Basic & Clinical Pharmacology & Toxicology, 2014, 115, 185–192 Doi: 10.1111/bcpt.

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MiniReview

Drug-Induced Peripheral Neuropathy

Ole Jakob Vilholm1, Alex Alban Christensen1, Ahmed Hussein Zedan2 and Mustapha Itani1
1
Department of Neurology, Lillebaelt Hospital, Vejle, Denmark and 2Department of Oncology, Lillebaelt Hospital, Vejle, Denmark
(Received 28 January 2014; Accepted 21 April 2014)

Abstract: Peripheral neuropathy can be caused by medication, and various descriptions have been applied for this condition. In
this MiniReview, the term ‘drug-induced peripheral neuropathy’ (DIPN) is used with the suggested definition: Damage to nerves
of the peripheral nervous system caused by a chemical substance used in the treatment, cure, prevention or diagnosis of a dis-
ease. Optic neuropathy is included in this definition. A distinction between DIPN and other aetiologies of peripheral neuropathy
is often quite difficult and thus, the aim of this MiniReview is to discuss the major agents associated with DIPN.

Peripheral neuropathy is a well-known condition most com-

monly caused by diabetes, alcohol abuse, paraneoplastic syn-
dromes or toxins. With this MiniReview, we discuss iatrogenic
peripheral neuropathy caused by medications. Various descrip-
tions have been used for this condition: medication-induced/
drug-induced/toxic and iatrogenic neurotoxicity/-pathy and
polyneuropathy [1–4]. In this MiniReview, the term ‘drug-
induced peripheral neuropathy’ (DIPN) is used and defined as
damage to nerves of the peripheral nervous system caused by a
chemical substance used in the treatment, cure, prevention
or diagnosis of a disease. Optic neuropathy is included in
this definition.
Drug-induced peripheral neuropathy is a condition that
requires the physician’s knowledge and awareness to be recog-
nized and subsequently treated. It often presents as a sensory
polyneuropathy with paraesthesia that might be accompanied
by pain with a distal, symmetric sock and glove-shaped neu-
ropathy caused by affection of the myelin sheath of the
peripheral nerve (demyelination) with or without affection of
the nerve axon itself (axonal degeneration). Motor symptoms
and signs are generally minor. Although there are different
clinical symptoms and signs, all the various drugs presented
can induce neurological impairment so severe and persistent
as to restrict the patient’s daily activities.
Drug-induced peripheral neuropathy can begin weeks to
months after initiation of treatment with a particular drug and
reach a peak at, or after, the end of treatment. In most cases,
the pain and paraesthesia completely resolve after cessation of
treatment. However, in some cases, DIPN is only partially
reversible and can be permanent [5].
Author for correspondence: Ole J. Vilholm, Department of Neurology,
Lillebaelt Hospital, Vejle, Kabbeltoft 25, 7100 Vejle, Denmark
(fax +45 79 40 68 63, e-mail ole.vilholm@rsyd.dk).
Drugs Reviewed
Cardiovascular agents.
Statins and amiodarone used for treatment in cardiovascular
medicine have been linked to peripheral neuropathy.
Statins: Inhibitors of the 3-hydroxy-3-methyl-glutaryl coen-
zyme A-reductase, also referred to as ‘statins’, are among the
most frequently prescribed drugs worldwide. A well-docu-
mented adverse effect of statin treatment is the onset of
peripheral neuropathy, and although the condition is often
reversible after discontinuation of statin treatment, the mecha-
nism behind the development remains unclear.
In 2002, Gaist et al. [6] found that of 1084 patients diag-
nosed with neuropathy, incidence was higher in patients
treated with statins. One hundred sixty-six cases of patients
with peripheral neuropathy, of which 35 were considered
definite, were matched with a control group showing an
overall 4.6 odds ratio for developing peripheral neuropathy,
a 16.1 odds ratio for the patients with definite neuropathy
and a 26.4 odds ratio for patients who had been in treat-
ment >2 years.
Other cohort studies have confirmed this association
between statins and peripheral neuropathy. Corrao et al. com-
pared 2040 Italian patients diagnosed with neuropathy with a
control group of 36,041 patients matched for age and sex.
