Chemotherapy-induced neuropathic pain

Paul Farquhar-Smith
Royal Marsden NHS Foundation Trust, London, UK
Correspondence to Paul Farquhar-Smith, MA, FRCA,
PhD, FFPMRCA, Department of Anaesthetics, Royal
Marsden Hospital, Fulham Road, London, SW3 6JJ,
UK
Tel: +44 207 352 8171 x2727;
e-mail: paul.farquhar-smith@rmh.nhs.uk
Current Opinion in Supportive and Palliative
Care 2011, 5:1–7
Purpose of review
To discuss the importance, clinical features, possible pathology and treatments of
chemotherapy-induced neuropathic pain. Newer biological agents such as bortezomib
will be considered in greater detail.
Recent findings
Chemotherapy-induced peripheral neuropathy (CIPN) is a frequent complication of
common anticancer therapies. It may lead to treatment compromise, significantly adds
to the symptom burden and interferes with quality of life of cancer survivors. Recent
investigations have identified processes involved in CIPN which may give some insight
for the development of novel treatments. CIPN induced by different anticancer therapies
may be heterogeneous and present as distinct neuropathic pains. Recent work has
focussed on the newer anticancer drugs such as bortezomib. Contemporaneous
studies have failed to find good evidence for the use of several common antineuropathic
agents and further research is required.
Summary
Painful CIPN remains under recognized and undertreated. It is an important cause of
pain during cancer treatment and is a common pain in the cancer survivor. Difficulties
in assessment and limitations in treatment contribute to management problems.
Improvements in education (patient and clinician), assessment and treatment would
potentially reduce the often debilitating effects of painful CIPN.

Keywords
bortezomib, cancer pain, neuropathy, survivorship

Curr Opin Support Palliat Care 5:1–7

ß 2011 Wolters Kluwer Health | Lippincott Williams & Wilkins
1751-4258

or perception that it is not important to the

Introduction
The concept of cancer survivorship is relatively new [1].
Patients with cancer are living longer and in many cases
there is a symptom burden associated with this increased
longevity. Pain due to cancer itself is well known, but
often forgotten is pain associated with cancer treatments
(e.g. surgery and chemotherapy) which may persist
long after cure or remission. Chemotherapy-induced
peripheral neuropathy (CIPN) is a major source of pain
that interferes with activities of daily living, significantly
reduces quality of life in cancer survivors [2] and
increases the use of NHS resources [3]. As with other
pain in cancer survivors, treatment of the symptoms of
CIPN is an area of unmet need due to the following
reasons:
(1) Failure or reluctance to recognize symptoms of CIPN
by clinicians [4].
(2) Difficulties in diagnosis.
(3) No universally accepted assessment tool and lack of
interobserver agreement [5].
(4) Patients’ reluctance in reporting symptoms either
due to worries that treatment may be compromised
1751-4258 ß 2011 Wolters Kluwer Health | Lippincott Williams & Wilkins
physician.
(5) Limited options for prevention and treatment.
Clinical presentation
Neurotoxicity is common with several chemotherapeutic
agents and may involve many parts of the nervous system.
However, peripheral sensory nerves are most commonly
affected leading to sensory abnormalities and often pain.
The incidence of CIPN and pain depends on dose
(usually cumulative) and type of agent and is more
common with patients with preexisting nerve damage
either from previous CIPN or from other causes (e.g.
diabetes). Symptomatology depends on the sensory fibres
affected: small fibre damage is more likely to lead to
alterations in temperature and pain, including neuro-
pathic pain and allodynia [6].
There are several common clinical features of CIPN:
(1) Symptoms are predominantly sensory (although cer-
tain agents cause motor and autonomic dysfunction).
(2) Symptoms should be temporally related to chemo-
therapy and may occur at any time during the
DOI:10.1097/SPC.0b013e328342f9cc

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 2 Pain: cancer

Table 1 Proposed mechanisms for chemotherapy-induced peripheral neuropathy from animal models
Treatment Chemotherapy Mechanism Reference

Antisense TRPV4 Paclitaxel TRPV4 receptors [14]

