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Mexiletine suppresses nodal persistent sodium currents in sensory axons of patients with neuropathic pain
Clinical Neurophysiology 121 (2010) 719–724
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Mexiletine suppresses nodal persistent sodium currents in sensory axons of patients with neuropathic pain Sagiri Isose a, Sonoko Misawa a, Kenichi Sakurai b, Kazuaki Kanai a, Kazumoto Shibuya a, Yukari Sekiguchi a, Saiko Nasu a, Yuichi Noto a,c, Yumi Fujimaki a,d, Koutaro Yokote b, Satoshi Kuwabara a,* a
Department of Neurology, Graduate School of Medicine, Chiba University, 1-8-1, Inohana, Chuo-ku, Chiba, Japan Department of Clinical Cell Biology and Medicine, Graduate School of Medicine, Chiba University, 1-8-1, Inohana, Chuo-ku, Chiba, Japan Department of Neurology, Kyoto Prefectural Medical University, Kyoto, Japan d Department of Neurology, Tokyo Metropolitan Neurological Hospital, Tokyo, Japan b c
a r t i c l e
i n f o
Article history: Accepted 24 December 2009 Available online 22 January 2010 Keywords: Polyneuropathy Pain Paresthesia Sodium channel Mexiletine
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 superficial 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 conditioning-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 neuropathic pain. Significance: Latent addition can be used for indirect in vivo monitoring of nodal Na+ currents in large sensory fibers, and future studies using this approach in small fibers would provide new insights into the peripheral mechanism of neuropathic pain. Ó 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 that changes in the expression, types, and distribution of Na+ channel 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; Cummins et al., 2007; Devor et al., 1993; Matzner and Devor, 1994). For motor axons, it has been shown that abnormal muscle cramping is associated with increased nodal Na+ currents in human axonal neuropathy and motor neuron diseases (Tamura et al., 2006), * Corresponding author. Tel.: +81 43 222 7171x5414; fax: +81 43 226 2160. E-mail address: [email protected] (S. Kuwabara).
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 bioavailability instead of repeated intravenous infusion (Dejgard et al., 1988; Jarvis and Coukell, 1998; Oskarsson et al., 1997; Markman and Dworkin, 2006; Stracke et al., 1992). This agent has been tested in several neuropathic conditions and the results were controversial, 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 potential, termed as ‘‘persistent” Na+ channels, and this conductance is
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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 applied 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 neuropathy (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 chemotherapeutic drugs. The remaining two had moderate axonal polyneuropathy, but the cause of neuropathy was not identified, and classified into ‘‘idiopathic”. All the patients had symmetric sensory-dominant polyneuropathy, and pain/paresthesias in their distal 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 significantly alter the membrane potential and axonal excitability properties (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 University Graduate School of Medicine.
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). Follow-up assessments were made 3 months after the start of maintenance 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 sometimes 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. 2.3. Latent addition and strength-duration time constant using threshold tracking The technique of latent addition was performed in the superficial radial sensory axons and median motor axons, using a computerized program (QTRAC with multiple excitability protocol, LA99SDS; Ó, 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 neuropathy 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 required 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 hyperpolarizing stimulus from 0.02 to 0.5 ms inter-stimulus test interval, fixed at 90% of the threshold current. The decay of the
Table 1 Clinical and electrodiagnostic profiles of patients with treated with mexiletine. Patient
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 Median (range)
Age/sex
47/M 47/M 32/M 60/M 48/M 68/M 49/F 55/F 72/M 38/M 57/M 73/F 38/M 45/M 58/M 75/M 52/M
Diagnosis
Diabetes Diabetes Diabetes Diabetes Diabetes Diabetes Vasculitis Idiopathic Diabetes Diabetes Diabetes Drug induced Diabetes Beriberi Idiopathic Diabetes Diabetes
Durationa (month)
12 5 4 4 6 6 7 5 58 3 5 60 2 40 12 12 84
Nature of pain/paresthesia
Pricking Burning/tingling Pricking Tingling Burning/tingling Burning/tingling Pricking/tingling Burning Pricking Pricking/burning Pricking Pricking/tingling Pricking/tingling Pricking Pricking Pricking/tingling Pricking/tingling
7 (3–84)
Data are given according to the pain disability scale and visual analogue scale reduction. VAS = visual analogue scale. a Duration from the onset of pain. * p < 0.001, compared with scores before treatment.
