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M E D I C A T I O N -I N D U C E D N EUR O PATHIE S

Louis H. Weimer, M.D.

Introduction

Idiopathic polyneuropathy constitutes a significant proportion of peripheral neuropathy cases. In


addition, a number of identifiable causes of neuropathy have no preventative or curative
interventions available, only symptomatic treatment. Thus, detection of toxic or medication induced
neuropathy can be an important diagnosis that impacts quality of life. Medication-induced
neuropathies are uncommon (2-4% of cases in one outpatient neurology setting)1, but crucial to
recognize because intervention can lead to significant improvement or symptom resolution.
Numerous medications have been associated with neuropathy (Table 1), but many more agents are
suspected of causing neurotoxicity, including peripheral neuropathy than have convincing proof.
Also, many subclinical or unsuspected cases likely remain undiagnosed.

Many iatrogenic neuropathies are due to medications uncommonly prescribed (disulfiram), not used
in the U.S. (perhexiline, almitrine), normally used in low doses with minimal toxicity (phenytoin, ara-
C), or typically used for short duration (metronidazole). Nevertheless, medications continue to
rapidly increase in number and uncommon side effects may not become apparent until after
widespread usage. In addition, expansion or changes in usage have increased the importance of toxic
neuropathies (e.g. thalidomide). A number of agents produce tolerable neuropathies because the
underlying disease is severe, notably malignancies and HIV infection. In these cases evolving
research has been directed toward identifying secondary agents or delivery methods to blunt or
prevent toxicity.

Identification of a toxic effect is simplest when acute or subacute onset of symptoms occurs soon
after the initial drug exposure or a change of medication dosage. Most patients fall into this category.
In contrast, it is much more problematic to diagnose a slowly progressive neuropathy starting many
months or years after starting a chronic agent. Statin drugs provides a recent case in point and is
discussed below.

Susceptibility of peripheral nerve


Peripheral nerve is protected by a blood-nerve barrier and would seem to be at lesser risk than other
organs for toxicity. However, a number of factors enhance peripheral nerve vulnerable, especially
compared to the central nervous system.1 Some examples include:
• Blood flow to peripheral nerve is not autoregulated and is vulnerable to sudden
microenvironment changes.
• Dorsal root ganglia (DRG) lack an efficient vascular barrier to some large molecules making
the cell body and not axon a target in some cases
• Endothelial cells in the epineurium are fenestrated and allow escape of some blood proteins
in the extracellular space.
• The blood-nerve barrier is less efficient than the BBB, allowing easier access for potential
neurotoxins into the periphery.
• Endoneural nerves have no lymphatic system to remove toxins.
• Peripheral nerve has nothing analogous to the sink action of CSF

A number of other factors render some individuals more vulnerable to potentially toxic medications.
A well-known and increasingly supported predisposition is the presence of an underlying neuropathy
that may be of unrelated genetic or acquired cause.2,3 In some conditions (e.g. malignancy and HIV),
an inherent neuropathy can be difficult to distinguish from treatment-induced neuropathy. Other

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genetic factors may alter toxicity especially impairments in metabolism which may be either
detrimental or protective depending on whether exposure to the primary drug or toxic metabolites is
the offensive factor. More recently, genes known to promote neuronal axon survival have been
shown to blunt certain neurotoxic effects. For example, presence of the WldS slow Wallerian
degeneration gene, can protect against both axotomy and vincristine exposure neuropathy.4
Transfection of this gene into rat DRG cells in vitro has conferred this beneficial property onto these
neurons, raising intriguing possibilities for future treatments.5

Most toxic neuropathies, including medication-induced forms, principally induce axonal degeneration
in a “dying back” pattern disproportionately affecting the distal segments of the most vulnerable,
usually longest nerves. However, a number of agents may cause segmental demyelination or target
Schwann cells, dorsal root ganglia and autonomic neurons, or peripheral myelin.