Ethosuxamide Paclitaxel T-type voltage sensitive Ca channels [15]
Vincristine
Anti-Ca2þ Paclitaxel Decrease Ca2þ flux [16]
(TMB-8, EGTA) Vincristine
Gabapentin Paclitaxel, vincristine Binding to a2d subunit of Ca2þ channel [17]
Pregabalin Oxaliplatin (acute) [18]
IL-10 gene therapy/IL-1ra Paclitaxel Anticytokine [19]
NSAID Vincristine IL-6 [20]
COX products
Acetyl-L-carnitine Paclitaxel, vincristine unknown [21]
[22]
Cannabinoids [23]
WIN 55,212-2 Cisplatin CB receptors [24]
AM1241 Paclitaxel CB2 receptors
TTX Paclitaxel TTX sensitive Naþ channel [25]
PL37 Vincristine Inhibition of enkephalin metabolism [26]
Bradykinin antagonist Vincristine B1 B2 receptors [27]
Nitric oxide synthase inhibitor Nitric oxide
Glutamate production inhibition Cisplatin Glutamate carboxypeptidase inhibition [28]
Paclitaxel
bortezomib
CB, cannabinoid; EGTA, ethylene glycol tetraacetic acid; IL, interleukin; NGF, nerve growth factor; PLC, phospholipase C; TRPV, transient receptor
potential vanilloid; TTX, tetrodotoxin.

course of chemotherapy, even after stopping (this is
also known as ‘coasting’).
(3) Symptoms are usually symmetrical, but may be worse
on one side.
(4) Distal parts of limbs are affected in a ‘stocking/glove’
distribution. Although dependent upon agent, feet
are often affected first.
Knowledge of the pathology of CIPN can aid explanation
of symptoms and identify putative treatments.
Pathology
Many texts suggest the mechanism of CIPN is secondary
to disruption of microtubules leading to interruption of
nutrient transport causing a distal axonopathy resulting in
the ‘stocking/glove’ distribution of symptoms. However,
in some animal models of CIPN, there is little evidence
of gross damage to nerves [7]. Furthermore, some agents
that cause significant neuropathy and neuropathic pain
(e.g. bortezomib) do not affect microtubules. Other
agents that disrupt axonal transport, such as colchicine,
do not cause pain [8]. The microtubule explanation also
does not account for acute painful toxicity of oxaliplatin
which occurs long before any anatomical damage could
occur.
Investigation of animal models of painful CIPN have
identified mechanisms related to those involved in the
generation and maintenance of other types of neuro-
pathic pain. Activation of mitogen-activated protein
kinases and extracellular signal-related kinases have been
shown to be involved in cisplatin-induced apoptosis [9]
and play an important role in many pain states, including
neuropathic pain [10]. Mitochondrial caspase activation
is integral to apoptosis by proteosome inhibitors such as
bortezomib [11] and has been shown to be involved in
vincristine-induced neuropathic pain [12]. Mitochondrial
dysfunction has also been postulated as an important
CIPN mechanism and correlates directly with pain beha-
viour [7]. Inhibition of these mitochondrial changes
by acetyl-L-carnitine is associated with a reduction of
paclitaxel-induced neuropathic pain [13–26,27,28]
(Table 1). Disruption of intracellular calcium regulation
is involved in bortezomib apoptosis [29] and has been
demonstrated to be important in painful CIPN [16].
Correction of the disrupted calcium channels appears
to reduce pain behaviours [15,16,18,30].
Alteration of expression of many genes for pain mediators
has been demonstrated in the spinal cord dorsal horn
after vincristine exposure [31]. These include moieties
involved in other types of pain, including cytokines, ion
channels and growth factors [31]. Deficiency of NGF is
found in early diabetic neuropathy and neuropathic pain
[32]. Similarly, the degree of cisplatin-induced peripheral
nerve toxicity correlates with a reduction in NGF levels
[33].
Other potential important mechanisms have been
demonstrated in animal models of CIPN (Table 1).
Some of these are integral to the development of per-
ipheral and central sensitization, processes themselves
pivotal in neuropathic pain [34]. Abnormal spontaneous
electric discharge in A and C fibres, found in neuropathic