Pain disability scale
Reduction of VAS (%)
Before treatment
After treatment
3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 2
1 1 1 1 1 1 1 1 1 1 1 2 2 2 2 3 2
90 88 86 81 80 71 71 60 60 50 50 70 50 50 43 0 20
3 (2–3)
1 (1–3)*
60 (0–90)
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S. Isose et al. / Clinical Neurophysiology 121 (2010) 719–724 Table 2 Pain scale and radial sensory electrophysiological indices before and after mexiletine treatment.
Pain scale* (median, range) Nerve conduction study Superficial radial SNAP amplitude (lV) Conduction velocity (m/s) Sural SNAP amplitude (lV) Conduction velocity (m/s) Excitability testing Latent addition Threshold change at 0.2 ms (%) Time constant Fast component (ls) Slow component (ls) SDTC (ms)
A Normal
B Patients (n = 17)
C
(n = 35)
Before
After
3.0 (2–3)
1.0 (1–3)
37.5 (1.7) 59.0 (0.6)
22.6 (2.6) 52.4 (1.4)
23.7 (3.1) 55.1 (2.0)
<0.001 <0.001
NS NS
15.5 (0.7) 51.5 (0.5)
6.0 (1.4) 42.8 (1.8)
7.2 (1.6) 45.3 (1.7)
<0.001 <0.001
NS NS
13.0 (0.6)
17.5 (0.9)
12.6 (1.1)
<0.001
<0.001
50.9 (2.0) 210.8 (7.6) 0.59 (0.02)
57.9 (3.7) 245.4 (16.7) 0.60 (0.02)
55.5 (2.7) 207.2 (6.9) 0.54 (0.02)
NS NS NS
NS 0.03 <0.001
p-value A vs B
B vs C <0.001
Data are given as mean (SEM); SNAP = sensory nerve action potential; NS = not significant; SDTC = strength-duration time constant. See the text.
*
The fast component (the conditioning-test interval, 0.02–0.2 ms) is determined by a passive input membrane constant, and the slow component (0.2–0.5 ms) depends on a persistent Na+ current active at the resting membrane potential. The increase in threshold current measured at the 0.2 ms-interval (a time when the first exponential had decayed almost to zero) was used as an indicator of nodal persistent Na+ currents (Bostock and Rothwell, 1997; Tamura et al., 2006; Misawa et al., 2006a,b). The strength-duration time constant (SDTC) is a classical measure of axonal excitability, which depends on both persistent Na+ conductance and membrane constant (Mogyoros et al., 1996, 1998; Misawa et al., 2005). The strength-duration curves of superficial radial sensory and median motor axons were recorded using the same computerized program for calculating SDTC. The threshold current required to produce 40% of the test stimulus was systematically changed from 0.06 ms to 1.0 ms. The resulting strength-duration curve was hyperbolic, and the SDTC was calculated using Weiss’s formula, according to which time constant is given by the negative intercept of the regression line on the duration axis (Mogyoros et al., 1996, 1998). Because persistent Na+ channels are voltage-dependent, and resting membrane potential has significant effects on persistent Na+ currents, excitability indices that are particularly sensitive to membrane potential such as threshold electrotonus and supernormality (Kiernan et al., 2000) were measured using a computerized program (QTRAC with multiple excitability protocol TRONDHM; Ó, Prof. Hugh Bostock, Institute of Neurology, London, UK) as described elsewhere (Kanai et al., 2006). 2.4. Statistical analyses Results of excitability testing and nerve conduction studies were compared before and after treatment by the paired t test when the data showed a Gaussian distribution using the Statcel software for Windows 2001 (OMS Co. Ltd., Tokyo, Japan). When the data did not show a Gaussian distribution, the Wilcoxon test was used. Fig. 1. Changes in threshold changes at 0.2 ms in latent addition (A) and SDTC (B) before and after mexiletine administration in patients with neuropathic pain/ paresthesias (n = 17). Evaluation of mexiletine treatment was made 3 months after the initiation of this agent. There were significant decreases in both parameters after treatment. Error bars indicate SEM.
threshold increase produced by the hyperpolarizing stimulus is the sum of two exponential components (Bostock and Rothwell, 1997).
