classifications of pain
Acute Pain
Acute pain onset is typically sudden and related to a specific event, such as illness,
injury, or surgery. Acute pain serves a protective purpose, as it warns of danger and
limits utilization of injured or diseased body parts. In terms of duration, acute pain is
short-lived. The actual duration of acute pain often correlates with the causative
factor, and, therefore, its course is relatively predictable.
Acute pain is generally accompanied by autonomic responses that include
tachycardia, rapid breathing, and increased blood pressure. Patients with acute
pain may be anxious about their condition, but they generally have an optimistic
outlook about obtaining relief. Acute pain resolves after successful intervention or
healing. Analgesics generally provide effective pain relief, and both patient and
clinician can expect acute pain to diminish once treatment begins.
Chronic Pain
Chronic pain has a gradual onset and is characterized by pain that continues despite
treatment or apparent healing. This type of pain serves no biologic purpose and has
little protective significance. Chronic pain may be continuous or intermittent and is
long in duration. It should be noted that definitions of chronic pain may vary insofar
as they are based on duration; for instance, some sources classify chronic pain as
the persistence of pain for 3 months or longer, while others define chronic pain as
pain lasting for at least 6 months. Causes of chronic pain in a particular case may or
may not be well defined. They vary widely, but causes can be linked to headaches,
back pain, arthritis, cancer, and neuropathy.
Autonomic responses are less prominent with chronic pain. Patients do, however,
exhibit symptoms of irritability, lack of energy, fatigue, and an impaired ability to
concentrate. Chronic pain can affect all aspects of an afflicted person's life, with
physical and social functioning implications. This type of pain creates emotional
turmoil and distress. Patients are often depressed, socially withdrawn, and see no
relief in sight — only long-term pain. Anxiety and pain-related sleep disturbances
such as insomnia are also common.
Chronic pain is a complex syndrome that requires a multidisciplinary approach for its
management. Treatment is difficult, as chronic pain is often refractory to analgesic
therapy. Treatment may therefore require additional resources and the coordinated
efforts of a broadly based treatment team. If left untreated, the pain becomes the
disorder itself, rather than merely a symptom of an underlying condition.
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Describe the different classifications of pain
Summary of Acute and Chronic Pain
Table 1A summarizes information on acute and chronic pain.
Click on the icon to reinforce what you have learned about pain.
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4
Describe the different classifications of pain
Nociceptive Versus Neuropathic Pain
Pain may be classified as either nociceptive or neuropathic based on the physiologic
origin of the pain. Nociceptive pain arises in response to injury of somatic or visceral
tissues through the excitation of nociceptors located mostly in the skin or internal
organs. When acute, nociceptive pain serves as a warning sign to the body that it is
being harmed and has a protective function. For example, nociceptive pain may be
caused by:
• injury, such as a cut, bruise, bone fracture, crush injury, burn, or anything that
damages tissues, resulting in pain that is typically aching, sharp, or throbbing
• surgery, resulting in pain that may be constant or intermittent, often worsening
when a person moves, coughs, laughs, or breathes deeply, or when the
dressings over the surgical wound are changed
• cancer, occurring when a tumor invades bones and organs, causing mild
discomfort or severe, unrelenting pain; surgery and radiation therapy to treat
cancer can also cause nociceptive pain
• note that pain from cancer can also have a neuropathic component
Once the causative factor is removed or addressed, the pain is eliminated or
diminished. Most pain is nociceptive pain.
Conversely, neuropathic pain is initiated or caused by a primary lesion or
dysfunction in the nervous system. Unlike nociceptive pain, neuropathic pain has no
protective function. It is a type of chronic pain in which the nervous system itself
generates and perpetuates pain, in the absence of the stimuli from injury that are
typical of nociceptive pain. Neuropathic pain may be felt as a burning or tingling
sensation or as hypersensitivity to touch or cold.
Although precise estimates of the prevalence of neuropathic pain are not available, it
is more common than generally recognized. In the United States, pDPN and PHN
are 2 of the most common types of neuropathic pain. Approximately 23.6 million
people in the United States have diabetes. It is estimated 60% to 70% of this
population has diabetic neuropathy. One in 4 of these patients are affected by
pDPN, and 9 out of 10 patients with pDPN report moderate or severe pain. Of the
1 million patients per year who experience herpes zoster, 10% to 20% will develop
PHN.
Click on the icon to view a video that provides an overview of
nociceptive and neuropathic pain.
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5
Describe the different classifications of pain
Progress Check
There may be more than one correct answer to each question.
1.
Which of the following are characteristics of chronic pain?
A
patients exhibit symptoms of irritability, lack of energy, fatigue, and an impaired
ability to concentrate
B
C
D
onset is gradual
analgesics provide effective pain relief
onset is typically sudden and related to a specific event, such as illness, injury, or surgery
E
F
may be continuous or intermittent and is long in duration (usually >6 months)
actual duration often correlates with the causative factor
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Identify the causes and types of neuropathic pain
Causes and Types of Neuropathic Pain
Neuropathic pain may be caused by various factors, including:
• metabolic diseases such as diabetes and hypothyroidism
• infections such as HIV or herpes zoster
• certain drugs, toxins, certain vitamin deficiencies, connective tissue diseases,
trauma, and inherited neuropathies
Depending on the location of the damage in the nervous system from these causes,
neuropathic pain syndromes are often classified as:
• central pain, which refers to pain due to lesions in the CNS (the brain and spinal
cord)
• peripheral pain, which refers to pain due to lesions in peripheral nerves
• other, in which the location of the damaged nervous tissue cannot be determined
• mixed pain, encompassing both nociceptive and neuropathic pain
Clinically, the distinction between neuropathic pain and nociceptive pain is not
always clear. For example, nociceptive pain may be associated with early clinical
findings that are generally considered neuropathic, such as allodynia and
paresthesia. Also, nociceptor sensitivity to painful stimuli can be amplified through
sensitization, which leads to neuropathic pain.
In practice, a syndrome known as mixed pain, encompassing both nociceptive and
neuropathic pain, is recognized. Mixed pain syndromes primarily arise from
diseases of the spinal cord and the closely associated nerve roots. Major examples
are:
• cervical pain, which may be radiculopathic
• low back pain, which may be radiculopathic or musculoskeletal
• cancer-related pain, such as pain due to spinal metastases
pDPN (a complication of diabetes that affects nerve tissue) and PHN (pain persisting
or recurring at the site of herpes zoster rash) are both types of peripheral
neuropathic pain.
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Identify the causes and types of neuropathic pain
Progress Check
1.
Neuropathic pain arises:
A
B
2.
primarily from dysfunction in the nervous system.
in response to injury of somatic or visceral tissues through the excitation of nociceptors.
pDPN (a complication of diabetes that affects nerve tissue) and PHN (pain persisting or
recurring at the site of herpes zoster rash) are both types of __________ neuropathic pain.
A central
B
peripheral
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Describe the mechanisms of neuropathic pain
Mechanisms of Neuropathic Pain
Neuropathic pain can occur via one or more of several mechanisms, including:
• direct stimulation of pain-sensitive neurons
• peripheral sensitization and the theory of central sensitization
• automatic (also called spontaneous) firing of damaged nerves
• deafferentation
• sympathetically mediated pain
Note that voltage-dependent calcium channels may be important in modulating
neuropathic pain transmission. For example, N-type calcium channels play a role in
the increased transmission that can result in spontaneous pain. It is important to
note that N-type calcium channels are different from L-type calcium channels, to
which calcium channel blockers (such as amlodipine) bind.
Within a given neuropathic syndrome, several mechanisms are likely responsible for
the pain experienced.
Direct Stimulation of Pain-Sensitive Neurons
One mechanism through which neuropathic pain can occur is by the direct
stimulation of pain-sensitive neurons. A-delta fibers and C fibers are 2 key types
of nerve fibers that function as nociceptors. A-delta fibers are myelinated and
conduct electrical impulses 5 to 50 times faster than unmyelinated fibers. They are
responsible for the sharp, initial pain resulting from injury or illness (perceived as
noxious stimulation). C fibers are unmyelinated and therefore conduct impulses
more slowly. They are responsible for the aching or burning sensation that follows
sharp initial pain. These pain-sensitive neurons are directly stimulated and begin
firing in response to:
• mechanical stretching of nerves
• compression of nerves
• certain chemicals, such as prostaglandins or other mediators of inflammation
The pain is perceived in the distribution area of involved nerve structures.
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Describe the mechanisms of neuropathic pain
The following animation illustrates the direct stimulation of pain-sensitive neurons.
Peripheral Sensitization and the Theory of Central Sensitization
Nociceptor sensitivity to painful stimuli can be amplified and lead to neuropathic pain
through:
• peripheral sensitization
• central sensitization
Peripheral Sensitization
In normal circumstances, nociceptors are activated when incoming stimuli reach an
activation threshold determined by mediators that surround the terminals of the
nociceptors.
However, intense or prolonged pain stimuli, applied in the presence of tissue or
nerve damage or inflammation, can result in a variety of changes:
• surrounding cells can increase production of chemical mediators or produce
different chemical mediators
• the destruction of neurons can also result in a shift in the amounts or types of
chemical mediators
These events can lower the activation thresholds of nociceptors and increase their
firing rates, a process called peripheral sensitization. In tissues that have been
sensitized by this process, even stimuli that are normally harmless can feel painful.
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Describe the mechanisms of neuropathic pain
The Theory of Central Sensitization
Nociceptor sensitization is only partially explained by the changes that occur with
peripheral sensitization. Following injury, a secondary zone of increased
responsiveness develops in the uninjured tissue surrounding the injured site. This
zone is thought to arise due to changes that occur in the dorsal horn of the spinal
cord, and the process is known as central sensitization. The end result of central
sensitization is increased pain.
Central sensitization is thought to occur when the dorsal horn neurons receive a
massive discharge of signals from nociceptors. The barrage of sensory signals
causes changes in the dorsal horn neurons, including:
• a progressive increase in the activity of the dorsal horn neurons (sometimes
referred to as wind-up), so that the neurons are more sensitive to other input
• response by the neurons to stimuli that would normally be outside their receptive
area
• an increase in the magnitude and duration of response
• a reduction in threshold, so that stimuli that would not normally be perceived as
pain now activate nociceptors
The wind-up phenomenon is mediated by the N-methyl-D-aspartate (NMDA)
receptor, which is a type of glutamate receptor. Glutamate is an excitatory
neurotransmitter in the spinal cord. When NMDA receptors are activated, the
excitability of the neurons is increased. The wind-up phenomenon — that is, the
spontaneous firing in C fiber sensory neurons that results in continual input to the
dorsal horn — causes sensitization of dorsal horn neurons. This sensitization
increases the excitability of the dorsal horn neurons, causing them to have an
exaggerated response to normal inputs, a condition known as hyperalgesia. As a
result, stimuli that are normally harmless become painful, a condition known as
allodynia.