Their study showed that exposure to simvastatin, pravastatin
and fluvastatin is associated with a significant risk of develop-
ing peripheral neuropathy [7]. The case group did show a
higher prevalence of concurring diseases such as renal failure,
anaemia or diabetes; however, the adjusted odds ratio for these
pathologies still showed an elevated odds ratio of 1.19. De
Langen and van Puijenbroek were also able to show a signifi-
cant odds ratio of 3.7 for peripheral neuropathy in patients
treated with statins compared with patients treated with other
medications listed in a national registry [8].

© 2014 Nordic Association for the Publication of BCPT (former Nordic Pharmacological Society)
186 OLE J. VILHOLM ET AL.
Overall, case reports and clinical studies appear to support
the association of treatment with statins and the development
of neuropathy, especially after extended exposure to the
drugs. Although the benefits with regard to cardiovascular
protection seem to outweigh the side effects, this paper under-
lines the benefits of raised awareness of the temporal associa-
tion between statin treatment and the onset of peripheral
neuropathy.
Amiodarone: Amiodarone is a class III antiarrhythmic
drug used primarily in the treatment of atrial and ventricular
arrhythmia. Common adverse drug effects include hepatoxic-
ity and thyreoid affection, and the drug was initially reported
to have a strong association to neurotoxicity, including
reversible peripheral neuropathy, occurring at a maintenance
dose of 600 mg/day [9,10]. However, it appears as if this
association is weaker than previously assumed. In an analy-
sis of 707 patients treated at the Mayo Clinic from 1996
through 2008, those who developed neurological symptoms
with amiodarone treatment being the plausible cause were
registered [11]. Two patients developed peripheral neuropa-
thy while 9 others were identified with symptoms such as
tremor or gait ataxia. These numbers are consistent with
results of newer studies but differ from earlier studies pub-
lished in the 1980s. Thus, the incidence of neurotoxicity
from treatment with amiodarone was shown to be drastically
lower than previously believed, where neurological symp-
toms were found to occur in every third patient. It is noted
that the incidence of neurological symptoms are directly
related to a significant reduction in maintenance doses of
amiodarone from 600 mg to 200 mg, while the highest risk
factor for adverse drug effects apart from increased dose
appears to be the length of drug therapy. As a result of
advances in surgical procedures, the use of amiodarone has
declined over the years.
Chemotherapeutic agents.
Chemotherapy-induced peripheral neuropathy (CIPN) might
be regarded as a subclass of DIPN. Several chemotherapeutic
agents are known for this adverse effect.
Vinca alkaloids such as vincristine, vinblastine, vindesine,
vinorelbine, and vinflunine are used to treat haematologic and
lymphatic malignancies as well as solid tumours. Of these
drugs, vincristine is the most neurotoxic; however, the mecha-
nism behind the onset of peripheral neuropathy from all the
drugs is unclear. Sensory fibres are affected earlier and more
severely than the motor neurons with initial manifestation of
vincristine-induced peripheral neuropathy in the form of
decreased deep tendon reflexes, followed by paraesthesia
[12,13]. Neuropathy seen in patients treated with other vinca
alkaloids is often less severe: Both Vinorelbine- and vinblas-
tine-induced peripheral neuropathy are similar to but milder
than what is seen in patients treated with vincristine. Vinorel-
bine-treated patients usually develop a mild, distal axonal sen-
sorimotor neuropathy with affection of the deep tendon
reflexes (94%), paraesthesia (50%) and hypopallesthesia (9%)
[14].
© 2014 Nordic Association for the Publication of BCPT (former Nordic Pharmacological Society)
MiniReview
Taxanes such as paclitaxel and docetaxel are used in the
treatment of various types of solid tumours. The development
of peripheral neuropathy is most likely caused by an effect on
axonal transport through disruption of the microtubules [15].
Symptoms of peripheral neuropathy including decreased vibra-
tion perception, sense of position, loss of pain and temperature
sensation, as well as deep tendon reflex impairment are evi-
dent on clinical examination; however, the underlying mecha-
nism is not entirely understood [16]. In patients receiving
paclitaxel chemotherapy, the incidence of CIPN might
approach 70% when the drug is combined with either cisplatin
or carboplatin [17].
