od
zu
aro
cDepartment of Neurology, Kyoto Prefectural Medical University, Kyoto, Japan
dDepartment of Neurology, Tokyo Metropolitan Neurolo
a r t i c l e i n f o
Article history:
Accepted 24 December 2009
Available online 22 January 2010
that changes in the expression, types, and distribution of Na chan-
nel in peripheral small sensory axons or neurons following nerve
injury could be important for ectopic impulse generation, and
thereby neuropathic pain (Cummins and Waxman, 1997; Cum-
mins et al., 2007; Devor et al., 1993; Matzner and Devor, 1994).
For motor axons, it has been shown that abnormal muscle cramp-
ing is associated with increased nodal Na+ currents in human axo-
nal neuropathy and motor neuron diseases (Tamura et al., 2006),
and Dworkin, 2006; Stracke et al., 1992). This agent has been tested
in several neuropathic conditions and the results were controver-
sial, but previous studies have used only subjective pain rating
scale, such as visual analogue scale (Chabal et al., 1992; Jarvis
and Coukell, 1998). It would be necessary to assess neuropathic
pain more objectively for evaluation of therapeutic effects.
In addition to the classical transient Na+ channels, there are
many different types of Na+ channels in mammalian axons.
Approximately 1.0–2.5% of the total Na+ channels in human axons
are slowly inactivating and active at the resting membrane poten-
tial, termed as ‘‘persistent” Na+ channels, and this conductance is
* Corresponding author. Tel.: +81 43 222 7171x5414; fax: +81 43 226 2160.
Clinical Neurophysiology 121 (2010) 719–724
Contents lists availab
ro
.e lE-mail address: kuwabara-s@faculty.chiba-u.jp (S. Kuwabara).sory fibers, and future studies using this approach in small fibers would provide new insights into the
peripheral mechanism of neuropathic pain.
 2010 International Federation of Clinical Neurophysiology. Published by Elsevier Ireland Ltd. All rights
reserved.
1. Introduction
Pain and paresthesias are common manifestations of peripheral
nerve injury and one of the major factors that disturb activities of
daily living in patients with neuropathy. Neuropathic pain arises
from both peripheral and central mechanisms (Campbell and
Meyer, 2006), whereas previous experimental studies have shown
+
but the relationship between Na+ currents in sensory axons and
sensory symptoms (neuropathic pain/paresthesias) has rarely been
studied in neuropathic patients.
Mexiletine is structurally related to lidocaine and can offer the
benefits of Na+ channel blockade in oral form with high bioavail-
ability instead of repeated intravenous infusion (Dejgard et al.,
1988; Jarvis and Coukell, 1998; Oskarsson et al., 1997; MarkmanKeywords:
Polyneuropathy
Pain
Paresthesia
Sodium channel
Mexiletine1388-2457/$36.00  2010 International Federation o
doi:10.1016/j.clinph.2009.12.034gical Hospital, Tokyo, Japan
a b s t r a c t
Objective: To investigate changes in axonal persistent Na+ currents in patients with neuropathic pain and
the effects of mexiletine, an analogue of lidocaine, on axonal excitability properties.
Methods: The technique of latent addition was used to estimate nodal persistent Na+ currents in super-
ficial radial sensory axons of 17 patients with neuropathic pain/paresthesias before and after mexiletine
treatment. Brief hyperpolarizing conditioning currents were delivered, and threshold change at the con-
ditioning-test interval of 0.2 ms was measured as an indicator of the magnitude of persistent Na+
currents.
Results: Threshold changes at 0.2 ms in latent addition were greater in the neuropathic patients than in
the normal controls (p < 0.001). After mexiletine treatment, there was a reduction in clinical pain scores
(p < 0.001), associated with decreased threshold changes at 0.2 ms (p < 0.001).
Conclusions: In patients with neuropathy, nodal persistent Na+ currents in large sensory fibers increase,
and the abnormal currents can be suppressed by mexiletine. Pain reduction after mexiletine treatment
raises the possibility that excessive Na+ currents are also suppressed in small fibers mediating neuro-
pathic pain.
Significance: Latent addition can be used for indirect in vivo monitoring of nodal Na+ currents in large sen-aDepartment of Neurology, Graduate School of Medicine, Chiba University, 1-8-1, Inohana, Chuo-ku, Chiba, Japan
bDepartment of Clinical Cell Biology and Medicine, Graduate School of Medicine, Chiba University, 1-8-1, Inohana, Chuo-ku, Chiba, JapanMexiletine suppresses nodal persistent s
of patients with neuropathic pain
Sagiri Isose a, Sonoko Misawa a, Kenichi Sakurai b, Ka
Saiko Nasu a, Yuichi Noto a,c, Yumi Fujimaki a,d, Kout
Clinical Neu
journal homepage: wwwf Clinical Neurophysiology. Publishium currents in sensory axons
aki Kanai a, Kazumoto Shibuya a, Yukari Sekiguchi a,
Yokote b, Satoshi Kuwabara a,*
le at ScienceDirect
physiology
sevier .com/locate /c l inphed by Elsevier Ireland Ltd. All rights reserved.

one of the major determinants of axonal excitability (Bostock and
Rothwell, 1997). Latent addition using the computerized threshold
tracking technique is currently considered the best, non-invasive
way to estimate nodal persistent Na+ conductance in vivo (Bostock
and Rothwell, 1997). We have used this technique to investigate
changes in axonal persistent Na+ currents in large sensory fibers
of patients with neuropathic pain and the effects of mexiletine
on pain/paresthesias and axonal excitability. We assessed large
myelinated sensory fibers, and therefore the finding cannot be ap-
plied to the pathophysiology of small myelinated or unmyelinated
fibers which mediate neuropathic pain. However, this approach
could be a first step to elucidate ionic mechanisms for neuropathic
pain in future studies.