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Table 2 Features of certain types of chemotherapy-induced peripheral neuropathy
Chemotherapy Incidence Onset time (coasting)a
Cisplatin 40% From 1 month, at most
3 months (þ)
Carboplatin Mostly small fibres
Pain common
Oxaliplatin Acute 90% cold induced Acute occurs within
Chronic 30% an hour
Vincristine 30–40% Within 3 months (þ)
Lower limb more common
Paclitaxel 30–50% Maybe after single dose,
>50% after second dose (þ)
Docetaxel Most sensory modalities
affected
CIPN, chemotherapy-induced peripheral neuropathy. Data taken from [6,35,36,39].
a
(þ) denotes presence of coasting.
pain states, occurs in vincristine-induced and paclitaxel-
induced CIPN [22]. However, although CIPN may share
common mediators and processes with other types of
neuropathic pain, the disparity in efficacy of antineuro-
pathic agents suggests mechanistic differences exist.
Despite the similarity of diagnostic features of CIPN
secondary to different agents, sensory testing reveals that
sensory abnormalities can be quite distinct depending on
the chemotherapeutic agent [31]. This has ramifications
on potential treatment options.
Evaluation of chemotherapy-induced
peripheral neuropathy
The diagnosis of CIPN is usually made on clinical
grounds. History and examination often suffices.
Neurophysiological studies may strengthen diagnosis,
but does not always reflect clinical severity [35]. The
assessment of CIPN is complicated by its hetero-
geneous nature and by the multiple tools available,
some of which do not have any assessment of pain.
Several grading tools are in usage including Eastern
Cooperative Oncology Group and National Cancer
Institute of Cancer Common Toxicity Criteria (N-
CIC-CTC). These tools use subjective and objective
methods to assess the grade of CIPN. These tools
exhibit poor interobserver agreement in grading [5].
For example, only 42% of practitioners agreed on CIPN
grading using the NCIC-CTC tool [5]. Currently, there
is no universally accepted tool. More recent tools use
patient-based evaluation (including activities of daily
living and quality of life) and target specific types of
CIPN [36]. The Functional Assessment of Cancer
Therapy Gynecologic Oncology Group neurotoxicity
tool fulfils many of these criteria [37].
Quantitative sensory testing (QST) allows the identifi-
cation of fibre type involved in CIPN symptoms. How-
ever, QST findings do not always correlate with clinical
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Chemotherapy-induced neuropathic pain Farquhar-Smith 3
Duration/recovery after stopping Comments
Some recovery in 80% patients Carboplatin less
over some months/years CIPN (10–20%)
28% patients symptomatic
after some years
More severe less recovery
Acute 2–3 days Chronic CIPN similar
20% limited recovery to cisplatin
In most, some recovery after 30% CIPN at 2 years
3 months
More severe, less and slower
recovery
75% some recovery after Less common now due
6 months to changed dosing
Docetaxel less CIPN
symptoms, and requires specialist equipment and time
not always available in clinic. Although sensitive, there is
little evidence that QST can provide an earlier diagnosis
than patient symptom reporting [38]. Interest in mech-
anisms of neuropathic pain may increase the routine use
of QST, but at present it remains predominantly a
research tool.
Chemotherapy-induced peripheral
neuropathy features of selected agents
The major groups of chemotherapy anticancer drugs
include platins, vinca alkaloids, taxanes and the newer
biological agents including bortezomib. Key features of
CIPN induced by these agents is shown in Table 2
[6,35,36,39]. A more detailed consideration is available
from the source documents of the table. Although these
chemotherapies are important causes of CIPN, recent
developments have focussed on newer agents such as
bortezomib. This review will concentrate on bortezomib
(Velcade, Janssen-Cilag, High Wycombe, UK) and the
immunomodulator thalidomide.
Bortezomib
Bortezomib is a proteasome inhibitor licensed for the
treatment of refractory/relapsed myeloma, although has
been used for other cancer types. It is highly neurotoxic,
often leading to dose reduction or even stopping treat-
ment [40]. Bortezomib causes a sensory neuropathy
involving Ab, Ad and C fibres creating sensory changes
such as elevated touch detection and heat pain thresholds
and pain [41] (Table 3) [42,43,44,45–50]. Histological
examination shows pure small fibre neuropathy and
mixed small and large fibre involvement [44].
Up to 10% of patients present with postural hypotension
owing to autonomic dysfunction which may also lead to
dose reduction [51].
 4 Pain: cancer

Table 3 Features of bortezomib-induced peripheral neuropathy in the literature

Preexisting Emergent Dose modification
Study Treatment Treatment group CIPN (grade 3/4) (stopped) Recovery (median time)

SUMMIT CREST [42] Bortezomib Refractory 81% 35% (13%) 12% (5%) 71% improve/resolution
N ¼ 239
APEX [43] N ¼ 333 Bortezomib Relapsed 67% 37% (9%) 22% (9%) 64% improve (110 days)
[44] N ¼ 64 Bortezomib First-line induction 20% 64% (3%) 30% (14%) 85% resolution (98 days)
[45] Lenalidomide, First-line induction 80% (2%) 44%
bortezomib,
prednisolone
N ¼ 66 39% received
full dose
VISTA [46] BMP First-line induction 46% (13%) 43% (15%) 79% improve (1.9 months)
N ¼ 682 60% resolution (5.9 months)
[47] BMP First-line induction One time per 17% (4%) 64% resolution/improve
week (8%)
N ¼ 511 Bortezomib one Two times per 41% (16%) 66% resolution/improve
or two times week (28%) (2.3 months)
per week
RMH audit Bortezomib Refractory 47% 39% 47% (11%)
N ¼ 36 [48]
[49] N ¼ 100 retro Bortezomib Refractory 38% (6%) 53% resolution/improve
(3 months)
[50] Bortezomib Relapsed 39% 56% (22%) 14% (12%) In all, some improvement
N ¼ 78 retro More severe and longer
(grade 3/4, 8 months)
BMP, bortezomib with melphalan with prednisolone; CIPN, chemotherapy-induced peripheral neuropathy; RMH Royal Marsden Hospital.