A number of agents not discussed in detail bear some mention. Some agents convincingly associated
with neuropathy are generally safe with typical usage, but may be used at higher dose or more
chronically. One common example is colchicine typically taken intermittently for gout attacks, but in
some cases taken chronically for extended periods. Myopathy is the primary effect but additional
neuropathy is usually part of the syndrome. Allopurinol is also rarely associated with neuropathy but
the effect appears to be an idiosyncratic hypersensitivity reaction. Metronidazole is usually given in
short courses, generally less than 14 days, but some infections require extended treatment. In this
setting monitoring for toxic neuropathy is warranted. Much is known about disulfiram neuropathy
and the toxic mechanism is likely very similar if not identical to carbon disulfide. The drug is still
used in some settings and alcoholic neuropathy should not be assumed in treated patients. Phenytoin
neuropathy from chronic exposure remains controversial and based on a small number of reports but
affected patients described were generally on much higher than current doses (>500 mg/d) and
blood levels (> 20 µg/ml). A few examples of important agents with recent developments have been
selected for discussion.

Chemotherapeutic agents

Treatment of malignancies is one setting where medication toxicity is accepted, assuming the agent is
efficacious. Most agents cause neuropathy in a dose-dependent manner. Thus, a lower dose may
lessen neurotoxicity but could compromise efficacy. Because a number of important neurotoxic
chemotherapeutic drugs are commonly used, therapeutic interventions have focused on elimination
or reduction of the neuropathy, preferably by prevention. This field is especially attractive because of
the potential capability to pretreat, unlike most neurologic injuries. A separate critical issue is
whether preventative agents reduce drug efficacy, especially relevant when the neurotoxicity is
mediated by the same mechanisms as the anti-neoplastic effects.6 Selective blocking of the deleterious
processes is advantageous, but is only possible if the underlying processes are understood.6
Numerous secondary agents have been tried with cisplatin and to a lesser degree, taxoids and vinca
alkaloids.

Cisplatin and related analogs remain widely used against a variety of malignancies alone or in
combination therapy. The incidence of neuropathy varies between reports and according to dose,
but is roughly 12% at conventional dose and 70-100% with higher cumulative doses (540-600
mg/m2) and may be lower (14%) if used as a sole agent.1 The drug likely accumulates over time and
the phenomenon of “coasting”, when a neuropathy continues to progress for a time after the drug is
stopped can be seen. Usually this effect persists only 2-3 weeks, but longer intervals have been
described. The primary drug effect is not precisely known, but the effect on malignant cells appears
to be binding to and altering DNA. Cell division is arrested for DNA repair and if damage is
extensive, apoptosis is triggered.7 In contrast, the cause of neuronal injury is less clear, but apoptosis

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also occurs with evidence that neurons enter the cell cycle prior to apoptosis, implying that drugs
which block this transition, including nerve growth factor (NGF), could prevent cell death.7

Dorsal root ganglia (DRG) and axons show high platinum levels thus, differential drug access
appears to be an important factor, although, autonomic ganglia are relatively spared.6,8 In addition
mice with defective DNA repair abilities appear to have increased cisplatin susceptibility.9 Additional
clinical, pathological, and electrophysiologic evidence also supports the concept that the process is a
dorsal root ganglionopathy rather than a distal axonopathy.8,10 Effects of other drugs, especially
taxoids may have additive neurotoxicity.

Taxoids comprise a family of diterpene alkaloids, including paclitaxel (Taxol) and docetaxel
(Taxotere). Both are widely used in metastatic ovarian and breast cancer and are increasingly used in
earlier disease stages and in other cancer types. Higher doses are desirable to oncologists for efficacy
but toxicity, including peripheral neuropathy, is a limiting factor.

