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Assessment of Neuropathic Pain in
Cancer Patients
Deborah T. Blumenthal, MD
Corresponding author
Deborah T. Blumenthal, MD
Oncology Division, Tel-Aviv Sourasky Medical Center, 6 Weizmann
Street, 64239 Tel-Aviv, Israel.
E-mail: [email protected]
Current Pain & Headache Reports 2009, 13:282–287
Current Medicine Group LLC ISSN 1531-3433
Copyright © 2009 by Current Medicine Group LLC
Neuropathic pain is an increasingly common problem facing the cancer patient. Painful neuropathy can
come from various sources and significantly impact
quality of life. The most commonly observed scenario
is paraesthesia and dysesthesia as a result of toxic
effects of chemotherapies on the distal peripheral
nerves. Neuropathic pain should be addressed ideally
with the help of a neuro-oncologist, and it usually
can be successfully treated with a variety of agents,
including atypical analgesics such as antidepressants,
newer drugs with analgesic benefit, and opioids for
more refractory cases. Direct and indirect effects of
the primary neoplasm need to be considered in the
etiology of specific syndromes of mononeuropathies
and plexopathies.
burning, needle-like pain, or electric sensations. However,
some cases are refractory to most agents and require a more
aggressive approach with opioids. The element of hypoesthesia (numbness) is not effectively treated symptomatically and
recovers only with nerve regeneration, which occurs slowly
and not always completely, and is dependent upon the cumulative magnitude of the exposure to the toxic agent and the
individual’s inherent sensitivity [1•]. Patients with underlying
disorders such as diabetes may have enhanced sensitivity and
lowered threshold to the effects of neurotoxic agents.
In addition to neurotoxic chemotherapeutic agents,
cancer patients may suffer from painful neuropathies due
to direct involvement of their neoplasm in the form of
mononeuropathies, radiculopathies, or plexopathies, or
from paraneoplastic syndromes such as sensory ganglionopathy or vasculitic neuropathy. Adequate treatment of
these syndromes usually demands control of the cancer.
Toxic Neuropathy From Chemotherapy
Painful neuropathy is being seen with increasing frequency with the growing use of regimens with neurotoxic
chemotherapy agents. The most common neuropathic
scenarios seen in the clinic involve patients treated with
platinum analogs (cisplatin, oxaliplatin), taxanes, and less
commonly, fluorouracil (5-FU).
Introduction
Neuropathic pain is a problem seen with increasing
incidence in oncology clinics. With the increasing use of
chemotherapy regimens, including neurotoxic agents, the
clinician is commonly faced with the dilemma of assessing
the etiology and degree of neuropathic pain and deciding
what the threshold is to discontinue causative toxic treatment that may be important in controlling the primary
neoplasm. The Common Toxicity Criteria (CTC) scale
may be useful for assessing and grading the neuropathic
injury, but there are no defi nitively established guidelines
for when to discontinue therapy and how to predict irreversible or intolerable neuropathic toxicity. Elements of
neuropathy and neuropathic pain may differ depending
on the etiologic agent. Components of nonpainful paraesthesia, which can affect daily function, also need to be
considered in the assessment.
A number of typical and atypical analgesic agents can be
helpful in ameliorating dysesthesias (unpleasant sensations),
Causative agents
Most chemotoxic neuropathies are purely sensory and
often involve an element of pain. Small and/or large sensory fibers may be involved. Cisplatin is a heavy metal
platinum agent used largely in head and neck and gynecologic cancer regimens, usually in combination with other
agents or radiation. It can cause a distal sensory neuropathy that involves the large myelinated sensory fibers,
characterized by symmetric loss of distal sensory axons
with proprioception deficit. Loss of vibratory sense may
be proportionately large compared with other sensory
modalities. The peripheral neuropathy associated with
cisplatin may be associated with dorsal column spinal
cord involvement and damage to the dorsal root ganglion,
with clinical Lhermitte’s sign (an electric shock–like sensation involving the limbs or trunk, produced by neck
flexion). Cisplatin causes selective damage to the hair
cells in the organ of Corti, resulting in high-frequency
Assessment of Neuropathic Pain in Cancer Patients
hearing loss in 60% of patients treated with doses greater
than 600 mg/m 2 . Neuropathy usually develops when
cumulative doses exceed 400 mg/m 2 [2]. Long-term toxicity after a median of 15 years was studied in a cohort
of patients treated with cisplatin for testicular cancer. Of
these patients, 38% were found to have nonsymptomatic
neuropathy, 28% had symptomatic neuropathy, and 6%
had disabling polyneuropathy [3].