Dysregulation of gamma-aminobutyric acid (GABA), an inhibitory transmitter in the
dorsal horn, is also thought to be involved in central sensitization. Peripheral nerve
injury may reduce the amount of inhibitory control over dorsal horn neurons,
decreasing the amount of GABA. This increases the likelihood that a neuron will fire
spontaneously or in an exaggerated way in response to afferent input.
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Describe the mechanisms of neuropathic pain
Figure 1A depicts the process of sensitization.
Figure 1A: Peripheral Sensitization and the Theory of Central Sensitization
Automatic Firing of Damaged Nerves
Neuropathic pain has also been associated with automatic (also called
spontaneous) firing by damaged nerves. Nerve fibers that have been damaged by
injury or disease may begin spontaneous firing at the site of injury or at other
locations along the damaged nerve. The firing occurs only along the damaged
nerve. The resulting pain is often lancinating, stabbing, or shooting. When many
nerve fibers fire randomly, the pain sensation is one of continuous burning.
Pain, characteristic of diabetic peripheral neuropathy, has been associated, at least
in part, with this mechanism of automatic firing, which can produce persistent
physiologic pain. This mechanism also explains how pain can occur in a part of the
body that is numb. That is, when large-diameter fibers are damaged, causing
numbness, pain is perceived through impulses generated in small-diameter fibers,
C fiber nociceptors.
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Describe the mechanisms of neuropathic pain
The following animation depicts the neuropathic pain mechanism that involves
automatic firing of damaged nerves.
Deafferentation
Under normal conditions, sensations travel from peripheral tissues through a
connected chain of neurons to the spinal cord, brainstem, and brain through a
process known as afferent transmission. Deafferentation occurs when injury
interrupts any portion of the normal pain transmission pathway and results in firing of
nerves farther up the pathway (termed higher-order neurons) and, thus, ongoing
pain. That is, the firing occurs not at the damaged neuron, but in other neurons.
Examples of this type of neuropathic pain include diabetic peripheral neuropathy,
postherpetic neuralgia, phantom limb pain, and post-stroke pain; nerve damage
generates firing in higher-order nerves.
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Describe the mechanisms of neuropathic pain
The following animation depicts the neuropathic pain mechanism of deafferentation.
Click on the icon to reinforce what you have learned about the
neuropathic pain mechanism of deafferentation.
Sympathetically Mediated Pain
Painful stimuli can trigger autonomic activity. For instance, injury often triggers
localized changes in circulation and temperature, functions regulated by the
autonomic nervous system. In fact, injury can cause hyperactivity in the autonomic
system, particularly sympathetic hyperactivity. The sympathetic division of the
autonomic nervous system is responsible for energy mobilization when needed by
the body, such as when the body is undergoing stress. Sympathetic nerves release
norepinephrine, which stimulates the primary sensory nerve for pain, causing pain
and fueling further sympathetic activity. Persistence of this sympathetically
mediated pain is the cause of complex regional pain syndrome, which is sustained
burning pain.
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Describe the mechanisms of neuropathic pain
The following animation depicts the mechanism of sympathetically mediated pain.
Summary of Mechanisms of Neuropathic Pain
Table 1B summarizes information presented on the mechanisms of neuropathic pain.
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Describe the mechanisms of neuropathic pain
Progress Check
1.
Match each of the following mechanisms of neuropathic pain with the correct description of
the mechanism.
A nerve fibers that have been
B
Direct stimulation of paindamaged by injury or disease begin
sensitive neurons
spontaneous firing at the site of
C
Peripheral sensitization and
injury or at other locations along the
the theory of central
damaged nerve
sensitization
B
nociceptors
fire in response to
A
Automatic firing of damaged
mechanical stretching or
nerves
compression of nerves, or certain
E
Deafferentation
chemicals
D
Sympathetically mediated
C nociceptor sensitivity to painful
pain
stimuli is amplified
D sympathetic nerves release
norepinephrine, which stimulates
the primary sensory nerve for pain
E injury that interrupts any portion of
the normal pain transmission
pathway can result in firing of
nerves farther up the pathway
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16
Identify and describe key comorbidities of neuropathic
pain
Comorbidities of Neuropathic Pain
Patients with neuropathic pain frequently have associated comorbid conditions,
notably:
• pain-related sleep disturbances
• anxiety and depressive disorders
People with severe or chronic pain often experience disturbances in sleep and
mood. Severe pain, for example, is often accompanied by fear, anxiety, and
depression. In this complex interrelationship among pain, sleep, and mood, the
comorbid conditions may exacerbate each other. Various clinical trials, as described
in the following paragraphs, have demonstrated these associations.
Neuropathic Pain and Pain-Related Sleep Disturbances
The association between neuropathic pain and pain-related sleep disturbances has
been recognized for many years. At first glance, the connection between chronic
pain and pain-related sleep disturbances might seem to be a straightforward
causative relationship; however, the connection is actually more complex. Sleep
disturbances not only result from chronic pain, but some studies suggest that sleep
disturbances may actually contribute to the pain syndrome.
A large number of patients with neuropathic pain experience sleep difficulties — in
one survey, 88% experienced sleep difficulties, with 60% reporting moderate to very
severe discomfort from difficulty in sleeping. Data show that patients with chronic
pain report low sleep efficiency (time in bed actually sleeping) and frequent nighttime
awakenings, and give their sleep quality and restfulness poor ratings.
These changes in sleep patterns have a negative impact on sleep quality and lead
to the person feeling tired and not refreshed upon awakening.
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Identify and describe key comorbidities of neuropathic pain
pDPN and Sleep Disturbances
Brandenburg et al demonstrated in a cross-sectional survey of 255 patients with at
least 3 months of pDPN that increased pain severity is associated with greater sleep
problems. The impact of pDPN on sleep was measured using the Medical
Outcomes Study Sleep Scale (MOS-S), a 12-item, patient-completed questionnaire
that yields 7 subscales:
• sleep disturbance
• snoring
• awaken short of breath or with headache
• quantity of sleep
• optimal sleep
• sleep adequacy
• somnolence
A higher score within each subscale indicates more of the attribute being measured
(eg, more snoring, more adequate sleep, greater somnolence).
Figure 1B illustrates these results, which show that pDPN increases sleep problems
in general (a higher score indicates increased sleep difficulties).
Figure 1B: pDPN Increases Sleep Problems
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Identify and describe key comorbidities of neuropathic pain
PHN and Sleep Disturbances
One study measured scores on the MOS-S in 2 patient groups:
• patients with PHN
• the Medical Outcomes Study (MOS) population of patients with 1 of 5 diseases:
hypertension, congestive heart failure, type 2 diabetes, recent acute myocardial
infarction, or clinical depression
• this population was studied in the MOS and was identified from practices of
362 medical clinicians and 161 mental health providers
Compared to the MOS population, sleep quality was significantly reduced in the
PHN population according to several parameters: sleep disturbance, optimal sleep,
sleep adequacy, somnolence, and overall sleep index. These results are illustrated
in Figure 1C.
Figure 1C: Sleep Quality Is Significantly Reduced in Patients With PHN
Click on the icon to reinforce what you have learned about pDPN and
sleep problems.
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Identify and describe key comorbidities of neuropathic pain
Neuropathic Pain and Anxiety and Depressive Disorders
As mentioned, chronic pain not only interferes with sleep but also has a negative
impact on an individual's psychological well-being. The prevalence of anxiety and
depressive disorders in patients with chronic pain is higher than in the general
population. For example, in the 2004 Mental Health and Chronic Pain National
Comorbidity Survey, patients with chronic back or neck pain had a 2.4-fold
increased risk for an anxiety disorder and a 2.7-fold increased risk of a depressive
disorder.
pDPN and Anxiety and Depressive Disorders
Brandenburg et al measured symptoms of anxiety and depression using two
21-point (0 = normal; 21 = severe) subscales of the Hospital Anxiety and Depression
Scale (HADS), known as HADS-Anxiety (HADS-A) and HADS-Depression
(HADS-D). They demonstrated in a cross-sectional survey of 255 patients with at
least 3 months of pDPN that increased pain severity is associated with increasing
symptoms of anxiety and depression, as illustrated in Figure 1D.
Figure 1D: Pain Severity Is Associated With Increasing
Symptoms of Anxiety and Depression
PHN, Anxiety Disorders, and Depressive Disorders
In a national survey of 385 elderly patients with PHN, the mean rating of the
interference of PHN with mood was approximately 4.5 (moderate) on a 10-point
scale based on the Brief Pain Inventory (BPI).
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Identify and describe key comorbidities of neuropathic pain
Progress Check
There may be more than one correct answer to each question.
1.
Patients with neuropathic pain frequently have associated comorbid conditions, including:
A
pain-related sleep disturbances.
B
anxiety and depressive disorders.
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21
Describe the diagnosis of neuropathic pain
Diagnosing Neuropathic Pain
PHN, pDPN, and other neuropathic pain states are diagnosed by means of patient
history and physical examination. More specific tests are usually not necessary in
clinical practice. Instead, the clinical context of the pain is the critical factor. Several
conditions are frequently associated with neuropathic pain and may aid diagnosis.
For example, symptoms in patients with herpes zoster infection or diabetes may
justifiably lead a physician to suspect neuropathy. Other key diagnostic indications
of a neuropathic pain condition include:
• patient descriptions of the pain, particularly in terms of the quality, timing, and
distribution of pain
• key physical signs
The signs and symptoms of pain may assist in the identification of the underlying
mechanisms of neuropathic pain in a specific case. PHN and pDPN, for example,
likely have multiple mechanisms that account for the chronic pain present in those
disorders. However, in many cases, the precise mechanisms associated with
specific symptoms have yet to be elucidated. It therefore remains essential to
diagnose and treat neuropathic pain based on etiology (eg, to diagnose a patient
with pDPN or PHN).
