Oxaliplatin-Induced Hyperexcitability

Hamid Saadati, Muhammad Wasif Saif
Yale Cancer Center. New Haven, CT, USA
Summary
A recent pooled analysis and a meta-analysis suggested a survival benefit of gemcitabine-platinum doublets when compared with
single agent gemcitabine in pancreatic cancer. Sensory neurotoxicity is a potentially limiting toxicity associated with oxaliplatin
therapy. In this letter, we describe a case of a patient with metastatic pancreatic cancer who developed acquired neuromyotonia while
receiving intravenous oxaliplatin as part of her treatment. It is a condition characterized by cramps, muscle twitching, weakness,
myotonia and pseudomyotonia (slow muscle relaxation after forceful contraction). Her symptoms were ameliorated after initiation of
pregabalin. We postulate that hyperexcitability syndrome associated with administration of oxaliplatin can be treated with
pregabalin. Future studies will be needed to confirm this as well as to determine the long-term adverse effects associated with
pregabalin.
Introduction
Neurotoxicity is the principal and dose-limiting
toxicity of oxaliplatin, with two distinct syndromes.
Long-term administration of oxaliplatin produces a
sensory neuropathy, with loss of sensation and
dysesthesia in the distal extremities. Development of
sensory neuropathy is correlated with the cumulative
dose of oxaliplatin, which is also true for cisplatin.
Oxaliplatin also produces a unique syndrome of acute
neurosensory toxicity.
Shortly after infusion of oxaliplatin, patients develop
striking paresthesia and dysesthesia of the hands, feet,
and perioral region, jaw tightness, and unusual
pharyngolaryngo-dysesthesia.
The
latter
is
characterized by a loss of sensation of breathing
without any objective evidence of respiratory distress
but may rarely involve laryngospasm. Acute
neurotoxicity may be triggered or exacerbated by
exposure to cold.
These symptoms occur within hours of exposure and
are usually reversible over the following hours or days,
and they may increase in both duration and severity
with repeated administration. The differences in
symptom onset and clinical spectrum suggest a
different mechanism for the acute and chronic forms of
oxaliplatin-associated neurotoxicity. On cessation of
drug, the chronic neurotoxicities improve in the
majority of patients within 4 to 6 months and will
completely resolve in approximately 40% of patients
by 6 to 8 months. The likelihood of symptomatic
improvement on discontinuation of oxaliplatin
correlates inversely with cumulative dose [1].
We previously published a case of a 54-year-old
female undergoing chemotherapy with gemcitabine and
oxaliplatin for stage II-B pancreatic adenocarcinoma
demonstrated striking signs of reversible, peripheral-
nerve hyperexcitability after administration of
oxaliplatin. The clinical features are similar to those
seen in neuromyotonia, a disorder associated with
abnormal function of voltage-gated potassium channels
in peripheral nerves. We now describe a second case of
a patient with hyperexcitability syndrome after
treatment with oxaliplatin. This report is clinically
relevant as platinum remains the agents of choice to be
combined with gemcitabine as well as CONKO-003
(Charité Onkologie) study showed survival benefit of
folinic acid plus 5-fluorouracil plus oxaliplatin
(FOLFOX) in gemcitabine-refractory pancreatic
cancer. Other cases of hyperexcitability syndrome in
the literature include papers by Saif and Hashmi [2],
Lahrmann et al. [3], and Forte et al. [4].
Case Report
This patient was a 39-year-old female who initially
presented with obstructive jaundice. ERCP showed a 2
cm mass in the pancreatic head and a fine needle
aspirate of the lesion revealed pathologic findings
Received April 2nd, 2009 - Accepted May 26th, 2009
Key words Hypersensitivity; Isaacs Syndrome; oxaliplatin;
Pancreatic Neoplasms
Correspondence Muhammad Wasif Saif
Section of Medical Oncology, Yale University School of
Medicine, 333 Cedar Street; FMP: 116, New Haven, CT 06520,
USA
 

Page 2
JOP. J Pancreas (Online) 2009 Jul 6; 10(4):459-461.
JOP. Journal of the Pancreas - http://www.joplink.net - Vol. 10, No. 4 - July 2009. [ISSN 1590-8577]
460
consistent with pancreatic adenocarcinoma. She
underwent Whipple’s procedure and adjuvant
chemoradiation with gemcitabine and capecitabine.
However, her CEA levels continued to rise and a PET
scan showed increase in intensity and the extent of
abnormal FDG activity at the surgical bed suspicious
for recurrent disease. CT scan confirmed the suspicion.