The incidence of pain is high; up to half of those with
bortezomib-induced peripheral neuropathy (BIPN) suf-
fer pain [45]. One study showed 73% of patients required
dose modification due to BIPN, and 20% of these due to
pain [45]. Twice a week administration of bortezomib is
associated with an incidence of neuropathy of 28% grade
3/4 compared with 8% grade 3/4 BIPN with weekly
treatments [47].
Generally, BIPN exhibits the common features of other
CIPN with length dependence, symmetry and dose
dependence. Onset occurs at any time after treatment,
but usually after the second cycle. Most BIPN develops
before the fifth cycle. Some authors have suggested that
‘coasting’ (development of BIPN after treatment has
ceased) does not occur in BIPN, but we have reported
‘coasting’ in 8% of patients [48].
The incidence of worsening or emergent neuropathy is
high, although it varies between trials (Table 3).
Increasing awareness and surveillance of neuropathy
leading to earlier dose modification in some studies
may account for differences in BIPN. In patients who
had a dose reduction owing to BIPN, 68% had resolution
compared with 47% who did not have a dose reduction
[43]. Dose reduction may also protect against develop-
ment of higher grade toxicities [50] which is more likely
to recover [43]. Close neurological monitoring can
reduce the incidence of BIPN [52].
Preexisting neuropathy is common due to previous neu-
rotoxic chemotherapy. However, myeloma itself may
predispose to neuropathy, as many chemotherapy-naive
myeloma patients have pretreatment neuropathy [44]
and lung cancer patients receiving bortezomib have less
preexisting CIPN [53]. In one trial, 14% of patients with
preexisting CIPN developed at least grade 3 neuropathy
compared with 4% without [42]. In another study,
myeloma patients who received bortezomib for relapse
or progression were more likely to have painful BIPN,
took longer to recover and more often resulted in a dose
reduction compared with those for whom it was first-line
treatment [54].
Recovery is variable and appears to follow two main
patterns. As many as 80% of patients may become
asymptomatic after stopping bortezomib (at around
3–4 months) [55], but there appears to be a more severe
group of patients in whom recovery is limited and
delayed (Table 3).
Thalidomide
Thalidomide is used as an immunomodulatory agent in
myeloma. It acts by antiangiogenesis through TNFa.
It causes a sensory length-dependent neuropathy.
Sensory loss and painful paraesthesias occur in 20–
70% of patients [56]. Unlike other CIPN, its incidence
is related to daily dose and not cumulative dose [56]
and there is less capacity for recovery [35]. Thalido-
mide is frequently the cause of preexisting neuropathy
in patients receiving bortezomib and may increase
incidence and severity of BIPN [42,49]. Paradoxically,
there is some evidence that thalidomide may be pro-
tective for the development of BIPN [50], perhaps by