Classification of Symptoms of Neuropathic Pain
Neuropathic pain syndromes usually consist of a combination of:
• negative symptoms, which result from decreased or absent functioning of the
sensory systems; examples include sensation loss and numbness
• positive symptoms, which result from the hyperfunction of sensory symptoms;
examples include dysesthesias, paresthesias, and pain
These symptoms of neuropathic pain are commonly classified as either:
• spontaneous or stimulus-independent pain (that is, they occur on their own),
which can be described as shooting, lancinating, burning, stabbing, tingling, or
electric shock-like
– this may be continuous or intermittent, and most patients describe having
more than one type of spontaneous pain
• provoked or stimulus-evoked pain (that is, they occur in response to a stimulus,
but in an exaggerated fashion), notably hyperalgesia (exaggerated pain) and
allodynia (pain from ordinarily nonpainful stimuli)
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Describe the diagnosis of neuropathic pain
Signs and Symptoms Found at Examination
A common finding at examination is a pattern of sensory dysfunction, with or without
associated motor dysfunction. Sensory impairment may lead patients to experience
both severe pain and numbness at once, as well as a loss of reflexes at an affected
site. Motor dysfunction may lead to weakness.
Abnormal sensory perceptions may also be evident upon examination, with allodynia
being perhaps one of the most characteristic features of neuropathic pain. Allodynia
and other common features of neuropathic pain are described in Table 1C.
Click on the icon to reinforce what you have learned about the common
features of neuropathic pain.
Other physical signs associated with neuropathic pain may include:
• changes in skin color and temperature
• swelling of limbs
An important distinguishing factor of neuropathic pain is its timing: Unlike other
types of pain, neuropathic pain is often worse at night.
The distribution of neuropathic pain is also noteworthy for diagnostic purposes,
because the pain may follow a recognized anatomic nerve distribution. For
example, PHN is recognized as most commonly affecting the head and trunk
regions. Many diabetic neuropathies are associated with a glove-and-stocking
distribution of sensory loss and symptoms — that is, they initially and primarily affect
the nerves of the feet and hands, then progress toward the rest of the body.
It is important to emphasize that the pain associated with neuropathic syndromes
can be severe. One reason for this is that any damage to a nerve often results in
amplification of signals encoded by that nerve, which results in an intensified pain
syndrome that is more severe than the original injury.
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Describe the diagnosis of neuropathic pain
Evaluating Pain
Because patients may find it difficult to describe their pain, pain rating scales have
been developed to provide patients with a pain "vocabulary" and simple ways to
indicate pain intensity. These scales are an important tool in the diagnosis and
evaluation of pain. In clinical trials, they may be used to determine eligibility and
monitor the effectiveness of treatment. For example, pain rating scales can assess
the ability of a treatment to reduce overall pain intensity as well as to reduce specific
unpleasant qualities of the pain.
The Patient's Global Impression of Change (PGIC) is a commonly used and
validated 7-point scale often used as an overall measure in clinical trials. The PGIC
allows researchers to assess each patient's own evaluation of the change in health
status. Using the PGIC, patients rate their current health status, as compared to
their status at the start of the study, as:
• very much improved
• much improved
• minimally improved
• no change
• minimally worse
• much worse
• very much worse
Patient health status measures (such as the Short Form-36 [SF-36], a general
health survey instrument) are often included with pain rating scales in clinical trials of
pain therapies because of the negative impact of pain on patients' daily lives.
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Describe the diagnosis of neuropathic pain
Summary
Table 1D summarizes the information that is used to diagnose neuropathic pain.
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Describe the diagnosis of neuropathic pain
Progress Check
There may be more than one correct answer to each question.
1.
Which of the following is commonly found in a diagnosis of neuropathic pain?
A
Pain has a shooting, stabbing, lancinating, burning, tingling, or electric shock-like
quality.
B
Sensory dysfunction, with or without associated motor dysfunction, may be
present.
C
Patients commonly present with allodynia.
D
Other physical signs may include changes in skin color and temperature, and
swelling of limbs.
E
Pain is often worse at night.
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Section 2: Diabetic Peripheral Neuropathy
Objectives
Describe type 1 and type 2 diabetes
Discuss the epidemiology of DPN in the United States
Discuss the pathogenesis of DPN
Describe the classification of DPN
Discuss the diffuse neuropathies
Discuss the focal neuropathies
Describe the diagnosis of DPN
List the key healthcare providers involved in the diagnosis and treatment of DPN
Diabetes mellitus is a common metabolic disorder that is the most frequent cause of
peripheral neuropathy. Diabetic peripheral neuropathy (DPN) is a complication of
diabetes that affects nerve tissue. Approximately 23.6 million people in the United
States have diabetes. It is estimated that 60% to 70% of this population has diabetic
neuropathy. One in 4 of these patients are affected by pDPN, and 9 out of
10 patients with pDPN report moderate or severe pain.
This section provides a brief overview of type 1 and type 2 diabetes and then
discusses the epidemiology, pathogenesis, clinical course and characteristics, and
diagnosis of DPN, as well as a description of the key healthcare providers involved
in the diagnosis and treatment of DPN.
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Describe type 1 and type 2 diabetes
Overview of Type 1 and Type 2 Diabetes
Diabetes mellitus is a clinical syndrome in which chronic elevations in glucose,
termed hyperglycemia, result from defects in insulin production and, in some
cases, from a defect in insulin action termed insulin resistance. Left untreated,
diabetes may result in pervasive complications that affect virtually every system of
the body. The 2 types of diabetes most commonly associated with DPN are:
• type 1 diabetes
• type 2 diabetes
Type 1 Diabetes
Type 1 diabetes is an autoimmune disease in which patients are unable to produce
insulin due to the destruction of the beta-cells of the pancreas. This results in
absolute insulin deficiency. Without insulin, glucose accumulates in the blood.
Common symptoms of type 1 diabetes include:
• excessive urination (polyuria)
• excessive thirst (polydipsia)
• dehydration
• weakness
• weight loss
Left untreated, blood glucose levels skyrocket, leading to chronic hyperglycemia and
potentially fatal conditions (such as ketosis). Patients with type 1 diabetes must
take daily insulin injections in order to survive.
The causes of beta-cell destruction are currently unknown. However, most
individuals diagnosed with type 1 diabetes produce antibodies to beta-cells and/or
insulin. Both environmental and genetic factors are associated with development of
the disorder, which accounts for 5% to 10% of all cases of diabetes mellitus. Onset
typically occurs in children and young adults, but may happen at any age.
Type 2 Diabetes
Type 2 diabetes is by far the most common form of diabetes mellitus, accounting for
90% to 95% of all cases of the disorder in the United States. About one third of
cases remain undiagnosed. As in the case of type 1 diabetes, the specific causes of
type 2 diabetes are currently unknown. Onset typically occurs after age 40, and
many affected individuals are obese. However, type 2 diabetes is increasingly being
diagnosed earlier and in younger individuals — sometimes in children. Because
patients do not become very symptomatic from their hyperglycemia, diabetes may
remain undiagnosed for many years.
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Describe type 1 and type 2 diabetes
Pathophysiology
The progression of type 2 diabetes is quite different from that of type 1, and, in most
cases, involves both relative insulin deficiency and impairment of insulin action.
Instead of sudden, rapid beta-cell destruction, there is insidious beta-cell
dysfunction. For reasons that are unclear, the beta-cell is unable to detect and
respond appropriately to hyperglycemia. Insulin is produced, but in insufficient
quantities to maintain normal blood glucose levels.
Insulin resistance is a hallmark of type 2 diabetes and refers to the failure of body
tissues to respond to insulin. The interplay between insulin resistance and
diminished insulin secretion is a key factor in type 2 diabetes. The tissues involved
in this interaction include:
• the liver
• the pancreas
• muscle and fat
In a healthy individual, beta-cells in the pancreas sense changes in the level of
glucose circulating in the blood. Insulin is secreted to maintain a normal range of
glucose — insulin regulates glucose production by the liver and glucose uptake in
peripheral cells. When insulin production is inadequate, hepatic glucose production
is not properly controlled.
The presence of insulin resistance in combination with beta-cell dysfunction leads to
a further increase in blood glucose levels. Not only is there a deficiency in insulin
production, but target cells (such as muscle, liver, and fat) do not properly respond
to insulin. As a result, glucose is not transported into these cells as efficiently. In
cases where insulin resistance is present, the pancreas makes enough insulin to
maintain normal glucose levels. When beta-cells begin to fail (resulting in insulin
deficiency), insulin is not secreted in sufficient quantities to keep glucose levels
normal. Therefore, hyperglycemia develops and diabetes is diagnosed.
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Describe type 1 and type 2 diabetes
The following animation provides an overview of the metabolic processes involved in
type 2 diabetes.
Risk Factors for Type 2 Diabetes
The most powerful risk factor for type 2 diabetes is obesity: Over 80% of patients
with type 2 diabetes are obese. Severely overweight individuals have a 10 times
greater risk of developing the disorder than those who are not obese. Heredity also
plays a major role in the development of type 2 diabetes. In the United States, a
disproportionate number of cases of the disorder appear among ethnic minority
populations.
Click on the icon to reinforce what you have learned about the
pathophysiology of type 2 diabetes.
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Describe type 1 and type 2 diabetes
Long-term Complications of Diabetes
The long-term complications of inadequately controlled diabetes mellitus can be
devastating and potentially deadly. They include:
• neuropathy
• nephropathy (damage to the kidneys)
• retinopathy (damage to the eyes)
• cardiovascular disease
• cerebrovascular disease
• peripheral vascular disease
Click on the icon to see a physician’s perspective on diabetes and its
potential complications.
Summary of Types of Diabetes
Table 2A summarizes type 1 and type 2 diabetes.
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Describe type 1 and type 2 diabetes
Progress Check
There may be more than one correct answer to each question.
1.
2.
Type 1 diabetes:
A
is an autoimmune disease in which patients are unable to produce insulin due to
the destruction of the beta-cells of the pancreas, resulting in absolute insulin
deficiency and the accumulation of glucose in the blood.
B
accounts for 5% to 10% of all cases of diabetes mellitus.
Type 2 diabetes:
A
accounts for 90% to 95% of all cases of diabetes mellitus in the United States.
B
is associated with beta-cell dysfunction and insulin resistance, leading to chronic
hyperglycemia.