Oxaliplatin is a newer platinum derivative used as
a standard agent in regimens for colorectal malignancies [4]. Although it has an improved toxicity profi le
compared with older platinum agents, its dose-limiting
toxicity is typically neurologic. Oxaliplatin may cause
two distinct forms of neuropathy that can be disturbing for the patient. One form is a temperature-sensitive,
(cold)-induced, acute, painful neuropathic syndrome that
is usually time-limited to the day of treatment and several days thereafter. It manifests in perioral dysesthesias,
tingling, and laryngopharyngeal spasms. This acute neuropathy occurs in a majority of patients to some degree
early in their course of treatment; it is not cumulative and
is reversible. The possible underlying mechanism may be a
disturbance in voltage-gated sodium channels, which may
be related to calcium levels, leading to hyperexcitability
[5]. As such, administration of calcium and magnesium
has been given to lessen the severity of the hyperexcitability symptoms [6,7]. The serotonin-noradrenaline
reuptake inhibitor, venlafaxine, and the neuroprotective
amifostine have been used, but no defi nitive randomized
trials of these agents have been performed [8]. Avoidance
of offending cold agents is helpful during the transient
period after treatment.
The second form of oxaliplatin-induced neuropathy
involves the distal (sensory) nerves. This sensory axonal
and demyelinating neuropathy can lead to a debilitating
sensory ataxia. It intensifies with the degree of treatment
exposure. Less than 15% of patients will suffer from neuropathy when exposed to doses of 780 mg/m 2 , whereas
50% will manifest symptoms at doses of 1200 mg/m 2 .
More than 75% of patients will ultimately have improvement of their neuropathy following discontinuation, but a
subset may have irreversible symptoms. Most sequelae of
neuropathy from oxaliplatin reverse in 4 to 6 months and
completely resolve in 40% of patients by 6 to 8 months.
Patients may suffer from hypersensitivity or dysesthesia,
but most commonly they are bothered by numbness, which
can often affect activities of daily life involving fine coordination (eg, buttoning, sewing, and handling coins). There
is increasing information regarding mechanism-based biomarkers that may be able to identify patients at increased
risk of neurotoxicity from treatment with single-agent or
combination platinum chemotherapy regimens [9•].
Taxanes, namely paclitaxel, are antimicrotubule
agents—commonly used in gynecologic malignancies and
lung cancer—that have broad activity for a variety of other
cancers. Paclitaxel is much more commonly implicated in
neuropathy compared with docetaxel. Both taxanes can
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affect small- and large-fiber sensory nerves resulting in
a painful sensory neuropathy with a dysesthetic, hypersensitive component. The underlying toxic mechanism
is thought to be damage to the axonal mitochondria of
C fibers [10]. In as many as 17% of cases, paclitaxel can
cause a motor neuropathy that can present with disabling,
but usually reversible, proximal weakness that is likely
due to proximal denervation [11]. Transient visual scotomas have been described with taxane infusions in about
20% of cases, with a minority of these patients showing
subclinical optic neuropathy and decreased visual acuity
[12]. Taxane-platinum combined regimen neurotoxicity
may be ameliorated by substituting docetaxel for the more
neurotoxic paclitaxel [13].
Prophylactic treatment with acetyl-L-carnitine has
been proposed to prevent neuropathic pain associated
with paclitaxel. Animal models show a possibly protective effect via protection of C-fiber mitochondria [14]. A
randomized study of 86 colorectal patients treated with a
regimen of oxaliplatin and 5-FU showed significantly less
neurotoxicity in the group treated with oral glutamine
[15]; studies of oral glutamine with high-dose paclitaxel
also suggest a neuroprotective effect [16].
Vinca alkaloids (vincristine) are microtubule inhibitors
that are often used in leukemic malignancies and cause an
axonal sensory-motor neuropathy. A mild to moderate sensory neuropathy is seen in 7% to 31% of treated patients.