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immunomodulation or causing preexisting neuropathy
resulting in earlier dose modification.
Treatment and prevention
Many types of preventive strategies have been tried to
reduce CIPN. Any protective strategy should not com-
promise anticancer efficacy. Although there are some data
that suggest modest benefits for certain substances for
certain types of CIPN [57], it is difficult to recommend
routine use of any protective treatment. Vitamin E is
most widely used and has some evidence for reduction in
neuropathy after cisplatin and paclitaxel [58].
There have been many putative targets gleaned from
animal studies for CIPN treatment, yet there is scarce
evidence for effective treatment. First-line drugs for
other neuropathic pain states have been investigated. In
an uncontrolled trial, 75 patients with painful CIPN
reported significant improvement in pain with up to
800 mg/day of gabapentin compared with a control
group of those who refused gabapentin treatment
[59]. However, a crossover randomized controlled trial
(RCT) of 115 patients with multiple types of CIPN had
no improvement in pain compared with control even
with up to 900 mg gabapentin three times a day [60].
Pregabalin may reduce oxaliplatin-induced neuropathy
[61].
An RCT of 42 patients failed to demonstrate any benefit
of up to 50 mg/day of amitriptyline [62]. Nortriptyline
also failed to reduce pain in a crossover RCT of 51
patients at doses up to 100 mg/day [63]. One small
(n ¼ 12) open trial reported significant improvement with
venlafaxine, although two of the 12 patients withdrew
because of side-effects [64]. Lamotrigine had no effect on
pain, but increased side-effects in an RCT of 131 patients
[65]. Lack of efficacy of established antineuropathic
agents could be compounded by recruitment of patients
with multiple agent CIPN. Pooling all types of CIPN
does not address the potential differences between
CIPNs. Research into novel targets has not yet ‘trans-
lated’ into new treatments. However, menthol (a TRPM8
cold ion channel activator) has some activity in carbopla-
tin-induced CIPN [66] and a case report has suggested its
potential benefit in BIPN [67].
In the absence of clear evidence and despite some
negative data, current practice is to use existing guide-
lines for neuropathic pain empirically [68].
Conclusion
Many common anticancer therapies cause peripheral
sensory neuropathy. Pain is often a symptom of these
CIPNs, yet is both underreported and slow to be recog-
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Chemotherapy-induced neuropathic pain Farquhar-Smith 5
nized. Assessment is hindered by the lack of consensus
and by differences in the underlying pathologies and
presentations of CIPN. The use of the antimyeloma
agent bortezomib has led to BIPN becoming more preva-
lent and is associated with increased pain morbidity for
these patients during treatment and into survivorship.
Although investigation into the pathology of CIPN has
identified potential therapeutic strategies, there is lim-
ited evidence for pharmacological prevention and treat-
ment of CIPN. Treatments are based on current neuro-
pathic pain guidelines. Future investigation into the
processes that differentiate painful CIPN from other
neuropathic pain, and more clinical studies, may provide
enhanced treatment possibilities.
References and recommended reading
Papers of particular interest, published within the annual period of review, have
been highlighted as:
 of special interest
 of outstanding interest
Additional references related to this topic can also be found in the Current
World Literature section in this issue (p. 65).
1 Burton AW, Fanciullo GJ, Beasley RD, Fisch MJ. Chronic pain in the cancer
survivor: a new frontier. Pain Med 2007; 8:189–198.
2 Tofthagen C. Patient perceptions associated with chemotherapy-induced
 peripheral neuropathy. Clin J Oncol Nurs 2010; 14:E22–E28.
One of the few sources of information of the effect of CIPN on the activities of daily
living and quality of life of patients.
3 Reyes-Gibby CC, Morrow PK, Buzdar A, Shete S. Chemotherapy-induced
peripheral neuropathy as a predictor of neuropathic pain in breast cancer
patients previously treated with paclitaxel. J Pain 2009; 10:1146–1150.
4 Stephens RJ, Hopwood P, Girling DJ, Machin D. Randomized trials with
quality of life endpoints: are doctors’ ratings of patients’ physical symptoms
interchangeable with patients’ self-ratings? Qual Life Res 1997; 6:225–
236.
5 Postma TJ, Heimans JJ, Muller MJ, et al. Pitfalls in grading severity of
chemotherapy-induced peripheral neuropathy. Ann Oncol 1998; 9:739–
744.
6 Ocean AJ, Vahdat LT. Chemotherapy-induced peripheral neuropathy: patho-
genesis and emerging therapies. Support Care Cancer 2004; 12:619–625.
7 Flatters SJ, Bennett GJ. Studies of peripheral sensory nerves in paclitaxel-
induced painful peripheral neuropathy: evidence for mitochondrial dysfunc-
tion. Pain 2006; 122:245–257.
8 Kingery WS, Guo TZ, Poree LR, Maze M. Colchicine treatment of the sciatic
nerve reduces neurogenic extravasation, but does not affect nociceptive
thresholds or collateral sprouting in neuropathic or normal rats. Pain 1998;
74:11–20.