Platinum compounds such as cisplatin, carboplatin and oxa-
liplatin are known to produce axonal hyperexcitability and
repetitive discharges resulting from changes in voltage-depen-
dent Na+ channels [18] and might produce neuropathy from
oxidative stress [19]. Carboplatin-induced peripheral neuropa-
thy is less frequent and severe at conventional doses compared
with that in cisplatin-treated patients [20,21].
Oxaliplatin is a third-generation compound derived from
platinum that is widely used in colon cancer treatment. The
neurotoxicity presents as two different types: an acute and a
chronic sensory neuropathy.
Bortezomib and thalidomide are used in the treatment of
multiple myeloma. Neuropathy induced by bortezomib is seen
with varying severity in up to 75% of patients, with severe
symptoms possibly affecting up to 30% of those patients [22];
however, the mechanism underlying the peripheral neuropathy
induced by the drug is unknown. Thalidomide might also
cause dorsal root ganglia (DRG) neuronopathy [23].
Combination chemotherapy using bortezomib and thalido-
mide has been proposed as an option for refractory multiple
myeloma, but the risk of developing severe CIPN appears to
increase in these patients compared with that in patients hav-
ing a single-agent treatment [24]. Still, there is some contra-
dictory evidence of the protective effects of thalidomide
against development of bortezomib-induced CIPN [25].
Epothilones are used in the treatment of advanced breast
cancer. Ixabepilone is currently used primarily to treat refrac-
tory breast cancer and is shown to have induced severe CIPN
in 13–20% of treated patients, with an overall incidence of
neurotoxicity >70% [17].
Arsenic trioxides are used for treatment of acute promyelo-
cytic leukaemia and potentially for other neoplasms. These
agents have also been associated with CIPN [26].
Antibiotics.
Antimycobacterial agents: Tuberculosis (TB) infections con-
tinue to be a consistent factor in morbidity and death world-
wide. Standardized treatment consists of multi-drug therapy
using isoniazid, rifampicin, pyrazinamide and ethambutol,
and often requires treatment over the course of several
months because of the drug-resistant nature of mycobacteria.
Adverse drug effects associated with isoniazid are liver toxic-
ity, nausea, enhanced epileptic tendency and peripheral neu-
ropathy, which typically is sensory, reversible within weeks
MiniReview DRUG-INDUCED PERIPHERAL NEUROPATHY
after treatment ends and preventable with a daily prophylac-
tic treatment of 200 mg pyridoxine (vitamin B6), due to the
effect of isonicotinic acid on vitamin B6 synthesis [27,28].
Although clinical and pharmacological data regarding its neu-
roprotective effects are sparse, pyridoxine remains a valid
treatment option for the prevention of peripheral neuropathy
induced by isoniazid. On the other hand, there are reports
suggesting that Pyridoxine, in high daily doses, may induce
peripheral neuropathy. These effects are seen when the daily
dose exceeds 2 g/day.
Adverse drug effects with protective isoniazid treatment
among South African gold miners, who were tested negative
for TB, were investigated in a large randomized trial compris-
ing 24,221 individuals initiated on 300 mg isoniazid and
25 mg pyridoxine daily from June 2006 through July 2009
[29]. Fifty patients (0.21%) developed peripheral neuropathy
(46 cases mild and four cases moderate peripheral neuropa-
thy), with the median time from beginning of treatment to
symptom development being 34 days, and with 37 of 40
patients included in a follow-up examination after cessation
showing remission. These numbers need to be viewed in the
context of a reported HIV prevalence of 30%, in itself a risk
factor for developing peripheral neuropathy, as well as the
non-identification or exclusion of patients with other concur-
ring risk factors in the patient group.
In conclusion, isoniazide has the potential to cause revers-
ible peripheral neuropathy, which typically resolves after ces-
sation of treatment.
With regard to ethambutol, the onset of optic neuropathy is
a well-described adverse effect [31]; however, the drug has
not been associated with polyneuropathy.