C
D
is associated with long-term complications such as neuropathy.
is characterized by absolute insulin deficiency.
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Discuss the epidemiology of DPN in the United States
Epidemiology of DPN in the United States
Approximately 23.6 million people in the United States have diabetes. It is estimated
that 60% to 70% of this population has diabetic neuropathy. One in 4 of these
patients are affected by pDPN, and 9 out of 10 patients with pDPN report moderate
or severe pain. The most common type of pDPN is distal symmetric
polyneuropathy, which occurs in 72% of all patients diagnosed with diabetic
neuropathy. It is a progressive neuropathy that primarily affects the sensory nerves.
Risk factors for DPN have not been clearly identified, although studies have shown
that the incidence of diabetic peripheral neuropathy, both painful and nonpainful,
increases with time, and is related to glycemic control (that is, poor glycemic control
is associated with DPN).
Click on the icon to see a physician’s perspective on DPN.
Click on the icon to reinforce what you have learned about the
epidemiology of DPN.
Subjective Patient Health Status
pDPN has been shown to affect patient health status by decreasing physical and
emotional functioning. Figure 2A presents Short Form 36 (SF-36) data from a DPN
survey conducted in the United States. The SF-36 is a self-administered
questionnaire that measures each of the following 8 health concepts independently
of any specific disease condition: physical functioning, role limitations due to
physical problems, bodily pain, general health perception, social functioning, mental
health, role limitations due to emotional problems, and vitality. The SF-36 is widely
recognized and accepted, and it is relatively insensitive to treatment effect. As you
can see from Figure 2A, patients with diabetes and DPN have lower scores on these
concepts of health status compared to patients with diabetes but without DPN.
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Discuss the epidemiology of DPN in the United States
Figure 2A: SF-36 Subjective Patient Health Status in Patients With DPN
Compared to Patients With Diabetes but Without DPN
Economic Costs and Healthcare Utilization
The total cost of diabetes in the United States is staggering: In 2007, it was
$174 billion. Of this total, $116 billion was attributable to direct medical costs, and
$58 billion was attributable to indirect costs such as disability, work loss, and
premature mortality.
Studies have shown that increasing pain severity in DPN leads to an increasing
burden of illness for patients with pDPN:
• medication satisfaction decreased with increased pain severity
• DPN-related healthcare visits in the prior 3 months increased with increased
disease severity
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Discuss the epidemiology of DPN in the United States
Click on the icon to read about Rodney, a patient with pDPN, and to
answer a question about his presenting signs and symptoms.
C
A S E
S
T U D Y
Rodney — A Patient with pDPN
Rodney is a 66-year-old, overweight African American
man who was diagnosed with type 2 diabetes 22 years
ago. He does his best to control his blood glucose
throughout the day with oral antidiabetic agents and
diet. Rodney was diagnosed with hypertension 7 years
ago and takes amlodipine 5 mg once daily to control his
blood pressure.
Rodney is visiting Dr. Holmes, his primary care
physician, because of an intense, burning pain in his
feet that started 4 weeks ago and has gotten
progressively worse. The pain is particularly bad at
night and is so intense that it has begun to disturb
Rodney’s sleep.
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Discuss the epidemiology of DPN in the United States
Progress Check
1.
It is estimated that _____ adults in the United States have diabetes mellitus, and
approximately _____ of people with diabetes mellitus will develop pDPN.
A 5.7 million; 25%
B 18.2 million; 30%
C
D
23.6 million; 20%
36.8 million; 40%
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Discuss the pathogenesis of DPN
Pathogenesis of DPN
DPN is defined as nerve dysfunction that occurs in persons with established
diabetes. Diabetes is probably the most common cause of peripheral neuropathy in
the United States and is responsible for significant suffering, disability, and lower
extremity amputations. The exact pathogenesis of DPN is not known and probably
includes more than one mechanism.
Hyperglycemia
A primary theory of the pathogenesis of DPN involves persistent hyperglycemia.
Hyperglycemia and/or insulin deficiency characteristic of diabetes appear to be
common pathogenetic mechanisms for various neuropathies. In fact, the incidence
and severity of DPN may be reduced by maintaining glucose levels close to normal.
Click on the icon to see a physician’s perspective on hyperglycemia
and DPN.
Hyperglycemia and other metabolic consequences of insulin deficiency have been
linked to nerve damage, which includes both degeneration in peripheral nerve axons
and the loss of large and small myelinated fibers.
Click on the icon to see a video that illustrates the effect of
hyperglycemia on the nervous system.
The mechanisms of hyperglycemia-induced nerve damage are complex, but they
appear to involve metabolic changes that lead to oxidative stress and impaired
mitochondrial function, resulting in apoptosis of neurons and Schwann cells, which
form the myelin sheath. Most nerve fibers are coated with myelin, a fatty substance
that insulates the nerve fiber and helps to speed nerve impulse transmission; without
myelin, nerve cell function is affected, and signal conduction is altered. This, in turn,
ultimately leads to irreversible structural damage to nerve fibers.
Click on the icon to see a physician’s perspective on hyperglycemia
and complications of DPN.
Complications of hyperglycemia that cause nerve damage may include:
• abnormalities of nerve vasculature
• decreased nerve blood flow (which results in ischemia)
– ischemia eventually leads to nerve damage
• abnormalities in metabolic pathways
• nonenzymatic binding of glucose to nerve proteins
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Discuss the pathogenesis of DPN
Click on the icon to see a video that illustrates the neurovascular
pathology of DPN.
Figure 2B illustrates the pathogenesis of DPN.
Figure 2B: Pathogenesis of DPN
Click on the icon to reinforce what you have learned about the
pathogenesis of DPN.
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Discuss the pathogenesis of DPN
Progress Check
There may be more than one correct answer to each question.
1.
Which of the following statements about the pathogenesis of DPN is (are) true?
A The exact pathogenesis of DPN has been clearly defined.
B
The pathogenesis of DPN probably includes more than one mechanism.
C
A primary theory of the pathogenesis of DPN involves persistent hyperglycemia.
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Describe the classification of DPN
Classification of DPN
The onset of symptoms generally occurs 10 to 20 years after diabetes has been
diagnosed. Increasingly, it is being recognized that DPN can occur early in the
course of the disease and may even be the presenting symptom of diabetes.
Approximately 3% of patients with diabetes have a form of diabetic peripheral
neuropathy when diabetes is diagnosed. The percentage grows the longer the
patient has diabetes, from 4% in patients who have had diabetes less than 5 years
to 15% in patients who have had diabetes for 20 years.
Because diabetic peripheral neuropathy can affect almost any nerve in the body, it
presents as a wide and confusing variety of symptoms. There are several different
classification systems for this disorder, but most systems begin by dividing
neuropathy into:
• diffuse neuropathies (affecting nerves throughout the body), which include:
– distal symmetric polyneuropathy
– autonomic neuropathy
• focal neuropathies (affecting just one nerve or group of nerves)
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Describe the classification of DPN
Progress Check
There may be more than one correct answer to each question.
1.
Neuropathy can be classified as which of the following?
A
B
diffuse neuropathies
acute neuropathies
C
D
focal neuropathies
obtuse neuropathies
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Discuss the diffuse neuropathies
Diffuse Neuropathies
Distal Symmetric Polyneuropathy
The most common form of pDPN is a type of diffuse neuropathy termed distal
symmetric polyneuropathy. Distal symmetric polyneuropathy affects nerves involved
with sensation. To a more limited extent, it also affects nerves responsible for motor
control. This means that sensory deficits and symptoms are generally more
common than motor symptoms.
Clinical Course
Distal symmetric polyneuropathy has a gradual onset. It is a chronic and slowly
progressive neuropathy. Symptoms commonly appear in a symmetrical glove-andstocking distribution, as shown in Figure 2C, and then progress toward the rest of
the body. The most commonly affected areas are the feet and lower legs. When
symptoms reach the level of the knees, similar symptoms begin at the fingertips and
gradually spread up the arms; motor involvement occurs later with distal loss of
strength.
Diabetic polyneuropathy may take either an acute (lasting <12 months) or a chronic
form. As the neuropathy progresses, the pain subsides and eventually disappears,
while a sensory deficit in the lower extremities persists.
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Discuss the diffuse neuropathies
Figure 2C: Glove-and-Stocking Distribution of Distal Symmetric
Polyneuropathy
Signs and Symptoms
The clinical presentation of distal symmetric polyneuropathy ranges from symptoms
of severe pain in the feet and legs to numbness in the foot or no symptoms at all.
Symptoms can include:
• sensations of burning, tingling, or numbness that occur either spontaneously or
on contact (ie, paresthesias or dysesthesias), such as the brushing of bed sheets
against toes
• allodynia and severe hyperesthesias
• diminished sense of touch, vibration, pressure, pinprick, temperature, and
position
• loss of ankle reflex, and gait and joint abnormalities
• abnormal position sense
• pain, cramping, and weakness
The pain — which may be shooting, stabbing, lancinating, or burning — is often
worse at night. There may be continuous burning or throbbing pain, with sudden
and intense "lightning" pains in the feet and legs. The pain may also interfere
substantially with daily activities, notably sleep, enjoyment of life, and recreational
activities.
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Discuss the diffuse neuropathies
The signs and symptoms of distal symmetric polyneuropathy in a particular patient
depend on which classes of nerves are involved. The condition affects both large
sensory and motor fibers as well as small nerve fibers. For example, spontaneous
neuropathic pain, such as dysesthesias, indicates the involvement of small nerve
fiber dysfunction.
Click on the icon to read more about Rodney, a patient with pDPN, and
to answer questions about Dr. Holmes’s hypothesis and his physical
examination of Rodney.
C
A S E
S
T U D Y
Rodney — A Patient with pDPN
During the appointment, Rodney tells Dr. Holmes that
about 5 years ago, he began to feel numbness in the
toes of both of his feet. Over the last year, the
numbness gradually spread to his feet and calves and
worsened to a feeling of overwhelming discomfort. In
the last 12 weeks, the feeling of discomfort in his feet
and calves began to transition into a “stabbing” pain.
Rodney tells Dr. Holmes that in the last 4 weeks, the
pain has gotten so bad that he has been using a cane to
get around, and that the pain gets worse at night and he
is having trouble sleeping.
When Dr. Holmes asks about his diabetes, Rodney
admits that he has “probably not been doing such a
great job” of monitoring his blood sugar and taking his
medication over the past few years.