9 Scuteri A, Galimberti A, Maggioni D, et al. Role of MAPKs in platinum-induced
neuronal apoptosis. Neurotoxicology 2009; 30:312–319.
10 Ji RR, Gereau RW, Malcangio M, Strichartz GR. MAP kinase and pain. Brain
 Res Rev 2009; 60:135–148.
This article is a review concerning the role of MAP kinases in pain states and gives
insight as to why this might be important in other neuropathic pains such as CIPN.
11 Mitsiades N, Mitsiades CS, Poulaki V, et al. Molecular sequelae of proteasome
inhibition in human multiple myeloma cells. Proc Natl Acad Sci U S A 2002;
99:14374–14379.
12 Joseph EK, Levine JD. Caspase signalling in neuropathic and inflammatory
pain in the rat. Eur J Neurosci 2004; 20:2896–2902.
13 Jin HW, Flatters SJ, Xiao WH, et al. Prevention of paclitaxel-evoked painful
peripheral neuropathy by acetyl-L-carnitine: effects on axonal mitochondria,
sensory nerve fiber terminal arbors, and cutaneous Langerhans cells. Exp
Neurol 2008; 210:229–237.
14 Alessandri-Haber N, Dina OA, Yeh JJ, et al. Transient receptor potential
vanilloid 4 is essential in chemotherapy-induced neuropathic pain in the rat.
J Neurosci 2004; 24:4444–4452.
15 Flatters SJ, Bennett GJ. Ethosuximide reverses paclitaxel- and vincristine-
induced painful peripheral neuropathy. Pain 2004; 109:150–161.
 6 Pain: cancer
16 Siau C, Bennett GJ. Dysregulation of cellular calcium homeostasis in
chemotherapy-evoked painful peripheral neuropathy. Anesth Analg 2006;
102:1485–1490.
17 Xiao W, Boroujerdi A, Bennett GJ, Luo ZD. Chemotherapy-evoked painful
peripheral neuropathy: analgesic effects of gabapentin and effects on
expression of the alpha-2-delta type-1 calcium channel subunit. Neuroscience
2007; 144:714–720.
18 Ling B, Coudore F, Decalonne L, et al. Comparative antiallodynic activity
of morphine, pregabalin and lidocaine in a rat model of neuropathic pain
produced by one oxaliplatin injection. Neuropharmacology 2008; 55:
724–728.
19 Ledeboer A, Jekich BM, Sloane EM, et al. Intrathecal interleukin-10 gene
therapy attenuates paclitaxel-induced mechanical allodynia and proinflamma-
tory cytokine expression in dorsal root ganglia in rats. Brain Behav Immun
2007; 21:686–698.
20 Cata JP, Weng HR, Dougherty PM. Cyclooxygenase inhibitors and thalido-
mide ameliorate vincristine-induced hyperalgesia in rats. Cancer Chemother
Pharmacol 2004; 54:391–397.
21 Flatters SJ, Xiao WH, Bennett GJ. Acetyl-L-carnitine prevents and reduces
paclitaxel-induced painful peripheral neuropathy. Neurosci Lett 2006;
397:219–223.
22 Xiao WH, Bennett GJ. Chemotherapy-evoked neuropathic pain: abnormal
spontaneous discharge in A-fiber and C-fiber primary afferent neurons and its
suppression by acetyl-L-carnitine. Pain 2008; 135:262–270.
23 Vera G, Chiarlone A, Cabezos PA, et al. WIN 55,212-2 prevents mechanical
allodynia but not alterations in feeding behaviour induced by chronic cisplatin
in the rat. Life Sci 2007; 81:468–479.
24 Rahn EJ, Zvonok AM, Thakur GA, et al. Selective activation of cannabinoid
CB2 receptors suppresses neuropathic nociception induced by treatment
with the chemotherapeutic agent paclitaxel in rats. J Pharmacol Exp Ther
2008; 327:584–591.
25 Nieto FR, Entrena JM, Cendan CM, et al. Tetrodotoxin inhibits the develop-
ment and expression of neuropathic pain induced by paclitaxel in mice. Pain
2008; 137:520–531.
26 Thibault K, Elisabeth B, Sophie D, et al. Antinociceptive and antiallodynic
effects of oral PL37, a complete inhibitor of enkephalin-catabolizing enzymes,
in a rat model of peripheral neuropathic pain induced by vincristine. Eur J
Pharmacol 2008; 600:71–77.
27 Bujalska M, Makulska-Nowak H. Bradykinin receptors antagonists and nitric
 oxide synthase inhibitors in vincristine and streptozotocin induced hyperal-
gesia in chemotherapy and diabetic neuropathy rat model. Neuro Endocrinol
Lett 2009; 30:144–152.
One of the first demonstrations of the importance of bradykinin and nitric oxide
synthase inhibitors in the development of painful CIPN. These compounds have
been shown to be important in many other chronic pain and neuropathic pain
states.
28 Carozzi VA, Chiorazzi A, Canta A, et al. Glutamate carboxypeptidase inhibition
 reduces the severity of chemotherapy-induced peripheral neurotoxicity in rat.
Neurotox Res 2010; 17:380–391.
A novel mechanism of pain that could not only potentially be beneficial for painful
CIPN but also for other types of pain state
29 Landowski TH, Megli CJ, Nullmeyer KD, et al. Mitochondrial-mediated dis-
regulation of Ca2þ is a critical determinant of Velcade (PS-341/bortezomib)
cytotoxicity in myeloma cell lines. Cancer Res 2005; 65:3828–3836.
30 Xiao W, Naso L, Bennett GJ. Experimental studies of potential analgesics for
the treatment of chemotherapy-evoked painful peripheral neuropathies. Pain
Med 2008; 9:505–517.
31 Cata JP, Weng HR, Lee BN, et al. Clinical and experimental findings in
humans and animals with chemotherapy-induced peripheral neuropathy.
Minerva Anestesiol 2006; 72:151–169.
32 Anand P. Neurotrophic factors and their receptors in human sensory neuro-
pathies. Prog Brain Res 2004; 146:477–492.
33 Cavaletti G, Pezzoni G, Pisano C, et al. Cisplatin-induced peripheral
neurotoxicity in rats reduces the circulating levels of nerve growth factor.
Neurosci Lett 2002; 322:103–106.