Human paclitaxel neurotoxicity is most commonly a dose-dependent, predominantly sensory


neuropathy. Although evident at low doses (<200 mg/m2), symptoms are usually not clinically
significant. At high dose, neuropathy is common and has been the major limiting factor in some
trials.11 Symptoms may begin after one dose and can appear simultaneously in proximal sites prior to
distal foot symptoms, again suggesting a possible neuronopathy. However, the pattern usually
coalesces into a more typical distal predominance. Dysautonomia is not uncommon and often
overlooked. Motor involvement is much less common but can be seen at high dose. Docetaxel
toxicity appears to be similar. Early animal findings did not mimic the human manifestations of
predominately small and large fiber sensory and autonomic and lesser motor impairment, but more
recent animal studies have better modeled human taxol acute and chronic painful neuropathy.12

The neurotoxic mechanisms are unknown. In fact, it is not even certain whether the primary target is
the sensory or autonomic neuron, axon, or myelin. Most likely all three are vulnerable in part. A
major effect on tumor cells that may be relevant to neurotoxicity is the assembly of large arrays of
disordered microtubules, in contrast to numerous other neuropathy-inducing agents that inhibit
microtubular assembly (colchicine, vinca alkaloids, podophyllin resin).

Chemoprotectants. Some agents have been empirically tried with anecdotal but unproven benefit
including steroids and vitamin E. Glutamate paradoxically has been reported to be a neuropathy
protectant against both paclitaxel and cisplatin rat models without apparent inhibition of the
therapeutic effects and warrants further study.13 Amifostine is an agent approved specifically for
reduction of cisplatin toxicity. Amifostine is a tissue activated prodrug, which decreases renal toxicity
by detoxifying cisplatin metabolites and by free radical scavenging, with theoretical higher activity in
normal tissue. Any neurologic benefit is likely due to improved toxin clearance. Studies of patients
with advanced ovarian and other cancers have shown modest prevention of neuropathy from
cisplatin in some series without altering efficacy, but the neurologic benefits are not clearly
established at present. Studies with paclitaxel have not been promising to date.14,15 The free radical
scavenger Glutathione has been shown to reduce cisplatin nephrotoxcity and possibly secondarily,
neurotoxicity by preventing drug accumulation.16 In a blinded placebo-controlled study of patients
treated with oxaliplatin, glutathione administration showed improved clinical and sensory nerve
conduction outcomes compared to placebo treatment.17 Org 2766 is an ACTH derived hexapeptide
that has shown promise in several small trials and animal studies with incomplete blunting of
cisplatin and other systemic toxicity. However, a large clinical trial failed to demonstrate any
benefit.18

Neuronal growth factors have attracted much interest in various areas of neurology and
neuroscience, but are still awaiting proven clinical applications. A number of neurotrophins have been

3
studied in the prevention of toxic neuropathies and show promise and are only agents that can
completely prevent neurotoxicity in some models.6,11 Receptors for these agents are unlikely to be
present on tumor cells, reducing the risk of blunting chemotherapy efficacy.6 In both tissue culture
and animal models, several neurotrophins, including NGF, insulin-like growth factor-1, brain derived
neurotrophic factor, leukaemia inhibitory factor (LIF), and neurotrophin-3 (NT-3) have shown
protective effects against neurotoxicities of cisplatin and analogs, taxoids, vincristine, and suramin; in
some cases, the neuroprotective outcomes are marked. In addition, NT-3 introduced by virally-
mediated or non-viral electroporation-mediated genetic transfer has been shown to protect against
acrylamide, pyridoxine, and cisplatin-induced neuropathies using in vivo animal models.19,20 Thus,
despite the disappointing outcomes of clinical trials of patients with diabetic and HIV neuropathies,
these agents may be efficacious if applied as a preventative therapy. No human studies have been
reported despite reasonable tolerability of these agents; however, leukaemia inhibitory factor (LIF) is
currently being tested in phase II clinical trials.21

A number of other agents have shown some promising results in early studies and more are likely to
follow. Glutamine was shown to reduce symptoms but not nerve conduction abnormalities after high-
dose paclitaxel.22 Other promising compounds in animal models include Prosaptides (neurotrophic
activity) and the antibiotics radicicol and geldanamycin.