The oxazolidinone linezolid, which inhibits bacterial protein
synthesis, is a newer antibiotic agent used as treatment in par-
ticular multi-drug-resistant (MDR-) TB. Because of the high
costs, as well as frequent and severe adverse drug effects with
a standard treatment dose of 600 mg twice daily, including
pancytopenia and irreversible peripheral neuropathy, linezolid
remains a second-line treatment option. In a comparative retro-
spective study by Legout et al. [31], nine of 94 patients trea-
ted with linezolid alone or in combination with rifampicin of
other drugs as treatment for osteomyelitis, developed periph-
eral neuropathy. No difference between treatment regimen and
peripheral neuropathy was seen suggesting that the neurotoxic-
ity is related to Linezolid.
In a retrospective trial comprising 30 patients being treated
for MDR-TB with 600 mg linezolid daily, in combination
with at least three other antibiotics and vitamin B6 at dosages
of 50–100 mg, five patients developed peripheral neuropathy
[32]. Because of the prophylactic treatment with vitamin B6
as well as the multi-drug regimen applied in this study, it is
difficult to deduce the correlation between linezolid and
peripheral neuropathy as a side effect.
In a small clinical trial comprising eight patients with
MDR-TB who were treated with half the dosage of linezolid
in combination with at least four other drugs, four patients
developed peripheral neuropathy, which was irreversible after
cessation of treatment [33].
© 2014 Nordic Association for the Publication of BCPT (former Nordic Pharmacological Society)
187
In a retrospective study, 75 patients began individualized
treatment for MDR-TB [34]. These patients were treated with
an average combination of six drugs. Ten patients (13%)
developed symptoms of peripheral neuropathy with the diag-
nosis verified by nerve conduction studies. The median time
from the onset of treatment to the appearance of peripheral
neuropathy symptoms was 9.1 months. All symptoms were
reported from the lower extremities and all were sensory.
However, multi-drug treatment as well as treatment with pyri-
doxine obscures interpretation of these results.
Based primarily on the study by Legout et al., it can be
concluded that linezolide has the potential to cause peripheral
neuropathy.
Metronidazole (MNZ) is a 5-nitroimidazole used in the
treatment of anaerobic bacteria (AB) and protozoans (PZ). AB
causes infections such as ulcerative gingivitis; dental, brain,
lung and intraperitoneal abscesses; and vaginosis. MNZ is also
used in combination with amoxicillin in the treatment of gas-
troduodenal ulcers caused by Helicobacter pylori. MNZ is
also used in the treatment of parasitic infections such as
amoeba dysentery, amoeba liver abscesses, giardiasis as well
as vaginitis and urethritis caused by Trichomonas vaginalis.
Neuropathy is rarely seen as an adverse side effect of MNZ
treatment and is primarily seen in patients treated for pro-
longed periods with high doses [35].
Two randomized, controlled studies reported peripheral neu-
ropathy as an adverse side effect of MNZ therapy for infec-
tious diseases [36,37]. In addition, two clinical trials
investigated peripheral neuropathy as an adverse side effect of
treatment with MNZ in patients with Crohn’s disease. In the
first study by Duffy et al. [38], 13 patients with Crohn’s dis-
ease (aged 12–22 years) were assessed in terms of the preva-
lence of peripheral neuropathy resulting from oral MNZ
treatment. After 4–11 months of treatment, 11 of 13 patients
had developed sensory peripheral neuropathy, which was
determined by studies showing abnormal neurological function
or reduced nerve conduction. Only six of the 11 patients were
symptomatic. MNZ treatment was discontinued in nine of
these 11 patients. Follow-up evaluations 5.5–13 months later
showed complete resolution of peripheral neuropathy in five
patients, improvement in three and no change in one patient.
Two of the 11 patients had their dose reduced to <10 mg/kg/d.
After 10–12 months of continued therapy, one patient showed
worsening and one patient showed complete resolution of
peripheral neuropathy. This study clearly shows the correlation
between long-term MNZ treatment and sensory peripheral neu-
ropathy. It also supports the possible irreversibility of sensory
peripheral neuropathy in some patients.
The second study by St
ahlberg et al. [39] investigated the
tolerability of long-term MNZ treatment in patients with Cro-
hn’s disease using objective neurophysiological studies and
subjective neurological symptoms such as tingling and numb-
ness. The maximum daily dose of MNZ used was 800 mg.