3. Results 3.1. Clinical assessment Table 1 shows clinical profiles, pain disability scales and VAS before and after mexiletine treatment. After mexiletine treatment,
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(range) reduction of VAS scores was 60% (0–90%). The patients, who had suffered pain for less than 12 months, showed greater extent of alleviation of pain estimated by pain disability scale than the patients with longer duration of pain (12 months or more, p = 0.03). 3.2. Changes in axonal excitability indices in radial sensory axons Table 2 shows changes in sensory nerve conduction and excitability indices in the normal controls, and in patients before and after mexiletine treatment. Nerve conduction velocities and nerve action potential amplitudes did not change significantly by the intervention. In the latent addition studies, threshold changes at the conditioning-test stimulus of 0.2 ms were greater in patients with neuropathic pain than normal controls (p < 0.001), suggesting increased nodal persistent Na+ currents in the patients. The time constant of the slow component and SDTC did not differ between the normal controls and patients. After mexiletine treatment, the threshold changes at 0.2 ms and time constant of the slow component significantly decreased associated with reduction of pain, indicating that nodal persistent Na+ currents and resulting axonal hyperexcitability were suppressed by the agent (Table 1, Fig. 1A). SDTC was also shortened significantly, again suggestive of suppression of persistent Na+ currents by mexiletine treatment (Fig. 1B). Fig. 2 shows representative latent addition curves recorded from a normal control and one of the patients before and after treatment with mexiletine. Threshold change at 0.2 ms and time constant of the slow component were decreased by the mexiletine administration with reduction of pain disability scale from 3 to 1. There was no significant correlation between the reduction rate of threshold changes at 0.2 ms in latent addition, and the reduction rate of visual analogue scale score (R2 = 0.096; p = 0.39). 3.3. Changes in excitability indices in median motor axons Table 3 shows changes in excitability indices in median motor axons before and after mexiletine therapy. In latent addition, threshold increase at the 0.2 ms-interval in the patients tended to be greater than that in the normal controls before the treatment. After administration of mexiletine, threshold change at 0.2 ms and time constant of the slow component, and SDTC significantly decreased, indicating that mexiletine suppressed persistent Na+ currents in motor, as well as, sensory axons. Indices in threshold electrotonus and recovery cycle in the patients did not change significantly after the treatment, suggesting that membrane potential was not altered by mexiletine. 4. Discussion
Fig. 2. Representative latent addition curves recorded from a normal subject (A), and a patient (no. 5 in Table 1) before (B) and after (C) treatment with mexiletine. The decay of the raw threshold is the sum of the two exponentials. The fast component reflects passive membrane properties, whereas the slow component depends on persistent Na+ currents. Because the first component is nearly 0 at the 0.2 ms-interval, threshold changes at 0.2 ms can be used as an indicator of persistent Na+ currents. Threshold change at 0.2 ms and time constant of the slow component were decreased after treatment with reduction of pain disability scale from 3 to 1.
15 of the 17 patients experienced reduction of pain, whereas the remaining 2 had no improvement. Both pain disability scale scores (p < 0.001) and VAS scores (p < 0.001) decreased. The median
Our results show that axonal persistent Na+ currents estimated by latent addition and SDTC in large sensory fibers substantially increase in patients with neuropathic pain, and mexiletine significantly suppresses axonal Na+ currents and pain/paresthesias. These findings raise the possibility that nodal Na+ currents may similarly increase in small fibers, and this could be responsible for development of neuropathic pain. Our findings show that latent addition technique and SDTC measurement can be used to estimate the axonal ionic changes at least in large myelinated sensory fibers as objective measures, and it is necessary to assess small fibers responsible for neuropathic pain in future studies. SDTC depends on the two factors, persistent Na conductance and passive membrane properties at the nodes (Bostock et al., 1998). In this regard, latent addition is more sensitive to detect alternation of persistent Na+ currents, because the slow component purely reflects the currents.