Suramin is a promising experimental agent used mostly for hormone-refractory or metastatic


prostate cancer. The drug was introduced in the 1920s as an antiparasitic agent and later tried
unsuccessfully against the HIV virus. During these trials, ancillary benefits against Kaposi sarcoma
and lymphoma were noted. The drug currently shows promise against a variety of cancers including
prostate, colon, and lymphoma, although the drug is awaiting approval in the U.S. Toxic neuropathy
is a primary limiting factor. The drug is tightly protein-bound accounting for an extremely long half-
life (40-50 days), which is useful in prophylaxis against protozoal infections but detrimental after the
onset of neurotoxicity.

Suramin in rat models induces a length, dose, and time-dependent axonal sensorimotor
polyneuropathy associated with axonal degeneration, atrophy, and accumulation of glycolipid
lysosomal inclusions.23 However, detailed electrophysiologic studies of patients on suramin have
shown evidence of demyelination as frequently as axonal injury, and many patients had clinical
courses resembling Guillain-Barré syndrome (GBS).24,25 In patients with plasma levels of suramin
over 350 µg/ml, the incidence of neuropathy appears to be approximately 15%, but may be as high
as 40%.25 Suramin treated neuronal cultures have shown accumulation of GM1 gangliosides, and
ceramide, as well as other gangliosides.26 Ceramide levels, an important mediator of programmed
cell death, are boosted intracellularly in suramin treated cultured neurons, suggesting a possible
ceramide-induced apoptotic mechanism of neurotoxicity.26 Suramin also inhibits DNA polymerase
and some growth factors including NGF. This growth factor inhibition may be neurotoxic and
increasing suramin doses inhibit NGF-specific binding and conversely high-dose NGF can block
suramin toxicity on DRG neuron.26,27

Patients using the drug as an antibiotic most often describe distal burning paresthesias, but reports
have had limited details. High-dose suramin chemotherapy leads to sensorimotor neuropathy and in
some cases progresses to quadriplegia with respiratory compromise. Acute signs of demyelination
and high CSF protein have been observed in suramin-treated patients and are reminiscent of GBS.

Cardiovascular agents

Statins
Cholesterol lowering agent myopathy (CLAM) is well recognized among physicians and patients.
Less well known are the small number of patients on HMG-CoA reductase inhibitors (statins) who

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have shown signs of peripheral neuropathy, either in addition to or separately from CLAM. The
significance of these reports is uncertain since millions of individuals worldwide are on statins.28,29,30
However, a recent Danish study concluded that statin users appear to have an overall higher
incidence of idiopathic peripheral neuropathy.31 The effect correlated with dose, but individual
agents were not separated. Gaist et al had published an earlier English series that did not find a
statin-neuropathy effect but concluded their sample size was insufficient. They then conducted a
much larger population-based study in one Danish county (465,000 inhabitants) and cross referenced
a prescription registry to a national patient diagnosis registry from 1994-1998, when statin use in
Denmark dramatically increased. They identified 1084 registered patients with a diagnosis of
polyneuropathy. They excluded 492 with onset prior to 1994 or a concurrent cause of neuropathy
(diabetes, renal failure, monoclonal gammopathy, etc.). Only cases with clinical signs of distal,
symmetric neuropathy and an adequate workup including electrodiagnostic studies were analyzed and
categorized as definite, probable, or possible idiopathic neuropathy. Twenty-five controls were
randomly chosen per index case. In total 35 definite, 54 probable, and 77 possible neuropathy cases
from the registry (166 total) were found. Nine had been exposed to statins including simvastatin,
pravastatin, lovastatin, and fluvastatin. Odds ratios of neuropathy were calculated as 4.6 overall with
current users of statins compared to controls and 16.1 with definite neuropathy cases compared to
controls. They also calculated an interesting number needed to harm measure and found, based on their
odds ratios, one excess case of idiopathic peripheral neuropathy for every 2,200 person-years of
statin use. In light of these data, neuropathy was suggested as a more important public health
concern than myopathy in patients taking statins. One potential pitfall is whether all symptomatic
neuropathy causes were in fact excluded including associated conditions for patients requiring statins,
for example occult diabetes. In any event the study highlights the difficulties and trial size needed to
prove a modest, chronic neurotoxic drug effect and why most associations are made with acute or
high dose exposures. Although at most a rare effect, the large numbers of patients on these agents
makes this correlation potentially relevant.