This is typically distal in distribution, presenting with paresthesias. Doses above the usual cap of 2 mg may result in a
motor neuropathy with weakness, drop foot/feet, and (less
commonly) wrist drop. Patients with hereditary neuropathies, such as Charcot-Marie-Tooth [17], are particularly
susceptible to these toxic motor neuropathies. Constipation, ileus, and bowel pain can occur from involvement of
autonomic nerves. Symptoms are usually reversible, but the
motor-sensory deficits can be permanent. A small percentage (< 5%) of patients may suffer severe pan-neurotoxicity,
which can be fatal [18]. Focal cranial nerves also can be
involved, including facial pain, jaw pain, optic atrophy, and
extraocular muscle enervating nerves.
Thalidomide, used as an antineoplastic agent for multiple myeloma and Kaposi’s sarcoma, causes an axonal
sensory neuropathy in up to 30% of cases, presenting
with distal paresthesias and loss of sensation [19].
Less commonly, antimetabolites such as 5-FU (used for
treatment of colorectal cancers) can cause a sensorimotor
neuropathy. This is usually a painless hypoparaesthesia.
Oral capecitabine (used in breast and colorectal cancer)
can also elicit such symptoms [20]. Cytarabine, used most
commonly in hematologic malignancies, can be associated
with a peripheral neuropathy, but more commonly causes
cerebellar toxicity when given in high doses [21].
Characteristics of Painful Neuropathy
The characteristics of toxic neuropathy depend upon the
fibers injured from the causative chemotherapy. Small-fiber
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Table 1. NCI common terminology criteria for adverse events
Grade I
Neuropathy (motor)
Grade II
Grade III
Asymptomatic;
Symptomatic weakness
Weakness interfering
weakness on exami- interfering with function, with ADL; bracing or
nation/testing only
but not ADL
assistance to walk
Neuropathy (sensory) Asymptomatic; loss of
DTRs or paraesthesia
(tingling) not interfering with function
Grade IV
Life-threatening;
disabling (paralysis)
Sensory alteration or
Sensory alteration or
Disabling
paraesthesia (tingling)
paraesthesia interfering
interfering with function, with ADL
but not ADL
Pain (peripheral nerve) Mild pain not inter- Moderate pain; pain or
Severe pain; pain or
fering with function analgesics interfering with analgesics severely
function, but not ADL
interfering with ADL
Disabling
ADL—activities of daily living; DTR—deep tendon reflexes; NCI—National Cancer Institute.
(Data from the National Cancer Institute [33].)
involvement, as seen from taxane toxicity, results in burning, lancinating dysesthesias, and hyperesthesia/pressure
sensitivity, with loss of pain and temperature sensation.
Large-fiber involvement from cisplatin results in vibration
and proprioception loss. Autonomic neuropathy (taxanes
and vinca alkaloids) results in orthostatic hypotension
and gastrointestinal dysfunction.
Patients with chemotherapy-induced neuropathy most
commonly complain of a loss of sensation or numbness
in a stocking-glove distribution or “thickness” of the
extremity that involves the most distal aspects of the toes
and fi ngers, but spreads proximally with worsening. The
patient may wake from sleep because of dysesthesias.
Such complaints justify initiation of palliative symptomatic treatment. Neuropathy symptoms can begin early in
the course of treatment and worsen with increased exposure to the toxic agent. They may initially abate between
treatments, but tend to accumulate and become constant
after repeated exposures. Neuropathic symptoms can
worsen for more than a month after the discontinuation
of the offending agent, take months to plateau, and up to
a year or years (in some cases) to lessen in severity. There
may be worsening of the grade of neuropathy severity
for weeks to months after stopping the therapy. In some
cases, the symptoms do not reverse and the patient is left
with irreversible disability from neuropathy. Such cases
are thought to involve injury to the dorsal root ganglion
and lead to actual neuronal death [22]. Although there
are no clear guidelines as to when a toxic agent should
be stopped, when the patient approaches a degree of
disability or pain that cannot be tolerated long-term,
discontinuation of the causative chemotherapy drug or
change to a less neuropathic agent needs to be considered.
The degree of importance of the chemotherapy for the
individual patient (ie, adjuvant treatment of a low-stage
cancer vs essential therapy for residual or recurrent active
and responding disease) needs to be considered in regard
to changing therapy.
Sensory and motor neuropathy is graded by the
CTC scale, labelled as grades I through V (grade V
being death). Pain is classifi ed separately (Table 1). No
reliable data in the literature currently exist regarding
reversibility of the toxicity. Hence, caution should be
taken to stop chemotherapy before the patient reaches
an intolerable grade of damage.