Fifty-three patients were included and divided into three
groups: the first group (19 patients) had been receiving MNZ
for at least 1 year before the study; the second group (13
patients) had the same type of long-term treatment but had
188 OLE J. VILHOLM ET AL.
been off the drug for at least 3 months before entering the
study; the third group (21 patients) had never received treat-
ment with MNZ. No significant difference in neurophysiologi-
cal symptoms was found among the three groups. A few
patients from all three groups reported paraesthesia from time
to time. The paraesthesia was transient and, in patients taking
MNZ, not aggravated despite continuing treatment with an
unchanged dose. In this study, the sensory symptoms were
transient and the nerve conduction studies were performed
only after remission of the symptoms.
In conclusion, based primarily on the study of Duffy et al.,
MNZ seems to have the potential to cause sensory peripheral
neuropathy of a predominantly reversible character.
Nitrofurantoin is a synthetic antibiotic effective against Esc-
herichia coli and Enterobacteriaceae and is suitable for treat-
ment of urinary tract infections. Since its introduction in 1952,
peripheral neuropathy as an adverse effect of nitrofurantoin
has been proposed in several case reports, although at a mark-
edly declining rate after the 1980s. It is mainly described as
being non-dose-dependent and of a sensorimotor, primarily
axonal character [40–42].
Most recently, Tan et al. [43] reported two cases of small
fibre neuropathy associated with short-term prescriptions of ni-
trofurantoin. Nerve conduction study results were normal and
although nerve fibre density was not affected, skin biopsies
revealed significant morphological changes of axonal swelling
in papillary dermis, similar to changes seen in small fibre neu-
ropathy related to Sj€ogren’s syndrome. The mechanism caus-
ing this swelling is unknown.
Immunosuppressants.
Biologicals: Tumour necrosis factor-a (TFA-a) inhibitors such
as etanercept, infliximab or adalimumab are indicated for the
treatment of autoimmune diseases such as moderate to severe
rheumatoid arthritis, ankylosing spondylitis or inflammatory
bowel disease, reducing the effect of the biologically active cyto-
kine TNF-a, which plays an important role in normal inflamma-
tion as well as in immunoregulating mechanisms such as T-cell
regulation [44]. These agents inhibit TNF-a by combining
ligands of the TNF-a receptor with the Fc-fragment of IgG1 (eta-
nercept) or as monoclonal antibodies (infliximab, adalimumab).
There are several reviews associating TNF-a inhibitors to
neuropathy, proposing different pathomechanisms such as
T-cell or induced autoantibody attack against myelin, ischae-
mic processes or inhibition of axon signalling. The clinical
spectrum seems to be heterogenous, presenting as axonal,
symmetric sensory polyneuropathy or as mononeuropathy sim-
plex or multiplex or even as a conduction block [44,45]. A
report from the post-marketing database of the US Food and
Drug Administration (FDA) showed 15 patients developing
Guillain-Barre syndrome (GBS) after TNF-a inhibitor treat-
ment [46]. Several reports suggest that etanercept has a posi-
tive clinical effect as a second-line treatment option for
patients with chronic inflammatory demyelinating polyneropa-
thy (CIDP), compatible with evidence of elevated serum levels
of TNF-a in some CIDP patients [47–49].
© 2014 Nordic Association for the Publication of BCPT (former Nordic Pharmacological Society)
MiniReview
Interferons are cytokines with immunomodulatory properties
and a wide range of indications. As such, interferon b-1-a has
been used as first-line treatment of multiple sclerosis, while
interferon alpha is a cytokine used for treatment of hepatitis B
and C, and appears to be able to cause neuropathy in rare
cases. The drug is administered in a PEGylated form and has
immunomodulatory properties such as inhibition of T-cell pro-
liferation, an increase of anti-inflammatory cytokines, and a
decrease of TNF-a. The mechanism being discussed at the
onset of neuropathy is the induction of antiganglioside anti-
bodies such as anti-GM1. There are case reports of patients
treated with plasmapheresis and interferon alpha developing
neuropathy, with clinical symptoms as well as raised antibody
levels regressing after cessation of therapy [50,51].