Amiodarone
Amiodarone (Cordone) is benzofuran derivative initially developed as an anti-anginal drug, but found
to be better as an anti-arrhythmic. It has been used extensively in Europe for this purpose, but only
approved for refractory, life-threatening ventricular arrhythmias in the U.S., mainly because of
toxicity. Peripheral neuropathy is one of the primary forms of toxicity, occurring in 6% of patients in
one series. Other forms of neurotoxicity are known including tremor (40%) and ataxia, although
some tremor and neuropathy cases likely overlap.32 Other neurotoxic effects are much less common
including myopathy, optic neuropathy, movement disorders, and encephalopathy, possibly because
the drug does not normally cross the blood-brain or blood-nerve barriers. Virtually all patients will
experience some side effects many in other organ systems, almost all of which are susceptible.
Metabolism is extremely slow in the liver and the plasma half-life may be as long as 100 days. The
pharmacology of the main metabolite desethylamiodarone is less well known. Thus improvement
after drug cessation can be quite delayed.

Animal studies with high does amiodarone have reproduced weakness and tremor.33 Cytoplamic
lysosomal lipid inclusions were found in autonomic, dorsal root, myenteric plexi and other areas with
a missing BBB, e.g. area postrema, choroids plexus, and pituitary. Levels were also seen in areas with
injured BNB, such as after crush injury. Intraneural injections induced demyelination and conduction
block in rats. Higher doses caused axonal degneration.

Peripheral neuropathy is the second most common neurotoxic effect after tremor and correlates
poorly with daily dose or treatment duration. Most have received medication for months to years in
moderately high doses, but cases after 200 mg for <1 month are known. Symmetrical sensorimotor
neuropathy is most common in some cases with a motor predominance. Autonomic neuropathy is
also reported. A variety of patterns are described both clinically and on electrodiagnostic studies.

5
Cases with a predominant axonopathy with low amplitude and distal denervation are seen. Patients
with almost pure demyelination are also seen or a mixture of both processes. Many cases show slow
velocity. Small and large fibers are affected on biopsy samples. Nerve biopsies also demonstrate
lysosomal inclusion in Schwann cells and axons as well as adjacent cells such as fibroblasts,
endothelial cells, and perineural cells. Measures of amiodarone and desethylamiodarone were found
80 fold higher than serum in one case where intraneural levels were measured. Lesser signs of
myopathy are also seen in animal and human cases with proximal weakness and modest CK
increases, and also lipid inclusions, and myopathic EMG changes in some cases. Optic neuropathy is
also well known with abundant recent examples.

The mechanism of toxicity is less clear. Amiodarone is lipophilic similar to perhexiline maleate,
which also causes a toxic demyelinating neuropathy. Thus the drug may gain entry to lysosomes and
bind to polar lipids. Both drugs form intralysosomal lipid complexes leading to the inclusions seen in
many tissues. The drug is still frequently used but patients need to be watched closely for toxicity.

Antibiotics

Nucleoside Analogs
Antiviral nucleoside analogs are a class of drugs resembling nucleotide bases. When phosphorylated,
they compete with nucleotides for reverse transcriptase binding and help terminate HIV DNA
elongation. The class is a mainstay of highly active artiretroviral therapy (HAART).34 In some,
peripheral neuropathy is an important limiting factor, primarily zalcitabine (ddC, Hivid), didanosine
(ddI, Videx), and stavudine (d4T, Zerit). Other group members, including lamivudine (3TC), abacavir
(ABC, Ziagen), and zidovudine (AZT), cause minimal or no clinically significant neuropathy. All,
however, appear to be toxic to mitochondria and can produce increased lactate levels, severe in some
cases.35,36 The mitochondrial toxicity is associated with reduced mtDNA content through inhibition
of γ-DNA polymerase, which can improve after drug cessation.35,36 The neuropathy, as well as
acquired lipodystrophy, may be manifestations of these mitochondrial effects.34,37,38,39 However, the
development of neuropathy is likely multifactorial with other considerations including unmasking of
subclinical HIV neuropathy, low CD4 count and viral load, other coincident neurotoxins, or poor
drug clearance.37