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S. Isose et al. / Clinical Neurophysiology 121 (2010) 719–724 Table 3 Median motor axonal excitability indices before and after mexiletine treatment.
Latent addition Threshold change at 0.2 ms (%) Time constant Fast component (ls) Slow component (ls) SDTC (ms) Threshold electrotonus TEd (10–20 ms) TEd (90–100 ms) TEh (90–100 ms) Recovery cycle Supernormality Refractoriness at 2.0 ms Refractoriness at 2.5 ms
A Normal
B Patients (n = 17)
C
(n = 35)
Before
After
A vs B
B vs C
10.0 (0.6)
13.5 (1.3)
10.2 (0.7)
0.07
0.09
48.8 (0.9) 271.9 (17.1) 0.41 (0.01)
50.4 (1.7) 284.4 (13.4) 0.44 (0.03)
46.4 (2.2) 207.2 (15.7) 0.38(0.02)
NS NS NS
NS 0.02 0.02
52.1 (0.3) 47.1 (0.6) 121.6 (2.8)
54.9 (1.1) 45.0 (1.6) 123.9 (6.2)
55.8(1.4) 46.6 (1.2) 123.5 (5.4)
0.03 NS NS
NS NS NS
23.4 (1.0) 56.2 (3.8) 13.4 (1.7)
19.7 (2.1) 37.5 (6.7) 20.8 (7.0)
20.9 (2.5) 40.7 (7.1) 12.9 (5.6)
NS 0.03 NS
NS NS NS
p-value
Data are given as mean (SEM); SNAP = sensory nerve action potential; TEd (10–20 ms), TEd (90–100 ms) = threshold change between the specified latencies after the start of depolarizing current; TEh (90–100 ms) = threshold change between the specified latencies after the start of hyperpolarizing current; SDTC = strength-duration time constant; NS = not significant.
Axonal degeneration/regeneration is usually accompanied by remodeling of Na+ channels on the axolemma, which would be associated with pain (Devor et al., 1989, 1993; Matzner and Devor, 1994; Cummins and Waxman, 1997; Cummins et al., 2007). However such changes have never been demonstrated in patients with neuropathic pain, largely because of the lack of non-invasive technique to test axonal ionic conductances. Multiple excitability measurements using computerized threshold tracking are innovative strategies to investigate human ionic currents and membrane potential of the axons (Bostock et al., 1998; Burke et al., 2001; Nodera and Kaji, 2006). This is the first study that demonstrates a significant relationship of pain and nodal Na+ currents, and the effects of mexiletine on sensory axonal excitability in vivo. There are a number of limitations in this study. First, as mentioned in Section 1, neuropathic pain arises from small myelinated or unmyelinated fibers rather than large myelinated fibers tested in this study. In fact, there was no significant correlation between the reduction rate of threshold changes at 0.2 ms in latent addition, and the reduction rate of visual analogue scale score in our patients. The findings indicate that latent addition measured in large fibers is not a direct measure of neuropathic pain, that arises from small fibers, and future studies will be necessary to directly estimate persistent Na+ currents in small fibers, for example, using microneurography. In large myelinated nerve fibers, the sodium channel, Nav1.6, was expressed at the nodes of Ranvier. After nerve injury, Nav1.3 or other subtypes of Nav channel are significantly upregulated (Rogers et al., 2006). There are multiple isoforms, TTX-sensitive and resistant with different gating behavior, expressed differently on small myelinated and unmyelinated axons. The channel expression and gating behavior in axonal injury would also differ in these fibers. Interactions between multiple Na+ channel isoforms would contribute to increase Na+ currents and thereby, generation of neuropathic pain (Rogers et al., 2006). Our findings cannot be directly applied to small fiber properties. However, pain and paresthesias usually coexist, and both could be suppressed by Na+ channel blockade. Secondly, neuropathic pain predominantly affects the distal lower limbs. Therefore, our results might not directly reflect the ionic pathophysiology in patients with neuropathy. Further studies investigating small fibers in the lower limb nerves will be necessary. An overview of the clinical trials in neuropathic pain suggests that a single agent offers clinically important relief in only 40–60% of patients at best (Rowbotham, 2002). Surprisingly in this study, the large proportion of patients showed substantial