A new treatment option including gemcitabine,
oxaliplatin and panitumumab was offered to the
patient. At completion of cycle 2 oxaliplatin infusion,
she experienced significant muscle cramping of hands
and feet. She was unable to sit still due to discomfort
and her hands became rigid. She was given intravenous
diphenhydramine, magnesium sulfate and calcium
gluconate. After several minutes, the muscle
contractions resolved. She had a few recurrences for 2-
3 days after, each lasting several minutes. In retrospect,
she had vague recall of similar mild sensations after
cycle one. In addition, she had recurrence of
temporomandibular junction pain with eating. A sharp
jaw pain occurred after taking the first few bites of
each meal. It then resolved and she was able to
continue eating without any pain. It is worth noting that
patient did not have any autoimmune disorder nor she
was taking any medications that may have predisposed
her to acquired neuromyotonia. She was started on
pregabalin 50 mg per os three times a day and
subsequently did not have these symptoms.
Discussion
Single agent gemcitabine has been the main stay of
treatment approved for advanced pancreatic cancer.
Many clinical trials have compared the efficacy of
combination therapies to gemcitabine in the last
decade. Recently, a survival benefit was demonstrated
for gemcitabine-platinum combination therapy
compared to single agent gemcitabine.
Oxaliplatin, a platinum derivative, causes two types of
neuropathy mainly acute and chronic. Acute
neuropathy can begin during the infusion, within
minutes to hours, or within 1-2 days of administration.
This type of neuropathy is usually self-limited, often
resolving within days. Signs and symptoms associated
include paresthesia, hypoesthesia, and dysesthesia,
which usually begin in the feet or hands. The
neuropathy can also be associated with shortness of
breath or difficulty swallowing, but without
laryngospasm or bronchospasm. Patients have also
experienced an unusual sensation in the tongue, jaw
spasms, eye pain, and muscle spasms or cramps, which
are sometimes described as stiffness in the hands or
feet or the inability to release the grip. A feeling of
pressure in the chest has also been reported. Acute
neuropathy may be triggered by exposure to cold
temperatures and often returns on retreatment [5, 6].
This acute neuropathy causes a variety of distressing,
but transient, symptoms due to peripheral sensory and
motor nerve hyperexcitability [7]. This nerve
hyperexcitability can manifest as a distinct syndrome
that clinically exhibits as neuromyotonia known as
hyperexcitability syndrome. It is perhaps a rare but also
the most important neurological syndrome that
warrants immediate dose reduction or drug withdrawal
in clinical practice.
Neuromyotonia is a rare condition characterized by
muscle stiffness, slowed muscle relaxation, and
increased sweating, and less commonly paresthesia [8].
It has several causes. It may be autoimmune mediated
or associated with neuropathy [9], or a rare side effect
of drugs, radiotherapy, or toxins [10, 11, 12]. The exact
mechanism of neuromyotonia in humans is largely
unknown; however, it is postulated that either
persistent sodium channel activity or decreased
potassium conductance can be a mechanism for
producing axonal hyperexcitability and repetitive
discharges in human nerve cells. Non-inactivating
sodium channels in sensory axons are thought to
produce the repetitive discharges that underlie
paresthesia [13]. Direct autoimmune blockade of
voltage-gated potassium channels [14, 15] and
exposure of sodium channels in paranodal regions [13]
has also been implicated. Pregabalin, like gabapentin,
is an amino acid derivative of gamma-amino butyric
acid, it is pharmacologically active S-enantiomer of 3-
aminomethyl-5-methyl-hexanoic acid, and has a
similar pharmacological profile to gabapentin [16, 17].
Pregabalin has been shown in studies to provide
equivalent efficacy to gabapentin, however, at much
lower doses [18]. Because lower dosages can be used
to treat neuropathic pain, it is likely that pregabalin will
be associated with fewer dose-related adverse events.
Part of the reason why pregabalin requires a lower
dosage is that it has a much higher bioavailability (90
vs. 33-66%) and a rapid absorption (peak 1 h). Also,
plasma concentrations increase linearly with increasing
dose [19]. This is not true with gabapentin. Gabapentin
is slowly absorbed (peak 3-4 h post-dose) and more
importantly, plasma concentrations have been found to
have a non-linear relationship to increasing doses.
Since pregabalin has been found to have distinct
pharmacokinetic advantages over gabapentin, and the
efficacy of treating the neuropathic symptoms with
gabapentin has not been completely successful [20], we
opted to treat our patients with pregabalin for
hyperexcitability secondary to oxaliplatin that was
being administered to her for the treatment of her
pancreatic cancer.
Conflict of interest The authors have no potential
conflicts of interest
References
1. Saif MW, Reardon J. Management of oxaliplatin-induced
peripheral neuropathy. Ther Clin Risk Manag 2005; 1:249-58.