`
During the physical examination, Rodney’s vital signs
are normal, and there are no evident abnormalities
involving the major organs. The skin on Rodney’s feet
has a blue coloration and appears shiny and thin. The
pulses in his feet are symmetrical, but diminished.
Rodney exhibits good lower extremity strength, but his
deep tendon reflexes are significantly diminished at both
ankles. Dr. Holmes notes an absence of sharp, thermal,
and vibration sensations at Rodney’s midcalves. The
placement of a cool tuning fork directly against his feet
causes an increase in his pain level.
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Discuss the diffuse neuropathies
Complications
Late complications in patients with advanced distal symmetric polyneuropathy include:
• ulceration of the foot
• structural changes in the foot (eg, Charcot's joints)
As the neuropathy progresses, the feet of patients may become numb and,
therefore, insensitive to injury. As a result, patients are vulnerable to and may
present with calluses or ulcerations on their feet. Other causes of ulcerations
include abnormal weight bearing, peripheral vascular disease, and poor wound
healing. Amputation may be necessary in patients who develop serious infections in
ulcerations. In fact, the combination of loss of sensation leading to ulceration with
diminished circulation is the root cause of the large number of lower extremity
amputations in patients with diabetes, which account for approximately 50% of all
nontraumatic amputations in the United States.
In addition, motor nerve damage can lead to muscle breakdown and imbalance.
Patients with distal symmetric polyneuropathy often develop abnormal foot muscle
mechanics and structural changes in the foot, including prominent metatarsal
heads. Patients may also develop Charcot's joints — that is, destruction of joint
structures that may ultimately result in a flattening of the foot arch.
Autonomic Neuropathy
Another major type of diffuse neuropathy, autonomic neuropathy, affects those
nerves that control body organs and involuntary regulatory systems. The most
common symptoms of autonomic neuropathy are illustrated in Figure 2D.
Figure 2D: Symptoms of Autonomic Neuropathy
Click on the icon to reinforce what you have learned about diffuse
neuropathies.
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Discuss the diffuse neuropathies
Progress Check
There may be more than one correct answer to each question.
1.
Distal symmetric polyneuropathy is associated with:
A
symptoms that commonly appear in a symmetrical glove-and-stocking
distribution, then progress toward the rest of the body.
B
pain that is often worse at night.
C
late complications, including ulceration of the foot and structural changes in the
foot.
muscle weakness.
D
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Discuss the focal neuropathies
Focal Neuropathies
Focal neuropathies are sudden in onset and tend to occur in older patients with
diabetes. They usually have a self-limited course, from 1 to 3 months for many
cranial nerve neuropathies, and up to 1 year for others. Focal neuropathies are
characterized by pain in the distribution area of the affected nerves. Weakness in
the muscles innervated by involved nerves may also occur. Focal neuropathies are
classified according to the peripheral nerve distribution of the specific focal lesion, as
described in Table 2B.
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Discuss the focal neuropathies
Progress Check
There may be more than one correct answer to each question.
1.
Focal neuropathies:
A affect those nerves that control body organs and involuntary regulatory systems.
B
C
are sudden in onset and tend to occur in older patients with diabetes.
typically last for several years.
D
are characterized by pain in the distribution area of the affected nerves.
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Describe the diagnosis of DPN
Diagnosis of DPN
DPN is diagnosed by a medical practitioner through the following steps:
• patient interview to determine whether the patient is experiencing related
symptoms
• physical examination, including assessment of:
– distal temperature sensation
– distal pinprick or pressure sensation
– distal vibratory sensation
– position sense
The practitioner should exclude other potential causes of neuropathy before
attributing a patient's neuropathy to diabetes.
Recall that pDPN, like other neuropathic pain states, is primarily diagnosed by
means of:
• patient history
• physical examination
• patient descriptions of the pain (eg, quality, timing, and distribution of pain)
• key physical signs
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Describe the diagnosis of DPN
In actual clinical practice, more specific diagnostic tests are usually not required.
The clinical context of the patient’s pain is the critical diagnostic factor. For example,
signs and symptoms of pain in patients with long-standing type 2 diabetes may
justifiably lead a physician to suspect pDPN. However, because there are a number
of conditions frequently associated with neuropathic pain, the physician may need to
consider other causes of neuropathic pain. Table 2C shows some of the common
pain syndromes that are similar to pDPN that a physician may have to consider.
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Describe the diagnosis of DPN
Click on the icon to read more about Rodney, a patient with pDPN, and
to answer questions about how Dr. Holmes arrived at his diagnosis.
C
A S E
S
T U D Y
Rodney — A Patient with pDPN
Following the patient history and physical examination,
Dr. Holmes tells Rodney that he has a form of pDPN
called distal symmetric polyneuropathy. On hearing
this, Rodney is a little shaken and asks Dr. Holmes if he
is going to have to undergo a lot of tests. Dr. Holmes
tells Rodney that he is experiencing classic signs and
symptoms of DPN, so he does not think any diagnostic
tests are needed. At this point, Dr. Holmes believes it
would be best to start considering treatment options that
will help Rodney get some relief from the intense pain
he has been experiencing.
Click on the icon to see a physician’s perspective on diagnosing DPN in
Kate, a patient with type 2 diabetes.
Because pDPN likely has multiple mechanisms that account for the pain present in
this disorder, it is essential to diagnose neuropathic pain based on etiology (eg, to
diagnose a patient with pDPN).
Click on the icon to see a physician’s perspective on diagnosing DPN in
Jon, a patient with type 1 diabetes.
Section 2: Diabetic Peripheral Neuropathy
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Describe the diagnosis of DPN
Progress Check
There may be more than one correct answer to each question.
1.
Which of the following are primarily used to diagnose pDPN?
A
patient history
B
physical examination
C
patient descriptions of the pain
Section 2: Diabetic Peripheral Neuropathy
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52
List the key healthcare providers involved in the
diagnosis and treatment of DPN
Key Healthcare Providers Who Treat DPN
Throughout the patient care process, there are many different hands that will touch
the patient with DPN. Table 2D lists the many healthcare professionals who
diagnose, treat, and oversee the care of patients with DPN, including patients who
experience neuropathic pain.
Section 2: Diabetic Peripheral Neuropathy
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53
List the key healthcare providers involved in the diagnosis and treatment of DPN
The makeup of the patient’s healthcare team, including the mix of specialists, will
vary depending on the patient’s geographical location and his or her individual
needs. As the patient’s healthcare requirements change and evolve, additional
healthcare providers may be added to or removed from the mix of medical expertise.
Section 2: Diabetic Peripheral Neuropathy
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List the key healthcare providers involved in the diagnosis and treatment of DPN
Progress Check
1.
The physician responsible for the day-to-day oversight of patient care who coordinates all
necessary healthcare services for any needed specialized treatment is the:
A physiatrist.
B neurologist.
C
D
2.
primary care physician.
endocrinologist.
A physician who specializes in treating patients who have uncontrolled diabetes or are
experiencing diabetic complications is a(n):
A
B
C
D
endocrinologist.
rheumatologist.
podiatrist.
neurologist.
Section 2: Diabetic Peripheral Neuropathy
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55
Section 3: Postherpetic Neuralgia
Objectives
Describe herpes zoster infection and PHN
Describe the epidemiology of PHN
Discuss the pathogenesis of PHN
Describe the clinical course and characteristics of PHN
Describe the diagnosis of PHN
List the key healthcare providers involved in the diagnosis and treatment of PHN
Postherpetic neuralgia (PHN) is the most common complication of recurrent herpes
zoster infection and is particularly prevalent in elderly patients. This section begins
with an overview of herpes zoster and PHN, including epidemiologic data, and then
provides information on the clinical course and characteristics of PHN, the diagnosis
of PHN, and the healthcare providers involved in the diagnosis and treatment of
PHN.
Section 3: Postherpetic Neuralgia
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Describe herpes zoster infection and PHN
Overview of Herpes Zoster Infection and PHN
Herpes Zoster Infection
Herpes zoster, commonly known as shingles, is an acutely painful condition. After
acute infection with varicella-zoster virus (VZV; the virus that causes chickenpox),
generally during childhood, the virus remains latent in the sensory ganglia,
including those located on the:
• dorsal roots of spinal nerves
• sensory roots of the trigeminal nerve
When reactivated, the virus produces a characteristic vesicular rash in a
dermatomal pattern — that is, lesions appear on areas on the surface of the body
that are innervated by the corresponding sensory nerves. Rashes may affect the:
• trunk area (about 50%)
• head (20%)
• arms (15%) and legs (15%)
After several days, the rash becomes pustular, then forms a crust, and finally
disappears after an average of 3 weeks. The clinical presentation of herpes zoster
also often includes pain that precedes the appearance of the rash, known as
prodromal pain, as well as pain during the acute phase of the infection. Patients
report burning, aching, or shooting pain, itching, and paresthesias in affected areas.
PHN
While some individuals exhibit no symptoms beyond the duration of the acute zoster
infection phase, many others — from 10% to 20% of patients with herpes zoster —
develop PHN. PHN is the most common complication of herpes zoster infection,
particularly in elderly patients and immunocompromised patients, as well as one of
the most serious. Some clinicians consider herpes zoster and PHN separate
entities, while others view the disorders as a continuum.
Click on the icon to see a video that provides an overview of herpes
zoster infection and PHN.
Section 3: Postherpetic Neuralgia
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57
Describe herpes zoster infection and PHN
Important to Know
The efficacy of LYRICA for the
management of PHN was
established in three double-blind,
placebo-controlled, multicenter
studies. In these studies, PHN was
defined as pain persisting for at least
3 months following healing of the
herpes zoster rash.
PHN is defined by the persistence of pain after new lesions have
ceased and healing of the skin is complete. It can be difficult to
compare data on PHN from different studies, because different
investigators define PHN using different criteria. For example, while
some clinical trial inclusion criteria allow for patients with pain at 6 months after rash
onset, common definitions of PHN include pain:
• 1 month after rash onset
• 3 months after rash onset
• at rash healing
Key Differences Between Herpes Zoster Infection and PHN
Table 3A describes the key differences between herpes zoster infection and PHN.
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58
Describe herpes zoster infection and PHN
Progress Check
1.
Which of the following is/are common definitions of PHN?