response to mexiletine. Placebo effects could not be excluded. Moreover, there might be some sampling bias that most patients included in the present study had mild-to-moderate neuropathy with relatively short duration, because sensory nerve action potentials >10 lV at least are necessary for stable recording. Our findings raise the possibility that early therapeutic intervention could result in favorable responses to Na+ channel blockade, probably because sustained ectopic impulse generation would lead to central sensitization later. However, this should be clarified in placebo-controlled trials involving a larger number of patients. We believe that monitoring the axonal ionic pathophysiology of neuropathic pain in individual patients could be the basic and significant step towards development of new therapeutic approach. Funding This study is supported in part by Research Grant from the Ministry of Education, Culture, Sports, Science, and Technology of Japan (S.M., Kakenhi-21790834). Competing interests None. Copyright license statement I certify that all the authors have made significant contribution on the manuscript and agree with the content. Neither the entire paper nor any part of its content has been published or is being submitted for publication elsewhere. References Bostock H, Rothwell JC. Latent addition in motor and sensory fibres of human peripheral nerve. J Physiol (Lond) 1997;498:277–94. Bostock H, Cikurel K, Burke D. Threshold tracking techniques in the study of human peripheral nerve. Muscle Nerve 1998;21:137–58. Burke D, Kiernan MC, Bostock H. Excitability of human axons. Clin Neurophysiol 2001;112:1575–85. Campbell JN, Meyer RA. Mechanisms of neuropathic pain. Neuron 2006;52:77–92. Chabal C, Jacobson L, Mariano A, Chaney E, Britell CW. The use of oral mexiletine for the treatment of pain after peripheral nerve injury. Anesthesiology 1992;76:513–7. Cummins TR, Waxman SG. Downregulation of tetrodotoxin-resistant sodium currents and upregulation of a rapidly repriming tetrodotoxin-sensitive
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Clinical Neurophysiology journal homepage: www.elsevier.com/locate/clinph
Mexiletine suppresses nodal persistent sodium currents in sensory axons of patients with neuropathic pain Sagiri Isose a, Sonoko Misawa a, Kenichi Sakurai b, Kazuaki Kanai a, Kazumoto Shibuya a, Yukari Sekiguchi a, Saiko Nasu a, Yuichi Noto a,c, Yumi Fujimaki a,d, Koutaro Yokote b, Satoshi Kuwabara a,* a
Department of Neurology, Graduate School of Medicine, Chiba University, 1-8-1, Inohana, Chuo-ku, Chiba, Japan Department of Clinical Cell Biology and Medicine, Graduate School of Medicine, Chiba University, 1-8-1, Inohana, Chuo-ku, Chiba, Japan Department of Neurology, Kyoto Prefectural Medical University, Kyoto, Japan d Department of Neurology, Tokyo Metropolitan Neurological Hospital, Tokyo, Japan b c
a r t i c l e
i n f o
Article history: Accepted 24 December 2009 Available online 22 January 2010 Keywords: Polyneuropathy Pain Paresthesia Sodium channel Mexiletine
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 superficial 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 conditioning-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 neuropathic pain. Significance: Latent addition can be used for indirect in vivo monitoring of nodal Na+ currents in large sensory fibers, and future studies using this approach in small fibers would provide new insights into the peripheral mechanism of neuropathic pain. Ó 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 that changes in the expression, types, and distribution of Na+ channel 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; Cummins et al., 2007; Devor et al., 1993; Matzner and Devor, 1994). For motor axons, it has been shown that abnormal muscle cramping is associated with increased nodal Na+ currents in human axonal neuropathy and motor neuron diseases (Tamura et al., 2006), * Corresponding author. Tel.: +81 43 222 7171x5414; fax: +81 43 226 2160. E-mail address: [email protected] (S. Kuwabara).