2. Methods
2.1. Subjects
This study enrolled 17 consecutive patients (13 men and 4
women) with painful neuropathy who were referred to the EMG
clinic, Chiba University Hospitals, for evaluation of their neuropa-
After the clinical and electrophysiologic evaluations, patients
received oral mexiletine hydrochloride. The initial dose was
150 mg daily for 1–2 months, gradually increasing up to 450 mg
daily if the pain was not relieved (150–450 mg; mean 320 mg). Fol-
low-up assessments were made 3 months after the start of mainte-
nance dose.
2.2. Assessment of neuropathic pain
Patients were asked about the presence of limb pain (burning,
lancinating, and pricking pain) and paresthesias (tingling and
buzzing). A modified neuropathic pain scale (Dyck et al., 1976)
was used to evaluate the extent of disability in performing daily
activities: 0, no pain; 1, a complaint but no disability; 2, pain some-
times disturbing work or sleep; 3, severe pain disturbing work or
sleep daily. Visual analogue scale (VAS) was also used to estimate
the extent of pain/paresthesia. All the 17 patients included in this
study had the score 2 or 3. Pain and paresthesias coexisted in all,
and therefore severe paresthesia disturbing work or sleep was
regarded as pain.
f pa
ting
ting
ting
ting
burn
ting
ting
ting
ting
tion
720 S. Isose et al. / Clinical Neurophysiology 121 (2010) 719–724thy (Table 1). Patients’ age ranged from 32 to 75 years (mean,
54 years), and the mean duration from the onset of pain was
19 months (range, 3–84 months). Of the 17 patients, 15 patients
had neuropathy caused by diabetes, vasculitis, beriberi, or chemo-
therapeutic drugs. The remaining two had moderate axonal poly-
neuropathy, but the cause of neuropathy was not identified, and
classified into ‘‘idiopathic”. All the patients had symmetric sen-
sory-dominant polyneuropathy, and pain/paresthesias in their dis-
tal four limbs with mild-to-moderate decreases in touch, pin-prick,
and vibratory sensations. In diabetic patients, the hemoglobin A1c
(HbA1c) levels ranged from 5.2% to 8.5% (mean, 6.7%). We excluded
patients with renal failure, because serum K+ levels can signifi-
cantly alter the membrane potential and axonal excitability prop-
erties (Kuwabara et al., 2007).
The normal control data of axonal excitability testing were
obtained from 35 age-matched healthy subjects (14 men and 21
women; age, 20–86 years; mean 48 years). All patients and normal
subjects gave informed consent to the experimental procedures,
which was approved by the Ethics Committee of the Chiba Univer-
sity Graduate School of Medicine.
Table 1
Clinical and electrodiagnostic profiles of patients with treated with mexiletine.
Patient Age/sex Diagnosis Durationa (month) Nature o
1 47/M Diabetes 12 Pricking
2 47/M Diabetes 5 Burning/
3 32/M Diabetes 4 Pricking
4 60/M Diabetes 4 Tingling
5 48/M Diabetes 6 Burning/
6 68/M Diabetes 6 Burning/
7 49/F Vasculitis 7 Pricking/
8 55/F Idiopathic 5 Burning
9 72/M Diabetes 58 Pricking
10 38/M Diabetes 3 Pricking/
11 57/M Diabetes 5 Pricking
12 73/F Drug induced 60 Pricking/
13 38/M Diabetes 2 Pricking/
14 45/M Beriberi 40 Pricking
15 58/M Idiopathic 12 Pricking
16 75/M Diabetes 12 Pricking/
17 52/M Diabetes 84 Pricking/
Median (range) 7 (3–84)
Data are given according to the pain disability scale and visual analogue scale reduc
VAS = visual analogue scale.
a Duration from the onset of pain.
* p < 0.001, compared with scores before treatment.2.3. Latent addition and strength-duration time constant using
threshold tracking
The technique of latent addition was performed in the superfi-
cial radial sensory axons and median motor axons, using a comput-
erized program (QTRAC with multiple excitability protocol,
LA99SDS; , Prof. Bostock H, Institute of Neurology, London, UK).
For sensory nerve studies, the superficial radial nerve was selected,
because sensory nerve action potentials (SNAP) was frequently not
recordable or substantially reduced in the median nerve of neurop-
athy patients. Radial SNAPs were recorded from the anatomical
snuff box after stimulation 12 cm proximally at the forearm. The
compound muscle action potential (CMAP) was recorded from
the abductor pollicis brevis after median nerve stimulation at the
wrist (3 cm proximal to the wrist crease). The threshold current re-
quired to produce the target response, set to 40% of the maximal
SNAP or CMAP amplitude, was determined using a test stimulus
of 0.06 ms duration. The test stimulus was conditioned by a hyper-
polarizing stimulus from 0.02 to 0.5 ms inter-stimulus test inter-
val, fixed at 90% of the threshold current. The decay of the
in/paresthesia Pain disability scale Reduction of VAS (%)
Before treatment After treatment
3 1 90
ling 3 1 88
3 1 86
3 1 81
ling 3 1 80
ling 3 1 71
ling 3 1 71
3 1 60
3 1 60
ing 3 1 50
3 1 50
ling 3 2 70
ling 3 2 50
3 2 50
3 2 43
ling 3 3 0
ling 2 2 20
3 (2–3) 1 (1–3)* 60 (0–90)
.