Treatment
Neuropathic pain can be treated with typical analgesics
such as acetaminophen and NSAIDs, but these are often
not helpful for the aspects of burning dysesthesia, lancinating electric pain, or hypoesthesia. Although there are
no defi nitive trials to provide level I evidence, adjuvant
analgesics such as tricyclic antidepressants (TCAs; eg,
amitriptyline), antiepileptics, and newer agents mentioned
below may be useful in the treatment of neuropathic
pain. The therapeutic effect of these agents needs to be
balanced with side effects that often include sedation
and anticholinergic phenomena in the TCAs: dry mouth
and orthostasis. In general, an analgesic agent should
not be discounted as ineffective until it has been tested
adequately (typically for several weeks to a month) at a
maximally tolerated, side effect–limited dose.
Antiepileptics, such as carbamazepine and gabapentin, may be effective and remain fi rst-line agents for
treatment of neuropathic pain in trigeminal neuralgia
[23]. The agents used with increasing success include
gabapentin, pregabalin, and duloxetine. Gabapentin was
developed as an antiepileptic and has been found to be
effective for the treatment of atypical and neuropathic
pain. Starting doses begin at 100 to 300 mg twice or
three times daily, and it can be increased up to 3000 mg
a day in split doses. Pregabalin is an antiepileptic agent
thought to work via reduction of neuronal hyperexcitability. Treatment starts at 75 mg twice daily, and it can
be increased gradually to 150 mg twice daily. Duloxetine
is approved by the US Food and Drug Administration for
the treatment of diabetic painful neuropathy, at a oncea-day dose of 60 mg.
Occasionally, adequate trials of numerous atypical agents are unsuccessful, and the patient continues
to suffer from debilitating neuropathic pain. Opioids,
Assessment of Neuropathic Pain in Cancer Patients
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component, how to prevent this common toxicity, and
how to treat painful symptoms.
Mononeuropathies in Cancer Patients
Figure 1. Infiltration (arrow pointing to enhancing lesion) of proximal
radial nerve by systemic non-Hodgkin’s lymphoma.
beginning with short-acting agents and usually titrated
to longer-acting oral agents or transdermal forms, may
be appropriate in the treatment of such refractory painful neuropathy. Individuals with underlying metabolic
diseases such as diabetes or hereditary neuropathies may
have a much lower threshold for developing neuropathy
after exposure to toxic chemotherapy drugs [24]. These
patients can present with symptoms of paresthesias after
a much less cumulative exposure than other patients without underlying disease.
Many patients ask about preventive or helpful measures other than medications. There is no evidence
that massage, exercise, or alternative therapies have an
effect on painful neuropathy, either damaging or helpful. Patients should be advised to use protective gloves
if exposed to dishwashing or caustic cleaning materials.
In general, once the offending chemotherapy agent has
been discontinued, nerve recovery is time-dependent.
Nerve regeneration occurs at the rate of approximately
3 mm per year. Nerve conduction study and electromyogram (NCS/EMG) may be helpful in prognosis and in
gauging the rate of nerve regeneration during recovery.
Electrophysiologic tests may be useful in detecting unexpected patterns of neuropathy in patients treated with
toxic agents that may be caused by a differential of rarer
pathologies (eg, amyloid or sarcoid infi ltration [25] or
globulinopathies [26]) but will typically not add to the
clinically based diagnostic suspicion. These rarer causes
of neuropathy should be considered if the patient’s symptoms continue to worsen more than several months after
stopping treatment.
There is clearly a need for better delineation of painful neuropathy caused by chemotherapy agents to better
understand how to predict the degree of irreversible
Cancer patients may suffer from pain or paresthesias
related to involvement of single nerves, typically related to
direct infiltration or compression by tumor. Any peripheral or cranial nerve may be affected (Fig. 1). Systemic
lymphoma may have a predilection for nerve infiltration
[27]. The “numb chin syndrome” is a relatively common
scenario involving paraesthesias or dysesthesias involving
the distribution of the mental nerve or V3 branch of the
trigeminal nerve. It is caused by either direct nerve infiltration at the mental nerve, a bone lesion involving the jaw at
the mental foramen, or at the base of skull (foramen ovale
or cavernous sinus, along the trigeminal nerve’s route) at
the exit of the V3 branch. Cancers that create lytic lesions
of bone, such as prostate and breast, can commonly cause
such symptoms. Treatment includes systemic treatment of
the underlying tumor. If the local symptom is progressive
or painful and spreads to other neurologic structures, then
radiation (typically whole-brain) is recommended. The
other etiology of “numb chin syndrome” is leptomeningeal
involvement. Cerebrospinal fluid (CSF) involvement with
cancer usually presents with multiple symptoms, including cranial nerve symptoms, headache, nausea/vomiting,
or confusion, as well as radicular extremity or sphincter
symptomatology [28]. However, CSF cancer can present
with mononeuropathy or with a multiple, scattered radicular pattern (mononeuritis multiplex); lumbar puncture
should be considered in such a patient if a focal cause is not
apparent. Successful palliative treatment of carcinomatous
meningitis depends largely upon the underlying neoplasm.