34 Dickenson AH. The neurobiology of chronic pain states. Anaesth Intensive
Care Med 2008; 9:8–12.
35 Velasco R, Bruna J. Chemotherapy-induced peripheral neuropathy: an un-
 resolved issue. Neurologia 2010; 25:116–131.
A comprehensive and current literature review of CIPN including the most
up-to-date developments, including more recent biological therapies such as
bortezomib.
36 Quasthoff S, Hartung HP. Chemotherapy-induced peripheral neuropathy.
J Neurol 2002; 249:9–17.
Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
37 Calhoun EA, Welshman EE, Chang CH, et al. Psychometric evaluation of the
Functional Assessment of Cancer Therapy/Gynecologic Oncology Group-
Neurotoxicity (Fact/GOG-Ntx) questionnaire for patients receiving systemic
chemotherapy. Int J Gynecol Cancer 2003; 13:741–748.
38 Forsyth PA, Balmaceda C, Peterson K, et al. Prospective study of paclitaxel-
induced peripheral neuropathy with quantitative sensory testing. J Neurooncol
1997; 35:47–53.
39 Windebank AJ, Grisold W. Chemotherapy-induced neuropathy. J Peripher
Nerv Syst 2008; 13:27–46.
40 Stubblefield MD, Slovin S, Gregor-Cortelli B, et al. An electrodiagnostic
evaluation of the effect of preexisting peripheral nervous system disorders
in patients treated with the novel proteasome inhibitor bortezomib. Clin Oncol
(R Coll Radiol) 2006; 18:410–418.
41 Cata JP, Weng HR, Burton AW, et al. Quantitative sensory findings in patients
with bortezomib-induced pain. J Pain 2007; 8:296–306.
42 Richardson PG, Briemberg H, Jagannath S, et al. Frequency, characteristics,
and reversibility of peripheral neuropathy during treatment of advanced
multiple myeloma with bortezomib. J Clin Oncol 2006; 24:3113–
3120.
43 Richardson PG, Sonneveld P, Schuster MW, et al. Reversibility of sympto-
 matic peripheral neuropathy with bortezomib in the phase III APEX trial in
relapsed multiple myeloma: impact of a dose-modification guideline. Br J
Haematol 2009; 144:895–903.
The data from the APEX trial are examined specifically concerning peripheral
neuropathy reporting preexisting CIPN, development of new or worsening BIPN
and an examination of risk factors. Also reports at length on the natural history of
these patients with BIPN.
44 Richardson PG, Xie W, Mitsiades C, et al. Single-agent bortezomib in
 previously untreated multiple myeloma: efficacy, characterization of peripheral
neuropathy, and molecular correlations with response and neuropathy. J Clin
Oncol 2009; 27:3518–3525.
An important article documenting the differences in the incidence, severity and
progression of BIPN when bortezomib is used as a first-line therapy for myeloma.
The investigation includes measures of nerve damage and prognostic markers for
the development of BIPN.
45 Richardson PG, Weller E, Lonial S, et al. Lenalidomide, bortezomib, and
dexamethasone combination therapy in patients with newly diagnosed multi-
ple myeloma. Blood 2010; 116:679–686.
46 Mateos MV, Richardson PG, Schlag R, et al. Bortezomib plus melphalan and
prednisone compared with melphalan and prednisone in previously untreated
multiple myeloma: updated follow-up and impact of subsequent therapy in the
phase III VISTA trial. J Clin Oncol 2010; 28:2259–2266.
47 Bringhen S, Larocca A, Rossi D, et al. Efficacy and safety of once weekly
bortezomib in multiple myeloma patients. Blood 2010. [Epub ahead of
print]
48 Farquhar-Smith WP, Yen J, West S, Sohanpal I. Peripheral neuropathy in
patients receiving bortezomib for myeloma: an audit [abstract]. In: Program
and Abstracts of the IASP Annual Scientific Meeting Abstracts; 31 August
2010; Montreal, Canada.
49 El-Cheikh J, Stoppa AM, Bouabdallah R, et al. Features and risk factors of
peripheral neuropathy during treatment with bortezomib for advanced multiple
myeloma. Clin Lymphoma Myeloma 2008; 8:146–152.
50 Badros A, Goloubeva O, Dalal JS, et al. Neurotoxicity of bortezomib therapy in
multiple myeloma: a single-center experience and review of the literature.
Cancer 2007; 110:1042–1049.
51 Mohty B, El-Cheikh J, Yakoub-Agha I, et al. Peripheral neuropathy and new
 treatments for multiple myeloma: background and practical recommenda-
tions. Haematologica 2010; 95:311–319.
A review focussed on neuropathy secondary to antimyeloma agents, including
bortezomib and thalidomide. Recommendations for surveillance, detection and
treatment are suggested.
52 Velasco R, Petit J, Clapes V, et al. Neurological monitoring reduces the
 incidence of bortezomib-induced peripheral neuropathy in multiple myeloma
patients. J Peripher Nerv Syst 2010; 15:17–25.
A discussion of one strategy to reduce the incidence of BIPN. By close neuro-
logical monitoring, development of BIPN is recognized promptly and doses can be
adjusted before more severe nerve damage occurs.
53 Roccaro AM, Vacca A, Ribatti D. Bortezomib in the treatment of cancer.
Recent Pat Anticancer Drug Discov 2006; 1:397–403.
54 Corso A, Mangiacavalli S, Varettoni M, et al. Bortezomib-induced peripheral
neuropathy in multiple myeloma: a comparison between previously treated
and untreated patients. Leuk Res 2010; 34:471–474.
55 Chaudhry V, Cornblath DR, Polydefkis M, et al. Characteristics of bortezomib-
and thalidomide-induced peripheral neuropathy. J Peripher Nerv Syst 2008;
13:275–282.