Animal models in this field have focused on rabbits, not traditional mice or rats, and animals given
zalcitabine develop pathologic and electrophysiologic signs of demyelination, possibly through
Schwann cell mitochondrial toxicity.40 Didanosine and stavudine models have been less impressive
even at high dose. However, a sensory neuropathy similar to humans was induced in cynomolgus
monkeys with decreased large and small fiber sensory axons.34

Humans most commonly develop distal, predominantly axonal sensory neuropathy closely
resembling primary HIV-related distal small fiber neuropathy, which is sometimes difficult to
distinguish.39,41,42 Burning and shooting pain with decreased small more than large fiber sensory
modalities is typical.34 The rapidity of onset and eventual improvement may help distinguish the
processes, but not in all cases. Lower doses reduce toxicity, but may blunt efficacy. Aggressive
HAART including these agents may lessen symptoms and improve quantitative sensory thresholds of
primary HIV neuropathy by reducing viral load.43

Effects are dose related and nearly all will develop neuropathy if the dose is sufficiently high. At
conventional doses (2.25 mg/day) roughly a third develop evidence of neuropathy on zalcitabine, but
many continue to take the medication until the neuropathy reaches sufficient severity.44 Moyle and
Sadler reported approximately 10% of patients receiving zalcitabine or stavudine and 1-2% of
patients on didanosine stopped therapy because of severe neuropathy, but some have reported

6
incidence as high as 60%.44 Similar to other conditions, underlying neuropathy may enhance
neurotoxicity.

Newer considerations to help blunt neuropathy progression include NGF and levacecarnine (acetyl-
L-carnitine). Carnitine levels were preliminarily reported reduced in HIV patients on nucleoside
analogs with neuropathy suggesting possibly beneficial carnitine supplementation; 36,45 however,
recent attempts failed to show this effect in patients with or without neuropathy irrespective of
nucleoside analog use.46 Similarly, administration of NGF to HIV neuropathy patients, the majority
of who were on nucleoside analogs, produced blunting of pain but no improvement in other
measures including clinical exam, quantitative sensory testing, or epidermal nerve fiber density.47,48
Other than dosage adjustments, current symptomatic treatment is similar to other painful
neuropathies.

Miscellaneous medications

Thalidomide
Thalidomide use has slowly increased over the last 10-12 years due to its antiangiogenic and anti-
inflammatory properties. Current applications are for a wide variety of disorders including Behçets
and HIV-related ulcers, discoid lupus and other dermatological conditions, ulcerative colitis,
rheumatoid arthritis, leprosy, graft-vs-host disease, and others.1,49 It is also increasingly used as a
chemotherapeutic agent, notably in prostate and renal cancers. In addition to the infamous
teratogenic effects, sensory neuropathy reached near epidemic levels in 1960-61, before the drug was
withdrawn. Animal and in vitro models of thalidomide neuropathy have revealed mild and
unconvincing effects. For example, a recent negative study in dogs treated with various doses of
thalidomide for over a year and included nerve conduction studies, thus highlighting the limitations
of animal models with some toxins.50

The true incidence and dose response relationships of thalidomide induced neuropathy remain
unknown. Over the years, reports have claimed widely variable incidence rates, in part due to
differences in dosage levels, treatment duration, and neuropathy ascertainment. Some patients
appear to tolerate higher doses for extended periods, and genetic differences in metabolism have
been suspected but not demonstrated.51 Molloy et al recently performed an open-label prospective
study of 67 metastatic prostate cancer patients.52 Many (55) stopped the drug early due to lack of
effect, but 24 continued thalidomide for at least 3 months. Of these, 6 developed neuropathy.
Virtually all individuals treated for more than six months developed either clinical or
electrophysiologic signs of neuropathy. Because the neuropathies were generally in early stages when
the drug was discontinued, recovery generally occurred. However, in other studies recovery has been
variable and may be incomplete, arguing for a presumed effect on DRG neurons. Electrophysiology
has shown reduced or absent sensory potentials with minor motor changes.52,53 Autopsy findings
have shown loss of sensory axons, DRG neurons, and dorsal column fibers. Physicians prescribing
the drug, namely rheumatologists, immunologists, oncologists, and dermatologists, should be aware
of these toxic effects and closely monitor patients for evidence of neuropathy.