Lymphoma, germ cell, and breast cancers are more amenable to palliative intrathecal treatments, whereas most
solid tumors are refractory to therapy.
Plexopathy
Cancer patients can suffer from painful neuropathy from
disease of the plexus caused by direct infi ltration of the
plexus (breast, lung), and head and neck cancers and lymphoma (involving the cervical lymph nodes). Colorectal,
prostate, chordoma, lymphoma, and gynecologic cancers
may involve the lumbo-sacral plexus. Pain is a primary
component of plexopathy from direct cancer infi ltration
[29]. Depending on the level of the plexus involved (typically the lower trunk of the brachial plexus if breast or
lung cancer), the distal hand is involved fi rst, with symptoms ascending proximally. Pain is followed subacutely
by sensory change, weakness, and eventually trophic
changes. The main differential in cancer plexopathy from
direct invasion of the neoplasm or compression from
involvement of regional lymph nodes is radiation-induced
plexopathy if the patient has undergone radiation treatments. Pain may be a somewhat less prominent component
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in radiation-induced plexopathy, and fibrosis and surface
skin changes may be supportive of such a diagnosis. Contrast fat-saturated CT scan, gadolinium MRI, or axillary
ultrasound can be helpful in differentiating between
active disease and treatment-related effect. NCS/EMG
can be helpful if myokymia is identified. Myokymia is a
specific electrophysiologic phenomenon related to cell
membrane instability seen in radiation plexopathy but not
seen in plexopathy due to cancer infiltration [30]. Cancer
involving the plexus may be palliated by radiation; radiation-induced plexopathy is unfortunately fairly refractory
to treatments. There have been case reports and some
laboratory-based rationale of therapies, including anticoagulation and neuroprotection with vitamin E, but they
have not been proven helpful. Palliative therapy is based
on pain management and physical therapy.
prolonged more than several months, or if the condition
worsens months after treatment or has atypical features.
Better measures and documented clinical data are
needed for assessing the severity and reversibility of toxic
damage from chemotherapy agents.
Paraneoplastic Neuropathy
1.•
Painful sensory neuronopathy, or ganglionopathy, is one
of the common manifestations of the uncommon paraneoplastic disorders. Paraneoplastic disorders are thought to
occur as a result of dysregulation of autoimmunity in misdirection of antibodies targeted against the foreign agent
(neoplasm), which are targeted to specific neurons—in
the case of neuronopathy, the dorsal ganglion cells. The
resultant neuropathy presents with burning, severe dysesthesias. As the ganglion cells are targeted, the syndrome
is not typically reversible, as is the distal sensory neuropathy seen from toxic chemotherapy exposure, in which the
distal-most nerve is affected. This syndrome is seen most
commonly in the setting of small cell lung cancer and typically involves the anti-Hu antibody [31].
Paraneoplastic microvasculitis also can present with a
less symmetric distal painful neuropathy [32]. If suspected
clinically and supported by electrophysiologic testing, this
diagnosis can be made defi nitively by nerve biopsy, with
the appearance of perivascular infi ltrate of inflammatory
and plasma cells. Immune-modulating therapy (steroids,
plasma exchange, or immunoglobulins) and treatment of
the underlying cancer may be helpful.
Conclusions
Painful neuropathy is a problem that can adversely affect
the quality of life and functional status of the cancer
patient. The most common cause of painful neuropathy is
toxic chemotherapy exposure, and the degree of neuropathy may be the dose-limiting factor in deciding further
oncologic treatment. The clinician should have a low
threshold for increasing the strength of analgesic agents
and narcotics if adequate trials with fi rst-line and atypical
medications are not palliative.
Less commonly, other etiologies need be considered
as the source of painful neuropathy in the cancer patient.
Clinicians should consider other causes if recovery is
Disclosure
No potential confl ict of interest relevant to this article
was reported.
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