Leflunomide is an immunomodulating agent that inhibits the
mitochondrial dihydroorotate dehydrogenase and is essential in
the synthesis of pyrimidine antibodies, thereby inhibiting the
proliferation of activated T cells, and is shown to be beneficial
in the treatment of rheumatoid arthritis.
Common side effects include gastrointestinal symptoms,
liver affection and hypertension. In a trial performed in India
between 2000 and 2003, patients with rheumatoid arthritis sui-
ted for therapy with disease-modifying antirheumatic drugs
(DMARD; n = 150) were assigned to one group treated with
leflunomide with or without methotrexate (n = 50), while the
other group was treated with other DMARDs such as metho-
trexate or hydroxychloroquine [52]. The leflunomide group
showed a significantly higher incidence of polyneuropathy
than the methotrexate group (5/50 versus 2/100), which was
confirmed by reduced nerve conduction velocity in all seven
patients showing motor axonal neuropathy. Within 3 months
after treatment was stopped, the symptoms were fully remitted,
further pointing toward a relationship between the drug treat-
ment and neuropathy. Nerve biopsies performed on three
patients showed epineural perivascular inflammation and
prominent neovascularisation compatible with an axonopathic
process and vasculitis.
In a French cohort study of 130 patients receiving therapy
with leflunomide, eight new cases of polyneuropathy were
identified; however, there were no exclusion criteria, and it
was noted that those patients had concurring risk factors for
developing neuropathy, such as diabetes and use of neurotoxic
drugs [53].
Richards et al. presented a prospective cohort study
(n = 32) with 16 patients receiving leflunomide and 16 receiv-
ing DMARDs. Fifty-two percent of patients in the leflunomide
group and 8% of patients in the control group had an increase
in their symptom score, although a subsequent neurophysio-
logical examination did not show a correlation with the clini-
cal score [54].
Nucleoside Reverse Transcriptase Inhibitors
Nucleoside reverse transcriptase inhibitors (NRTIs) compete
with natural deoxynucleotides for integration in viral DNA, ter-
minating the chain because of their different structure, and are
an integral part of HIV highly active antiretroviral therapy
MiniReview DRUG-INDUCED PERIPHERAL NEUROPATHY
(HAART), as well as a common contributor to polyneuropathy
in HIV patients. Polyneuropathy in HIV patients is often multi-
factorial and can be difficult to distinguish, important factors
being low CD4+ cell count, neoplasms, high viral load or high
ethanol consumption. The pathomechanism is not fully under-
stood but appears to be associated with mitochondrial toxicity
with mtDNA depletion in Schwann cells, resulting in demyelin-
isation and presenting as a painful, primarily small fibres and
sensory neuropathy. There are major differences between the
nucleoside analogues, with approximately 10% of patients fol-
lowed in 1 British study receiving stavudine or zalcitabine and
1–2% of patients receiving didanosine developing severe poly-
neuropathy, while drugs such as zidovudine or lamivudine did
not show this association [55]. A large South African study
focusing on stavudine side effects showed 17.1% of 9040
patients with HAART treatment that included stavudine pre-
senting with polyneuropathy at a median follow-up time of
19 months versus 11.2% of participants on other regimens [56].
Another South African study reports a correlation between
HIV-related sensory neuropathy and age (>23 years) as well as
length (>185 cm), proposing an easy way to identify some risk
patients for consideration of more costly therapy alternatives
[57]. Acetyl-L-carnitine and Nerve Growth Factor have been
discussed as protective treatment options.
Miscellaneous agents.