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 bioavailability instead of repeated intravenous infusion (Dejgard et al., 1988; Jarvis and Coukell, 1998; Oskarsson et al., 1997; Markman and Dworkin, 2006; Stracke et al., 1992). This agent has been tested in several neuropathic conditions and the results were controversial, 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 potential, termed as ‘‘persistent” Na+ channels, and this conductance is
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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 applied 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 neuropathy (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 chemotherapeutic drugs. The remaining two had moderate axonal polyneuropathy, but the cause of neuropathy was not identified, and classified into ‘‘idiopathic”. All the patients had symmetric sensory-dominant polyneuropathy, and pain/paresthesias in their distal 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 significantly alter the membrane potential and axonal excitability properties (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 University Graduate School of Medicine.
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). Follow-up assessments were made 3 months after the start of maintenance 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 sometimes 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. 2.3. Latent addition and strength-duration time constant using threshold tracking The technique of latent addition was performed in the superficial radial sensory axons and median motor axons, using a computerized program (QTRAC with multiple excitability protocol, LA99SDS; Ó, 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 neuropathy 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 required 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 hyperpolarizing stimulus from 0.02 to 0.5 ms inter-stimulus test interval, fixed at 90% of the threshold current. The decay of the
Table 1 Clinical and electrodiagnostic profiles of patients with treated with mexiletine. Patient
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 Median (range)
Age/sex
47/M 47/M 32/M 60/M 48/M 68/M 49/F 55/F 72/M 38/M 57/M 73/F 38/M 45/M 58/M 75/M 52/M
Diagnosis
Diabetes Diabetes Diabetes Diabetes Diabetes Diabetes Vasculitis Idiopathic Diabetes Diabetes Diabetes Drug induced Diabetes Beriberi Idiopathic Diabetes Diabetes
Durationa (month)
12 5 4 4 6 6 7 5 58 3 5 60 2 40 12 12 84
Nature of pain/paresthesia
Pricking Burning/tingling Pricking Tingling Burning/tingling Burning/tingling Pricking/tingling Burning Pricking Pricking/burning Pricking Pricking/tingling Pricking/tingling Pricking Pricking Pricking/tingling Pricking/tingling
7 (3–84)
Data are given according to the pain disability scale and visual analogue scale reduction. VAS = visual analogue scale. a Duration from the onset of pain. * p < 0.001, compared with scores before treatment.
Pain disability scale
Reduction of VAS (%)
Before treatment
After treatment
3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 2
1 1 1 1 1 1 1 1 1 1 1 2 2 2 2 3 2
90 88 86 81 80 71 71 60 60 50 50 70 50 50 43 0 20
3 (2–3)
1 (1–3)*
60 (0–90)
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S. Isose et al. / Clinical Neurophysiology 121 (2010) 719–724 Table 2 Pain scale and radial sensory electrophysiological indices before and after mexiletine treatment.
Pain scale* (median, range) Nerve conduction study Superficial radial SNAP amplitude (lV) Conduction velocity (m/s) Sural SNAP amplitude (lV) Conduction velocity (m/s) Excitability testing Latent addition Threshold change at 0.2 ms (%) Time constant Fast component (ls) Slow component (ls) SDTC (ms)
A Normal
B Patients (n = 17)
C
(n = 35)
Before
After
3.0 (2–3)
1.0 (1–3)
37.5 (1.7) 59.0 (0.6)
22.6 (2.6) 52.4 (1.4)
23.7 (3.1) 55.1 (2.0)
<0.001 <0.001
NS NS
15.5 (0.7) 51.5 (0.5)
6.0 (1.4) 42.8 (1.8)
7.2 (1.6) 45.3 (1.7)
<0.001 <0.001
NS NS
13.0 (0.6)
17.5 (0.9)
12.6 (1.1)
<0.001
<0.001
50.9 (2.0) 210.8 (7.6) 0.59 (0.02)
57.9 (3.7) 245.4 (16.7) 0.60 (0.02)
55.5 (2.7) 207.2 (6.9) 0.54 (0.02)
NS NS NS
NS 0.03 <0.001
p-value A vs B
B vs C <0.001
Data are given as mean (SEM); SNAP = sensory nerve action potential; NS = not significant; SDTC = strength-duration time constant. See the text.