56 Bastuji-Garin S, Ochonisky S, Bouche P, et al. Incidence and risk factors for
thalidomide neuropathy: a prospective study of 135 dermatologic patients.
J Invest Dermatol 2002; 119:1020–1026.
57 Wolf S, Barton D, Kottschade L, et al. Chemotherapy-induced peripheral
neuropathy: prevention and treatment strategies. Eur J Cancer 2008; 44:
1507–1515.
58 Argyriou AA, Chroni E, Koutras A, et al. Vitamin E for prophylaxis against
chemotherapy-induced neuropathy: a randomized controlled trial. Neurology
2005; 64:26–31.
59 Tsavaris N, Kopterides P, Kosmas C, et al. Gabapentin monotherapy for the
treatment of chemotherapy-induced neuropathic pain: a pilot study. Pain Med
2008; 9:1209–1216.
60 Rao RD, Michalak JC, Sloan JA, et al. Efficacy of gabapentin in the manage-
ment of chemotherapy-induced peripheral neuropathy: a phase 3 randomized,
double-blind, placebo-controlled, crossover trial (N00C3). Cancer 2007;
110:2110–2118.
61 Saif MW, Syrigos K, Kaley K, Isufi I. Role of pregabalin in treatment of
oxaliplatin-induced sensory neuropathy. Anticancer Res 2010; 30:2927–
2933.
62 Kautio AL, Haanpaa M, Saarto T, Kalso E. Amitriptyline in the treatment of
chemotherapy-induced neuropathic symptoms. J Pain Symptom Manage
2008; 35:31–39.
Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
Chemotherapy-induced neuropathic pain Farquhar-Smith 7
63 Hammack JE, Michalak JC, Loprinzi CL, et al. Phase III evaluation of nortripty-
line for alleviation of symptoms of cis-platinum-induced peripheral neuropathy.
Pain 2002; 98:195–203.
64 Ozdogan M, Samur M, Bozcuk H, et al. Venlafaxine for treatment of chemo-
therapy-induced neuropathic pain. Turk J Cancer 2004; 34:110–113.
65 Rao RD, Flynn PJ, Sloan JA, et al. Efficacy of lamotrigine in the management of
chemotherapy-induced peripheral neuropathy: a phase 3 randomized, dou-
ble-blind, placebo-controlled trial, N01C3. Cancer 2008; 112:2802–2808.
66 Storey DJ, Colvin LA, Mackean MJ, et al. Reversal of dose-limiting carboplatin-
induced peripheral neuropathy with TRPM8 activator, menthol, enables
further effective chemotherapy delivery. J Pain Symptom Manage 2010;
39:e2–e4.
67 Colvin LA, Johnson PR, Mitchell R, et al. From bench to bedside: a case of
rapid reversal of bortezomib-induced neuropathic pain by the TRPM8 acti-
vator, menthol. J Clin Oncol 2008; 26:4519–4520.
68 Dworkin RH, O’Connor AB, Audette J, et al. Recommendations for the
 pharmacological management of neuropathic pain: an overview and literature
update. Mayo Clin Proc 2010; 85:S3–S14.
The contemporaneous evidence-based guidelines from an expert working group
detailing current recommendations for the treatment of neuropathic pain. In the
absence of sufficient data, especially for painful CIPN, these guidelines are
commonly used in the treatment of CIPN.