A pain at onset of herpes zoster rash
B
C
pain 1 to 3 months after onset of herpes zoster rash
pain 1 year after onset of herpes zoster rash
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59
Describe the epidemiology of PHN
Epidemiology of PHN
Since the criteria regarding the duration of pain for the diagnosis of PHN vary,
estimates of the incidence of PHN also range widely. The 12-month prevalence of
shingles or herpes zoster in the United States is approximately 1 million people. Of
that number, an estimated 10% to 20% will develop PHN. Although the number of
people who continue to experience pain decreases steadily over the 12-month
period after the initial outbreak, 4% to 22% of all PHN patients will continue to feel
pain more than 12 months after the rash has healed.
The best established risk factor for PHN is age. About 40% of patients aged 50
years and older with herpes zoster, and 75% of patients aged 75 years and older
with herpes zoster develop PHN. Gender may also be a factor, as PHN appears to
be more prevalent in women with herpes zoster (65%) than in men (35%).
Figure 3A illustrates the increase in incidence of PHN seen with increasing age in
2 studies.
Figure 3A: Incidence in PHN by Age Group
Adapted from Johnson, 1997
PHN may persist until death and has major implications for subjective patient health
status and use of healthcare resources.
Click on the icon to see a video that provides an overview of the
epidemiology of PHN.
Section 3: Postherpetic Neuralgia
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60
Describe the epidemiology of PHN
Click on the icon to reinforce what you have learned about the
epidemiology of PHN.
Subjective Patient Health Status
PHN has been shown to greatly impact a patient's health status and functional
status, as patients may experience psychological problems such as anxiety and
depression. Patients may develop sleep disorders and severe physical,
occupational, and social disabilities. PHN is associated with depression, as well as
with an increased incidence of suicide. Figure 3B illustrates data on the decreases
in SF-36 scores for patients with PHN compared to patients without that condition
aged 65 to 74 years.
Figure 3B: SF-36 Subjective Health Status in Patients With PHN
Compared to Patients Without PHN
In a survey of 385 elderly (age ≥65 years) patients with PHN, 40% of respondents
reported moderate or severe interference with general activities as a result of their
PHN. Respondents also reported that their PHN interfered with their mood, relations
with others, sleep, and enjoyment of life.
Section 3: Postherpetic Neuralgia
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61
Describe the epidemiology of PHN
Click on the icon to read about Jennifer, a patient with PHN, and to
answer a question about her presenting signs and symptoms.
C
A S E
S
T U D Y
Jennifer — A Patient with PHN
Jennifer is a 68-year-old Caucasian female who is a
retired office worker. Married for 41 years, she is the
mother of 2 children and grandmother of 3. Over the
last 12 years, Jennifer has been treated for a number of
chronic health problems including hypertension, chronic
obstructive pulmonary disease (COPD), and
osteoarthritis.
Two months ago, Jennifer was diagnosed with herpes
zoster infection. Her primary care physician,
Dr. Wagner, prescribed a 10-day course of acyclovir.
Jennifer is visiting Dr. Wagner because, even though
her initial rash healed, she has been experiencing
severe, persistent throbbing pain in the right chest wall,
extending from her back to the nipple line. The pain is
so intense, even the brushing of her blouse against her
skin has become difficult to tolerate.
Healthcare Utilization
Patients with PHN are also high users of healthcare resources. In the survey of
385 elderly patients with PHN, over half (56%) of respondents reported that they
used ≥2 prescription medications for their PHN, and 15% reported using ≥4
prescription medications for their PHN.
Section 3: Postherpetic Neuralgia
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62
Describe the epidemiology of PHN
Progress Check
1.
The 12-month prevalence of PHN in the United States is approximately 10% to 20% of the
_____ people who experience shingles or herpes zoster.
A 250,000
B 500,000
C 750,000
D
1,000,000
Section 3: Postherpetic Neuralgia
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63
Discuss the pathogenesis of PHN
Pathogenesis of PHN
Recall that after acute infection (generally during childhood), the varicella-zoster
virus remains latent in the sensory ganglia, including those located on the dorsal
roots of spinal nerves and the sensory roots of the trigeminal nerve.
Later in a patient’s life, usually after their immune system becomes compromised,
the varicella-zoster virus becomes reactivated. During this reactivation, the virus
migrates out of the spinal cord, travels along sensory nerves to the dermatome, and
appears on the surface of the skin as a rash. The rash associated with PHN, you
will also recall, is characteristically vesicular and appears in a dermatomal pattern,
with the trunk area, head, arms, and legs most commonly affected.
The mechanism of pain associated with PHN appears to be due to inflammatory
changes in or injury to the dorsal root ganglia of the spinal cord and the peripheral
nerves in the affected area of the body. As shown in Figure 3C, sensory neuron
fibers enter the spinal cord through the dorsal root. The nerve cell bodies of these
sensory neurons are found in the enlarged area of the dorsal root called the dorsal
root ganglion.
If the dorsal root or its ganglion is damaged, the corresponding area of the body is
affected. The dorsal root ganglia of the spinal nerves, particularly the thoracic
nerves (T3 through T12), and the trigeminal nerve (cranial nerve V) are the most
common sites for PHN.
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Discuss the pathogenesis of PHN
Figure 3C illustrates the dermatomal distribution of these spinal nerves, as well as
the area affected by the trigeminal nerve. As noted earlier, and as depicted in this
figure, PHN commonly affects the trunk and head regions.
Figure 3C: Spinal and Trigeminal Nerves — Affected Areas in PHN
Adapted from Marieb, 1997
Click on the icon to see a video that provides an overview of the
pathogenesis of PHN.
Click on the icon to reinforce what you have learned about the
pathogenesis of PHN.
Section 3: Postherpetic Neuralgia
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Discuss the pathogenesis of PHN
Progress Check
1.
The mechanism of pain associated with PHN appears to be due to:
A inflammation in or injury to the brain.
B
C
D
inflammatory changes in or injury to the dorsal root ganglia of the spinal cord and
the peripheral nerves in the affected area of the body.
peripheral nerve damage only.
none of the above; the mechanism of pain in PHN is largely unknown.
Section 3: Postherpetic Neuralgia
66
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Describe the clinical course and characteristics of PHN
Clinical Course and Characteristics of PHN
Clinical Course
Not all patients experience the same course of PHN onset. Approximately 70% to
80% of patients experience a prodrome of dermatomal pain several days prior to the
appearance of the herpes zoster rash. Following the initial pain of herpes zoster,
some patients may have a pain-free period prior to developing PHN. Others may
exhibit a pattern of frequent relapsing and remitting. In general, the pain associated
with PHN becomes less severe in most patients within the first year. However, in
other patients, it may persist for years or even for life and may, therefore, prove very
distressful. Remember that the temporal definition of PHN relative to the presence
of herpes zoster rash differs among researchers. Figure 3D illustrates the estimated
incidence of herpes zoster-associated pain (including PHN) over time before and
after rash appearance.
Figure 3D: Estimated Incidence of Herpes Zoster-Associated Pain (Including
PHN) Over Time Before and After Rash Appearance
Adapted from Johnson, 1997
Physical complications of PHN are rare in patients with healthy immune systems.
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Describe the clinical course and characteristics of PHN
Clinical Characteristics
PHN is described as pain that persists after acute infection of herpes zoster, even
after lesions heal. The timing criteria for the diagnosis of PHN have been defined in
many ways.
The pain associated with PHN can be severe and incapacitating. Table 3B
summarizes symptoms associated with PHN.
Click on the icon to see a video that provides an overview of the clinical
characteristics of PHN.
Section 3: Postherpetic Neuralgia
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Describe the clinical course and characteristics of PHN
Click on the icon to read more about Jennifer, a patient with PHN, and
to answer questions about Dr. Wagner’s hypothesis and her physical
examination of Jennifer.
C
A S E
S
T U D Y
Jennifer — A Patient with PHN
During the appointment, Jennifer tells Dr. Wagner that
she took the acyclovir as prescribed, but her pain never
went away, even though the initial lesions did. The pain
has been so bad in the last couple of weeks, it has
become painful to even wear a brassiere, blouse, or
nightgown. Jennifer tells Dr. Wagner that if she can’t get
relief for her pain, she’s not sure what she is going to do.
Because Jennifer has had a recent herpes zoster
infection, Dr. Wagner suspects that Jennifer may have
PHN. She takes special note of Jennifer’s statement
that “she’s not sure what she is going to do” if her pain
persists.
Dr. Wagner asks Jennifer some questions about her
mood, and notes that she seems to be experiencing
significant anxiety about her pain as well as possible
depression.
During the physical examination, Jennifer’s vital signs
are normal, and other than chronic bronchitis associated
with her COPD, there are no evident abnormalities
involving the major organs. Examination of Jennifer’s
thoracic area reveals some scarring from the healed
herpes zoster lesions, plus areas of pigmented skin that
are extremely sensitive to a very light touch. When
Dr. Wagner asks Jennifer to rate her pain on a scale
ranging from mild to excruciating, Jennifer tells
Dr. Wagner the pain is excruciating. She describes it as
continuous, burning pain, with periodic flashes that feel
like an electric shock.
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69
Describe the clinical course and characteristics of PHN
Progress Check
There may be more than one correct answer to each question.
1.
Which of the following statements about PHN is (are) true?
A
B
Not all patients experience the same onset or clinical course of PHN.
Physical complications of PHN are common.
C
PHN has been shown to greatly impact a patient's subjective health status and
functional status.
D
In general, the pain associated with PHN becomes less severe in most patients
within the first year.
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Describe the diagnosis of PHN
Diagnosis of PHN
Diagnosis of PHN includes a detailed assessment of the pain. A medical history
should be taken, and the following details obtained from the patient:
• type of pain
• timing of pain
• effects of pain on general health status and sleep
In patients with PHN, symptoms usually appear in a radicular pattern. Physical
findings usually include a painful hypopigmented area in a dermatomal distribution.
A neurologic examination may be performed to determine cold and heat thresholds,
extent and type of allodynia, and areas of altered sensation. As described in the
previous section, there may be dysesthesia, paresthesia, and hypalgesia in the
involved areas. These findings, along with a history of the characteristic vesicles,
can usually confirm the diagnosis.
Click on the icon to read more about Jennifer, a patient with PHN, and
to answer a question about how Dr. Wagner arrived at her diagnosis.
C
A S E
S
T U D Y
Jennifer — A Patient with PHN
Following the patient history and physical examination,
Dr. Wagner tells Jennifer that her signs and symptoms
plus her history of herpes zoster lesions can usually
confirm that the pain she is experiencing is from PHN.