*
The fast component (the conditioning-test interval, 0.02–0.2 ms) is determined by a passive input membrane constant, and the slow component (0.2–0.5 ms) depends on a persistent Na+ current active at the resting membrane potential. The increase in threshold current measured at the 0.2 ms-interval (a time when the first exponential had decayed almost to zero) was used as an indicator of nodal persistent Na+ currents (Bostock and Rothwell, 1997; Tamura et al., 2006; Misawa et al., 2006a,b). The strength-duration time constant (SDTC) is a classical measure of axonal excitability, which depends on both persistent Na+ conductance and membrane constant (Mogyoros et al., 1996, 1998; Misawa et al., 2005). The strength-duration curves of superficial radial sensory and median motor axons were recorded using the same computerized program for calculating SDTC. The threshold current required to produce 40% of the test stimulus was systematically changed from 0.06 ms to 1.0 ms. The resulting strength-duration curve was hyperbolic, and the SDTC was calculated using Weiss’s formula, according to which time constant is given by the negative intercept of the regression line on the duration axis (Mogyoros et al., 1996, 1998). Because persistent Na+ channels are voltage-dependent, and resting membrane potential has significant effects on persistent Na+ currents, excitability indices that are particularly sensitive to membrane potential such as threshold electrotonus and supernormality (Kiernan et al., 2000) were measured using a computerized program (QTRAC with multiple excitability protocol TRONDHM; Ó, Prof. Hugh Bostock, Institute of Neurology, London, UK) as described elsewhere (Kanai et al., 2006). 2.4. Statistical analyses Results of excitability testing and nerve conduction studies were compared before and after treatment by the paired t test when the data showed a Gaussian distribution using the Statcel software for Windows 2001 (OMS Co. Ltd., Tokyo, Japan). When the data did not show a Gaussian distribution, the Wilcoxon test was used. Fig. 1. Changes in threshold changes at 0.2 ms in latent addition (A) and SDTC (B) before and after mexiletine administration in patients with neuropathic pain/ paresthesias (n = 17). Evaluation of mexiletine treatment was made 3 months after the initiation of this agent. There were significant decreases in both parameters after treatment. Error bars indicate SEM.
threshold increase produced by the hyperpolarizing stimulus is the sum of two exponential components (Bostock and Rothwell, 1997).
3. Results 3.1. Clinical assessment Table 1 shows clinical profiles, pain disability scales and VAS before and after mexiletine treatment. After mexiletine treatment,
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(range) reduction of VAS scores was 60% (0–90%). The patients, who had suffered pain for less than 12 months, showed greater extent of alleviation of pain estimated by pain disability scale than the patients with longer duration of pain (12 months or more, p = 0.03). 3.2. Changes in axonal excitability indices in radial sensory axons Table 2 shows changes in sensory nerve conduction and excitability indices in the normal controls, and in patients before and after mexiletine treatment. Nerve conduction velocities and nerve action potential amplitudes did not change significantly by the intervention. In the latent addition studies, threshold changes at the conditioning-test stimulus of 0.2 ms were greater in patients with neuropathic pain than normal controls (p < 0.001), suggesting increased nodal persistent Na+ currents in the patients. The time constant of the slow component and SDTC did not differ between the normal controls and patients. After mexiletine treatment, the threshold changes at 0.2 ms and time constant of the slow component significantly decreased associated with reduction of pain, indicating that nodal persistent Na+ currents and resulting axonal hyperexcitability were suppressed by the agent (Table 1, Fig. 1A). SDTC was also shortened significantly, again suggestive of suppression of persistent Na+ currents by mexiletine treatment (Fig. 1B). Fig. 2 shows representative latent addition curves recorded from a normal control and one of the patients before and after treatment with mexiletine. Threshold change at 0.2 ms and time constant of the slow component were decreased by the mexiletine administration with reduction of pain disability scale from 3 to 1. There was no significant correlation between the reduction rate of threshold changes at 0.2 ms in latent addition, and the reduction rate of visual analogue scale score (R2 = 0.096; p = 0.39). 