Tacrolimus (ProGraf, FK-506)


This agent is a novel immunosuppresant increasingly used in transplant medicine, largely replacing
cyclosporin A (CSA). The agent is a macrolide antibiotic that suppresses both cellular and humoral
mediated immune responses. Neurotoxicity is common in part because of relatively high doses
usually given. Central toxicity is more common with a variety of findings including
leukoencephalopathy, seizures, behavioral changes, headache, or other cortical signs, many of which
are dose dependant. Peripheral neuropathy appears to take the form of a severe multifocal
demyelinating neuropathy resembling chronic inflammatory demyelinating neuropathy (CIDP)

7
although two cases with acute motor axonal neuropathy are also reported.54,55 Some patients have
responded to IVIg or plasmapheresis.

Both CSA and tacrolimus act through calcineurin inhibition, though by different means (tacrolimus
binding protein: FKBP-12). The calcineurin inhibition through several steps decreases T-cell
proliferation. This pathway is also the likely cause of much of the central neurotoxicity and possibly
the peripheral effects. Tacrolimus also has an additional separate function through a different
binding protein (FKBP-52) that acts as a nerve stimulator and is beneficial to nerve regeneration in
nerve axotomy and ischemia models.56 FKBP-52 is part of a steroid receptor complex and may
represent a target for future regenerative therapies separate from the growth factor/Trk pathways.
The mechanism of why in some patients an immune attack resembling CIDP or possibly trigger of
an underlying condition occurs, but additional patients will likely be uncovered as use widens. A
similar agent sirolimus is also approved but no analogous cases have been reported to date.

Conclusions

Many more agents are suspected of causing neuropathy than discussed. Despite the lengthy and
fastidious drug approval process, rare and idiosyncratic causes of medication-induced neuropathy
may only become evident after wide-usage. Medication-induced toxicity should be at least
considered in new cases of neuropathy including apparent idiopathic forms. Also importantly,
patients with existing neuropathy of known or presumed cause should have their current regimen
and planned therapy considered for potential neurotoxicity. Some preventative agents against
chemotherapy toxicity show promise, but none are yet approved for routine use against neurotoxic
effects. 57

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Table. Drugs associated with peripheral neuropathy

CHEMOTHERAPY CNS ACTING


5-Azacytidine Amitriptyline
5-Fluouracil Phenytoin
Cisplatin and analogs Chlorprothixene
Cytarabine (high dose) Gangliosides
Etoposide (VP-16) Gluthethimide
Gemcitabine Lithium
Hexamethylmelamine Nitrous oxide
Ifosphamide Phenelzine
Misonidazole Thalidomide
Suramin
VM-26 MISCELLANEOUS
Taxoids Allopurinol
Vinca alkaloids Almitrine
Botulinum toxin
ANTIBIOTICS Cimetidine
Nucleoside analogs Clofibrate
Chloroquine Colchicine
Chloramphenicol Cyclosporin A
Clioquinil Dichoroacetate
Dapsone Disulfiram
Ethambutol Etretinate
Fluoroquinolones Gold salts
Griseofulvin Interferons α-2A,2B
INH Penacillamine
Mefloquine Pyridoxine abuse
Metronidazole Sulphasalazine
Nitrofurantoin Tacrolimus (FK506, ProGraf)
Podophyllin resin Zimeldine
Sulfonamides

CARDIOVASCULAR
Amiodarone
Enalapril
Hydralazine
Statins
Perhexiline
Propafenone

Drugs with more common, more important, and better established associations are highlighted in
bold

11