Jennifer immediately asks if the pain is treatable.
Dr. Wagner tells her it is, and they can discuss
treatment options right away. Jennifer seems relieved
to hear this.
Section 3: Postherpetic Neuralgia
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71
Describe the diagnosis of PHN
Progress Check
There may be more than one correct answer to each question.
1.
Which of the following symptoms are associated with PHN?
A
analgesia
B
dysesthesia
C
paresthesia
D
hypalgesia
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72
List the key healthcare providers involved in the
diagnosis and treatment of PHN
Key Healthcare Providers Who Treat PHN
Throughout the patient care process, there are many different hands that will touch
the patient with PHN. Table 3C lists the many healthcare professionals who
diagnose, treat, and oversee the care of patients with PHN.
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List the key healthcare providers involved in the diagnosis and treatment of PHN
The makeup of the patient’s healthcare team, including the mix of specialists, will
vary based on the patient’s geographical location and his or her individual needs.
As the patient’s healthcare requirements change and evolve, additional healthcare
providers may be added to or removed from the mix of medical expertise.
Section 3: Postherpetic Neuralgia
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74
List the key healthcare providers involved in the diagnosis and treatment of PHN
Progress Check
There may be more than one correct answer to each question.
1.
2.
Which of the following physician types can specialize in pain management?
A rheumatologist
B
neurologist
C
D
anesthesiologist
podiatrist
A physician who focuses on the patient’s quality of life, with particular emphasis on pain
management is a:
A
B
C
D
physiatrist.
podiatrist.
rheumatologist.
anesthesiologist.
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Module Summary
(1) Pain classification: Pain can be classified in a number of ways. Two of the
most common differentiations in types of pain are:
• acute versus chronic pain
• nociceptive versus neuropathic pain
Although the duration of pain is a primary difference between acute and chronic
pain, chronic pain is not simply a temporal extension of acute pain. Acute pain:
• typically has a sudden onset related to a specific event
• serves a protective purpose
• is short-lived
• has a predictable course whose duration often correlates with the causative
factor
• is generally accompanied by autonomic responses, including tachycardia,
rapid breathing, and increased blood pressure
• may produce anxiety, but patients generally have an optimistic outlook about
obtaining relief
• resolves after successful intervention or healing
• is generally relieved by analgesics
Chronic pain:
• has a gradual onset
• is characterized by pain that continues despite treatment or apparent
healing
• serves no biologic purpose and has little protective significance
• may be continuous or intermittent and is long in duration
• is defined as pain lasting (by some definitions) ≥6 months
• may or may not have well-defined causes
• causes symptoms of irritability, lack of energy, fatigue, and an impaired
ability to concentrate
• affects physical and social functioning
• is often refractory to analgesic therapy
Nociceptive pain arises in response to injury of somatic or visceral tissues
through the excitation of nociceptors. When acute, nociceptive pain serves as
a warning sign to the body that it is being harmed and has a protective function.
Once the causative factor is removed or addressed, the pain is eliminated or
diminished. Neuropathic pain, which is initiated or caused by a primary lesion
or dysfunction in the nervous system, is a type of chronic pain in which the
nervous system itself generates and perpetuates pain, in the absence of the
stimuli from injury that are typical of nociceptive pain. Unlike nociceptive pain,
neuropathic pain has no protective function.
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76
Causes and types of neuropathic pain: Neuropathic pain may be caused by
various factors, including:
• metabolic diseases
• infection
• certain drugs, toxins, vitamin deficiencies, connective tissue diseases,
trauma, and inherited neuropathies
Neuropathic pain syndromes are classified based on the location of the
damage in the nervous system as:
• central pain (lesions in the CNS)
• peripheral pain (lesions in peripheral nerves)
• other (location of damaged nervous tissue cannot be determined)
• mixed (encompassing both nociceptive and neuropathic pain)
Mechanisms of neuropathic pain: Within a given neuropathic syndrome,
several mechanisms are likely responsible for the pain experienced, including:
• direct stimulation of pain-sensitive neurons, in which pain-sensitive neurons
(A-delta fibers and C fibers are 2 key types) are directly stimulated and
begin firing in response to the mechanical stretching of nerves, nerve
compression, or certain chemicals
• peripheral sensitization and the theory of central sensitization, in which
nociceptor sensitivity to painful stimuli is amplified
– in peripheral sensitization, intense or prolonged pain stimuli can lower the
activation thresholds of nociceptors and increase their firing rates, so that
even stimuli that are normally harmless feel painful
– in the theory of central sensitization, a secondary zone of increased
responsiveness is thought to develop in the uninjured tissue surrounding
the injured site due to changes that occur in the dorsal horn of the spinal
cord
• automatic (also called spontaneous) firing of damaged nerves, in which
nerve fibers damaged by disease or injury spontaneously fire at the site of
injury or at other locations along the damaged nerve
• deafferentation, which occurs when injury interrupts any portion of the
normal pain transmission pathway, resulting in firing of nerves farther up the
pathway and ongoing pain
• sympathetically mediated pain, in which injury causes hyperactivity in the
sympathetic nervous system, which releases norepinephrine, stimulating the
primary sensory nerve for pain, causing pain and fueling further sympathetic
activity
Comorbidities of neuropathic pain: Patients with neuropathic pain frequently
have associated comorbid conditions, notably:
• pain-related sleep disorders
• anxiety and depressive disorders
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77
Both pDPN and PHN have been associated with increased sleep difficulties
and reduced sleep quality. pDPN has been associated with increased anxiety
and depressive disorders, and PHN has been associated with interference with
mood.
Diagnosing neuropathic pain: Neuropathic pain is diagnosed through a
patient history and physical examination. The clinical context of the pain is a
critical factor. Other key diagnostic indications include patient descriptions of
the pain, and physical signs. Neuropathic pain syndromes usually consist of a
combination of negative (eg, sensation loss and numbness) and positive
symptoms (eg, dysesthesias, paresthesias, and pain), which are commonly
classified as either spontaneous (stimulus-independent), or provoked (stimulusevoked).
A common finding at examination is a pattern of sensory dysfunction, with or
without associated motor dysfunction. Sensory impairment may lead patients
to experience both severe pain and numbness at once, as well as a loss of
reflexes at an affected site. Motor dysfunction may lead to weakness.
Abnormal sensory perceptions may also be evident upon examination, with
allodynia being one of the most characteristic features. Finally, an important
distinguishing factor of neuropathic pain is its timing, as it is often worse at
night. The pain may also follow a recognized anatomic nerve distribution.
Because patients may find it difficult to describe their pain, pain rating scales
have been developed to provide patients with a pain vocabulary and simple
ways to indicate pain intensity.
(2) Overview of diabetes: Diabetes mellitus is a clinical syndrome in which
chronic hyperglycemia results from defects in insulin production and, in some
cases, from insulin resistance. The 2 types of diabetes most commonly
associated with diabetic peripheral neuropathy (DPN) are type 1 and type 2
diabetes.
Type 1 diabetes is an autoimmune disease in which patients are unable to
produce insulin due to the destruction of the beta-cells of the pancreas,
resulting in absolute insulin deficiency and the accumulation of glucose in the
blood. Common symptoms include excessive urination, excessive thirst,
dehydration, weakness, and weight loss. Patients with type 1 diabetes must
take daily insulin injections in order to survive. Type 1 diabetes accounts for
5% to 10% of all cases of diabetes mellitus.
Type 2 diabetes accounts for 90% to 95% of all cases of diabetes mellitus in
the United States. In patients with type 2 diabetes, beta-cells are unable to
detect and respond appropriately to hyperglycemia, so insulin is produced, but
in insufficient quantities to maintain normal blood glucose levels. Insulin
resistance is a hallmark of type 2 diabetes and refers to the failure of body
tissues to respond to insulin. Eventually, hyperglycemia develops.
Epidemiology of DPN: Approximately 23.6 million people in the United States
have diabetes. It is estimated that 60% to 70% of this population has diabetic
neuropathy. One in 4 of these patients are affected by pDPN, and 9 out of
10 patients with pDPN report moderate or severe pain.
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78
Pathogenesis of DPN: The exact pathogenesis of DPN is not known and
probably includes more than one mechanism. A primary theory of the
pathogenesis involves persistent hyperglycemia. Hyperglycemia and other
metabolic consequences of insulin deficiency have been linked to nerve
damage, which includes both degeneration in peripheral nerve axons and the
loss of large and small myelinated fibers. The mechanisms of hyperglycemiainduced nerve damage are complex.
Classification: Diabetic peripheral neuropathy can be divided into diffuse
neuropathies (affecting nerves throughout the body), and focal neuropathies
(affecting just one nerve or group of nerves).
Diffuse neuropathies: Distal symmetric polyneuropathy is a type of diffuse
neuropathy that is the most common form of pDPN. It affects nerves involved
with sensation and, to a more limited extent, it also affects nerves responsible
for motor control.
Distal symmetric polyneuropathy has a gradual onset and is a chronic and
slowly progressive neuropathy. Symptoms commonly appear in a symmetrical
glove-and-stocking distribution, then progress toward the rest of the body.
The most commonly affected areas are the feet and lower legs. Distal
symmetric polyneuropathy may take either an acute (<12 months) or chronic
form. As it progresses, the pain subsides and eventually disappears, while a
sensory deficit in the lower extremities persists.
Symptoms of distal symmetric polyneuropathy depend on which classes of
nerves are involved and range from severe pain in the feet and legs to
numbness in the foot or no symptoms at all.
Late complications in patients with advanced distal symmetric polyneuropathy
include ulceration of the foot and structural changes in the foot (eg, Charcot's
joints).
Autonomic neuropathy is another major type of diffuse neuropathy. It affects
nerves that control body organs and involuntary regulatory systems.
Focal neuropathies: Focal neuropathies are sudden in onset and tend to
occur in older patients with diabetes. They usually have a self-limited course
(1 to 3 months for many cranial nerve neuropathies; ≥1 year for others). They
are characterized by pain in the distribution area of the affected nerves.
Weakness in the muscles innervated by involved nerves may also occur. Focal
neuropathies are classified according to the peripheral nerve distribution of the
specific focal lesion.