Levodopa (L-DOPA, L-3,4-dihydroxyphenylalanine) is a pre-
cursor of dopamine capable of crossing the blood brain barrier
and a major entity in the treatment of Parkinson’s disease
(PD). Recently, a link between patients with idiopathic PD
and the onset of peripheral neuropathy has been proposed in
several case–control studies, suggesting that L-DOPA therapy
could be the culprit, with cumulative dose levels showing a
correlation to elevated methylmalonic acid (MMA) and homo-
cysteine levels as well as reduced levels of vitamin B12. Toth
et al. [58] compared 58 PD patients with 58 matched controls
with regard to the prevalence of clinical and electrophysiologi-
cal peripheral neuropathy, with 55% of the PD patients pre-
senting symptoms of peripheral neuropathy compared with
only 9% in the control group. This was suggested to be related
to elevations of MMA resulting from L-DOPA-inflicted vita-
min B12 deficiency, and led to a discussion about cobalamin
substitution as a possible treatment option to stabilize the
peripheral neuropathy. This study was followed up by Raja-
belly et al. [59], who aimed to assess the role of cobalamin in
PD patients under L-DOPA therapy and presenting with
peripheral neuropathy. Their results showed 37.8% of patients
in the PD group and 8.1% of the controls as having peripheral
neuropathy, low cobalamin levels being a more frequent cause
as well as cobalamin levels being lower than in controls with
peripheral neuropathy but without PD (286.8 ng/L versus
413.2 ng/L with deficiency defined as levels <300 ng/L). A
correlation between cumulative L-DOPA exposure and cobala-
min levels was seen only in PD patients with peripheral neu-
ropathy, suggesting pre-existing susceptibility in this group.
These findings remain controversial, but it appears reasonable
© 2014 Nordic Association for the Publication of BCPT (former Nordic Pharmacological Society)
189
to examine IPD patients in long-term treatment with L-DOPA
with regard to peripheral neuropathy as well as to measure
MMA, cobalamin and homocysteine levels to assess an indica-
tion for vitamin B12 supplementation.
Triazole: Antifungal drugs such as itraconazole and vorico-
nazole have recently been shown to increase the risk of
peripheral neuropathy. In 2010, Iwamoto et al. [60] reported
an increased incidence of peripheral neuropathy when itraco-
nazole was used in combination with bortezomide and in
2011, Baxter et al. found that 10% of a population being trea-
ted with triazole developed peripheral neuropathy within
4 months and that the symptoms ameliorated after cessation of
triazole treatment [61].
Treatment of DIPN
Most often, DIPN presents with only mild sensory paraesthe-
sias. In these cases, no specific treatment is required other
than a possible reduction or cessation of the specific agent
causing the neuropathy.
When the neuropathy is associated with pain, a specific
treatment may be required to relieve the pain. Pain associated
with DIPN can be regarded as a condition of neuropathic pain,
according to the definition by the International Association for
the Study of Pain (IASP): Pain caused by a lesion or disease
of the somatosensory system [62]. The drugs primarily used
for treatment includes tricyclic antidepressants, gabapentin and
pregabalin [63,64]. Treatment of neuropathic pain conditions
is often difficult. Referral to a specialized pain management
clinic may be necessary, if a satisfactory pain relief is not
obtained with the standard pain treatment.
Discussion
In this review of the literature, we have tried to provide an
overview of some of the medical agents that have been sus-
pected to cause peripheral neuropathy either from bigger ran-
domized trials, retrospective studies or case reports. In
addition, we suggest a new definition of ‘(DIPN)’.
For many of the medical agents, there is a need for further
investigation with study designs that adjust for concomitant
risk factors. This is true, for example in antimycobacterial
therapy, where several drugs are administered at the same time
to individuals, who are in high risk of developing polyneurop-
athy induced by immunosuppression and infections.
General risk factors.
Risk factors related to the specific treatment are listed in
table 1. In addition to this, awareness of the most common
general risk factors of developing peripheral neuropathy is
important. These include alcohol overuse, diabetes, toxins,
nutritional disorders (e.g. B-vitamin deficiency), infectious dis-
eases (e.g. TB and HIV), connective tissue diseases and meta-
bolic diseases. Hence, a thorough examination of the patients
suspected for DIPN is often necessary in the daily clinical
practice as well as in the setting of a clinical study.
 Table 1.
190

Overview of some of the drugs most commonly associated with DIPN.