[PMID 18360567]
2. Saif MW, Hashmi S. Successful amelioration of oxaliplatin-
induced hyperexcitability syndrome with the antiepileptic pregabalin
in a patient with pancreatic cancer. Cancer Chemother Pharmacol
2008; 61:349-54 [PMID 17849118]
3. Lahrmann H, Albrecht G, Drlicek M, Oberndorfer S, Urbanits S,
Wanschitz J, et al. Acquired neuromyotonia and peripheral

Page 3
JOP. J Pancreas (Online) 2009 Jul 6; 10(4):459-461.
JOP. Journal of the Pancreas - http://www.joplink.net - Vol. 10, No. 4 - July 2009. [ISSN 1590-8577]
461
neuropathy in a patient with Hodgkin's disease. Muscle Nerve 2001;
24:834-8. [PMID 11360270]
4. Forte F, Pretegiani E, Battisti C, Sicurelli F, Federico A.
Neuromyotonia as paraneoplastic manifestation of bladder
carcinoma. J Neurol Sci 2009; 280: 111-112 [PMID 19249799]
5. Gamelin E, Gamelin L, Bossi L, Quasthoff S. Clinical aspects
and molecular basis of oxaliplatin neurotoxicity: current management
and development of preventive measures. Semin Oncol 2002; 29(5
Suppl. 15):21-33. [PMID 12422305]
6. Leonard GD, Wright MA, Quinn MG, Fioravanti S, Harold N,
Schuler B, et al. Survey of oxaliplatin-associated neurotoxicity using
an interview-based questionnaire in patients with metastatic
colorectal cancer. BMC Cancer 2005; 5:116. [PMID 16168057]
7. Lehky TJ, Leonard GD, Wilson RH, Grem JL, Floeter MK.
Oxaliplatin induced neurotoxicity: acute hyperexcitability and
chronic neuropathy. Muscle Nerve 2004; 29:387-92. [PMID
14981738]
8. Bostock H, Burke D, Hales JP. Differences in behaviour of
sensory and motor axons following release of ischaemia. Brain 1994;
117:225-34. [PMID 8186950]
9. Auger RG. AAEM minimonograph No.44: diseases associated
with excess motor unit activity. Muscle Nerve 1994; 17:1250-63.
[PMID 7935547]
10. Zielasek J, Martini R, Suter U, Toyka KV. Neuromyotonia in
mice with hereditary myelinopathies. Muscle Nerve 2000; 23:696-
701. [PMID 10797391]
11. Reeback J, Benton S, Swash M, Schwartz MS. Penicillamine-
induced neuromyotonia. Br Med J 1979; 1:1464-5. [PMID 466063]
12. Caldron PH, Wilbourn AJ. Gold neurotoxicity and myokymia. J
Rheumatol 1988; 15:528-9. [PMID 3379631]
13. Hart IK, Waters C, Vincent A, Newland C, Beeson D, Pongs O,
et al. Autoantibodies detected to expressed K+ channels are
implicated in neuromyotonia. Ann Neurol 1997; 41:238-46. [PMID
9029073]
14. Nagado T, Arimura K, Sonoda Y, Kurono A, Horikiri Y,
Kameyama A, et al. Potassium current suppression in patients with
peripheral nerve hyperexcitability. Brain 1999; 122:2057-66. [PMID
10545391]
15. Maddison P, Newsom-Davis J, Mills KR Strength-duration
properties of peripheral nerve in acquired neuromyotonia. Muscle
Nerve 1999; 22:823-30. [PMID 10398198]
16. Mariani G, Garrone O, Granetto C, Numico G, LaCiura P,
Grecchi G, et al. Oxaliplatin-induced neuropathy: could gabapentin
be the answer? Proc Am Soc Clin Oncol 2000; 19:609, Abstract
2397.
17. Fehrenbacher JC, Taylor CP, Vasko MR. Pregabalin and
gabapentin reduce release of substance P and CGRP from rat spinal
tissues only after inflammation or activation of protein kinase C. Pain
2003; 105:133-41. [PMID 14499429]
18. Frampton JE, Foster RH. Pregabalin in the treatment of
postherpetic neuralgia. Drugs 2005; 65:111-20. [PMID 15610058]
19. Freynhagen R, Strojek K, Griesing T, Whalen E, Balkenohl M.
Efficacy of pregabalin in neuropathic pain evaluated in a 12-week,
randomised, double-blind, multicentre, placebo-controlled trial of
flexible- and fixed-dose regimens. Pain 2005; 115:254-63. [PMID
15911152]
20. Mitchell PL, Goldstein D, Michael M, Beale P, Friedlander M,
Zalcberg J, et al. Addition of gabapentin to a modified FOLFOX
regimen does not reduce oxaliplatin-induced neurotoxicity. Clin
Colorectal Cancer 2006; 6:146-51. [PMID 16945171

There are no products listed under this category.