Diagnosis: DPN is diagnosed through a patient interview and physical
examination, including assessment of the patient's sensation of distal
temperature, pinprick or pressure, vibration, and vibratory sensation, and sense
of position. Other painful conditions that can resemble pDPN that the physician
will have to consider include claudication, Morton’s neuroma, osteoarthritis,
radiculopathy, plantar fasciitis, and tarsal tunnel syndrome.
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Key healthcare professionals who treat DPN: The mix of healthcare
providers and specialists on the patient’s healthcare team can vary depending
on the geographical location and his or her individual needs. Some examples
of healthcare team members include primary care physicians (PCPs);
endocrinologists/diabetologists; neurologists, particularly those specializing in
neuromuscular medicine or pain management; anesthesiologists who
specialize in pain management; physiatrists, especially those specializing in
neuromuscular medicine or pain management; podiatrists; and
rheumatologists. As the patient’s healthcare requirements change and evolve,
additional healthcare providers and specialists may be added to or removed
from the mix of medical expertise.
(3) Overview of herpes zoster infection and PHN: Herpes zoster, commonly
known as shingles, is an acutely painful condition caused by varicella-zoster
virus (VZV). After infection in childhood, VZV remains latent in the sensory
ganglia and, when reactivated, produces a characteristic vesicular rash in a
dermatomal pattern. After several days, the rash becomes pustular, then forms
a crust, and finally disappears after an average of 3 weeks. The clinical
presentation of herpes zoster also often includes prodromal pain preceding the
appearance of the rash, as well as pain during the acute phase of the infection.
While some individuals exhibit no symptoms beyond the acute zoster infection
phase, many others develop PHN. PHN is defined by the persistence of pain
after new lesions have ceased and healing of skin is complete. Common
definitions include pain 1 month after rash onset, 3 months after rash onset,
and at rash healing.
Epidemiology of PHN: The 12-month prevalence of shingles or herpes zoster
in the United States is approximately 1 million people. Of that number, an
estimated 10% to 20% will develop PHN. About 40% of patients aged 50 years
and older with herpes zoster, and 75% of patients aged 75 years and older with
herpes zoster develop PHN. PHN may persist until death and has major
implications for patient health status and use of healthcare resources.
Pathogenesis of PHN: When reactivated, the varicella-zoster virus migrates
out of the spinal cord, travels along sensory nerves to the dermatome, and
appears on the surface of the skin as a rash. The rash associated with PHN is
characteristically vesicular and appears in a dermatomal pattern, with the trunk
area, head, arms, and legs most commonly affected. The mechanism of pain
associated with PHN appears to be due to inflammatory changes in or injury to
the dorsal root ganglia of the spinal cord, particularly the thoracic nerves and
the trigeminal nerve, and the peripheral nerves in the affected area of the body.
PHN commonly affects the trunk and head regions.
Clinical course and clinical characteristics: Not all patients experience the
same course of PHN onset. Approximately 70% to 80% of patients experience
a prodrome of dermatomal pain several days prior to the appearance of the
herpes zoster rash. Following the initial pain of herpes zoster, some patients
may have a pain-free period prior to developing PHN. Others may exhibit a
pattern of frequent relapsing and remitting. In general, the pain associated with
PHN becomes less severe in most patients within the first year. However, in
other patients it may persist for years or even life and can prove very
distressful.
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80
Physical complications of PHN are rare in patients with healthy immune
systems. PHN has been shown to greatly impact a patient's subjective health
status and functional status, as patients may develop depression, anxiety, sleep
disorders, and severe physical, occupational, and social disabilities.
Patients with PHN report 3 types of pain:
• a constant, deep, aching, or burning sensation
• a spontaneous, recurrent, lancinating, shooting, or electric shock-like pain
• an allodynic, superficial, sharp, radiating, burning, tender, or "itch-like"
sensation from clothing or gentle touch
Symptoms may also include analgesia, dysesthesia, paresthesia, hypalgesia,
pain exacerbation with touch, and pain induced by cold. There are usually no
pain-free periods with PHN.
Diagnosis: Diagnosis includes a detailed assessment of the pain, including
the type and timing of the pain and its effects on health status and sleep.
Key healthcare professionals who treat PHN: The mix of healthcare
providers and specialists on the patient’s healthcare team can vary based on
geographical location and his or her individual needs. Some examples of
healthcare team members include primary care physicians (PCPs);
neurologists, particularly those specializing in pain management;
anesthesiologists who specialize in pain management; physiatrists, especially
those specializing in neuromuscular medicine or pain management; and
rheumatologists. As the patient’s healthcare requirements change and evolve,
additional healthcare providers and specialists may be added to or removed
from the mix of medical expertise.
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Glossary
abducens
pertaining to cranial nerve VI
activation threshold
the point at which afferent nociceptors fire in response to stimulation
A-delta fiber
myelin-covered nerve fiber that carries sharp, initial pain sensations; has larger diameter
and faster conduction speeds than C fibers
allodynia
a condition in which ordinarily nonpainful stimuli evoke pain
amyotrophy
muscular wasting or atrophy
apoptosis
programmed cell death
autonomic
relating to the autonomic nervous system, the division of the nervous system that helps
regulate the body's internal environment
Bell's palsy
paresis or paralysis, usually unilateral, of the facial muscles, caused by dysfunction of the
seventh cranial nerve; probably due to a viral infection; usually demyelinating in type
beta-cells
the predominant cell of the islets of Langerhans that secretes insulin
brachial
relating to the arm
C fiber
nerve fiber that carries persistent, aching pain sensations; has no myelin covering; diameter
is smaller than A-delta fiber, and conduction speed is slower
central nervous system (CNS)
a division of the nervous system that consists of the brain and spinal cord; provides overall
coordination and interpretation of information and directs responses
cervical
relating to the neck
claudication
cramplike pains in the calves caused by poor circulation of the blood to the leg muscles
cutaneous
pertaining to the skin
deafferentation
elimination or interruption of afferent nerve impulses, as by destruction of afferent pathway
dermatome
an area of skin supplied by branches from a single spinal nerve
dermatomal
relating to an area of skin supplied by branches from a single spinal nerve
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dorsal horn
crescent-shaped projection of gray matter in spinal cord
dorsal root
the sensory root of a spinal nerve, located in the dorsal horn of the spinal cord
dorsal root ganglia
clusters of cell bodies of sensory neurons that enter the spinal cord at the dorsal root; these
neurons conduct impulses from the peripheral nerves into the spinal cord; their axons
constitute the dorsal root of a spinal nerve
dysesthesia
disagreeable sensation produced by ordinary stimuli
glucose
chief source of energy in human metabolism; the principal sugar of the blood
hypalgesia
decreased sensibility to pain
hyperalgesia
extreme sensitivity to painful stimuli
hyperglycemia
abnormally high concentrations of glucose in the blood
hypothyroidism
diminished production of thyroid hormone, leading to clinical manifestations of thyroid
insufficiency
insulin
a hormone produced by the pancreas; responsible for the absorption of glucose into the
cells
ischemia
lack of blood (and the oxygen it carries) in a region
ketosis
a condition characterized by the enhanced production of ketone bodies, as in diabetes
mellitus or starvation
lancinating
denoting a sharp cutting or tearing pain
metatarsal
the 5 long bones of the foot
myelinated
having a sheath of myelin, a fatty substance that insulates the nerve fiber and helps to
speed nerve impulse transmission
neuroma
a benign tumor generally arising from nerve tissue that is composed chiefly of neurons and
nerve fibers
nociceptor
afferent nerve (a nerve that conveys impulses from the periphery to the central nervous
system) receptor that collects information about pain
oculomotor
pertaining to cranial nerve III
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ophthalmoplegia
paralysis of one or more of the ocular muscles
osteoarthritis
arthritis in which one or more joints undergoes degenerative changes, including loss of
cartilage and formation of bone spurs
palsy
paralysis
paresthesia
an abnormal sensation such as burning, pricking, tickling, or tingling
peripheral nervous system (PNS)
part of the nervous system that is external to the brain and spinal cord
plantar fasciitis
one of the most common causes of heel pain; characterized by pain and inflammation of the
plantar fascia, a thick band of tissue that runs across the bottom of the foot and connects
the heel bone to the toes
polydipsia
excessive thirst that is relatively prolonged
polyuria
excessive excretion of urine resulting in profuse and frequent urination
prodromal
relating to an early or premonitory symptom of a disease
prostaglandins
any of a class of physiologically active substances present in many tissues, with effects
such as vasodilation, vasoconstriction, stimulation of intestinal or bronchial smooth muscle,
uterine stimulation, and antagonism to hormones influencing lipid metabolism
ptosis
a sinking down or prolapse of an organ
pulses
a rhythmic beating or vibrating movement
pustular
relating to or marked by pustules, superficial elevations of the skin containing purulent
material
radicular
relating to a radicle of a nerve, a nerve fiber that joins others to form a nerve
radiculopathic
related to a disorder of the spinal nerve roots
radiculopathy
distribution of focal lesions at the level of nerve roots
retro-orbital
behind the eye cavity
sensory ganglia
a cluster of primary sensory neurons forming a usually visible swelling in the course of a
peripheral nerve or its dorsal root; the sole afferent neural connection between the sensory
periphery and the central nervous system
somatic
relating to the body
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tachycardia
rapid beating of the heart, conventionally applied to rates over 100 beats per minute
tactile
relating to touch
tarsal
pertaining to the ankle bone
thoracic nerve
one of 12 nerves on each side, mixed motor and sensory, supplying the muscles and skin of
the thoracic and abdominal walls
thorax
the upper part of the trunk containing the lungs, heart, and part of the abdominal organs
tibial
pertaining to the largest bone in the lower leg
trigeminal nerve
the chief sensory nerve of the face and the motor nerve of the muscles of mastication
trochlear
pertaining to cranial nerve IV
type 1 diabetes
formerly known as insulin-dependent diabetes mellitus (IDDM); usually develops abruptly
before the age of 20; an autoimmune disease characterized by a complete failure of insulin
production
type 2 diabetes
formerly known as non-insulin-dependent diabetes mellitus (NIDDM); often of gradual onset,
usually in obese individuals over age 40; characterized by a relative lack of insulin
production and a decreased tissue response to insulin
ulceration
the formation of an ulcer, a lesion through the skin or a mucous membrane resulting from
loss of tissue, usually with inflammation
vesicular
relating to, characterized by, or containing vesicles (small elevations of the skin containing
fluid)
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