Risk factors related
Agent/Group Incidence rate Outcome measures to treatment Pathogenesis Type of neuropathy
Cardiovascular agents
Statins Odds ratio: Study-specific definitions Duration > 2 years Predominantly sensory neuropathy
1.2–4.6 of neuropathy
Chemotherapeutics
Vincristine 30–40% WHO,NCI-CTC, QLQC30, 1-Single dose level Dysfunction of cellular and axonal Predominantly sensory neuropathy
SWOG criteria, VPT 2-Cumulative dose level transport mediated by microtubules
Docetaxel Up to 50% Neurotoxicity Score, NCI-CTC 1-Single dose level Dysfunction of cellular and axonal Sensorimotor axonal neuropathy
2-Cumulative dose level transport mediated by microtubules
3-Infusion duration
Paclitaxel 70–95% TNS, NCS, Neurotoxicity 1-Single dose level Dysfunction of cellular and axonal Sensorimotor axonal neuropathy
Score, NCI-CTC 2-Cumulative dose level transport mediated by microtubules
3-Infusion duration
Cisplatin 30–40% WHO, NCI-CTC, QLQC30, SWOG 1-Single dose level Irreversible binding to DNA, Sensory neuropathy
criteria, FACT/GOGNtx 2-Cumulative dose level neuronal apoptosis
Oxaliplatin Acute: 65–98% OXL-specific scale, Debiopharm 1-Single dose level Acute: Dysfunction of Acute sensory symptoms and chronic
Chronic: neuro-toxicity scale, WHO, 2-Cumulative dose level voltage-dependent sodium channels sensory neuropathy
50–60% NCI-CTC, QLQC30, 3-Infusion duration Chronic: Irreversible binding
FACT/GOGNtx 4-Treatment duration to DNA, neuronal apoptosis
Bortezomid 30–64% TNSr, TNSc, NCS, NCI-CTC, 1-Single dose level Painful, small fibre sensory neuropathy
Neurological examination 2-Cumulative dose level
Thalidomide 14–70% Study-specific definitions of neuropathy 1-Single dose level Predominantly sensory neuropathy
2-Cumulative dose level
OLE J. VILHOLM ET AL.

3-Treatment duration
Antimicrobacterial agents
Isoniazid <1% Study-specific definitions of neuropathy Primarily sensory neuropathy, pain can be seen
Ethambutol 1–5% Study-specific definitions of neuropathy Optic neuropathy
Linezolid LNZ alone: 4% Study-specific definitions of neuropathy Sensory neuropathy
LNZ + other
agents: 11–56%
Metronidazole Up to 85% Study-specific definitions of neuropathy Predominantly sensory neuropathy
Nitrofurantoin Case reports Study-specific definitions of neuropathy Sensorimotor, primarily axonal large and
small fibre neuropathy
Immunosuppressants

© 2014 Nordic Association for the Publication of BCPT (former Nordic Pharmacological Society)
TNF-a inhibitors Case reports Study-specific definitions of neuropathy T-cell or induced autoantibody Axonal, sensory neuropathy,
attack against myelin, ischaemic mononeuropathy simplex or multiplex
processes or inhibition of axon signalling
Leflunomide 5–10% Study-specific definitions of neuropathy Primarily motor axonal neuropathy
NRTIs 8–10% Study-specific definitions of neuropathy
, Insufficient data.
Outcome measures: DIPN, drug-induced peripheral neuropathy; FACT/GOG-Ntx, Functional Assessment of Cancer Therapy Scale/Gynaecologic Oncology Group-Neurotoxicity scale; OXL-specific scale,
Oxaliplatin specific scale; NRTIs, nucleoside reverse transcriptase inhibitors; NCI-CTC, National Cancer Institute-Common Toxicity Criteria; WHO, World Health Organization; QLQ-C30, European Orga-
nization for the Treatment of Cancer quality of life questionnaire-30 items; NCS, nerve conduction studies; TNS, total neuropathy score. TNSc, TNS-clinical version; TNSr, TNS reduced version; VPT,
MiniReview

Vibration perception threshold; SWOG, South West Oncology Group.

MiniReview DRUG-INDUCED PERIPHERAL NEUROPATHY
Future research.
Early detection and subsequent modification of the treatment
regimen is one of the most important factors for reducing the
incidence and severity of DIPN. Better understanding of the
underlying pathophysiology of the specific DIPN is a corner-
stone for further improvement of both prevention and treat-
ment of DIPN. There is also a need for further randomized,
controlled trials to clarify the efficacy of possible neuroprotec-
tive agents.
Acknowledgements
None.
Disclosures
None.
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