3.3. Changes in excitability indices in median motor axons Table 3 shows changes in excitability indices in median motor axons before and after mexiletine therapy. In latent addition, threshold increase at the 0.2 ms-interval in the patients tended to be greater than that in the normal controls before the treatment. After administration of mexiletine, threshold change at 0.2 ms and time constant of the slow component, and SDTC significantly decreased, indicating that mexiletine suppressed persistent Na+ currents in motor, as well as, sensory axons. Indices in threshold electrotonus and recovery cycle in the patients did not change significantly after the treatment, suggesting that membrane potential was not altered by mexiletine. 4. Discussion
Fig. 2. Representative latent addition curves recorded from a normal subject (A), and a patient (no. 5 in Table 1) before (B) and after (C) treatment with mexiletine. The decay of the raw threshold is the sum of the two exponentials. The fast component reflects passive membrane properties, whereas the slow component depends on persistent Na+ currents. Because the first component is nearly 0 at the 0.2 ms-interval, threshold changes at 0.2 ms can be used as an indicator of persistent Na+ currents. Threshold change at 0.2 ms and time constant of the slow component were decreased after treatment with reduction of pain disability scale from 3 to 1.
15 of the 17 patients experienced reduction of pain, whereas the remaining 2 had no improvement. Both pain disability scale scores (p < 0.001) and VAS scores (p < 0.001) decreased. The median
Our results show that axonal persistent Na+ currents estimated by latent addition and SDTC in large sensory fibers substantially increase in patients with neuropathic pain, and mexiletine significantly suppresses axonal Na+ currents and pain/paresthesias. These findings raise the possibility that nodal Na+ currents may similarly increase in small fibers, and this could be responsible for development of neuropathic pain. Our findings show that latent addition technique and SDTC measurement can be used to estimate the axonal ionic changes at least in large myelinated sensory fibers as objective measures, and it is necessary to assess small fibers responsible for neuropathic pain in future studies. SDTC depends on the two factors, persistent Na conductance and passive membrane properties at the nodes (Bostock et al., 1998). In this regard, latent addition is more sensitive to detect alternation of persistent Na+ currents, because the slow component purely reflects the currents.
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S. Isose et al. / Clinical Neurophysiology 121 (2010) 719–724 Table 3 Median motor axonal excitability indices before and after mexiletine treatment.
Latent addition Threshold change at 0.2 ms (%) Time constant Fast component (ls) Slow component (ls) SDTC (ms) Threshold electrotonus TEd (10–20 ms) TEd (90–100 ms) TEh (90–100 ms) Recovery cycle Supernormality Refractoriness at 2.0 ms Refractoriness at 2.5 ms
A Normal
B Patients (n = 17)
C
(n = 35)
Before
After
A vs B
B vs C
10.0 (0.6)
13.5 (1.3)
10.2 (0.7)
0.07
0.09
48.8 (0.9) 271.9 (17.1) 0.41 (0.01)
50.4 (1.7) 284.4 (13.4) 0.44 (0.03)
46.4 (2.2) 207.2 (15.7) 0.38(0.02)
NS NS NS
NS 0.02 0.02
52.1 (0.3) 47.1 (0.6) 121.6 (2.8)
54.9 (1.1) 45.0 (1.6) 123.9 (6.2)
55.8(1.4) 46.6 (1.2) 123.5 (5.4)
0.03 NS NS
NS NS NS
23.4 (1.0) 56.2 (3.8) 13.4 (1.7)
19.7 (2.1) 37.5 (6.7) 20.8 (7.0)
20.9 (2.5) 40.7 (7.1) 12.9 (5.6)
NS 0.03 NS
NS NS NS
p-value
Data are given as mean (SEM); SNAP = sensory nerve action potential; TEd (10–20 ms), TEd (90–100 ms) = threshold change between the specified latencies after the start of depolarizing current; TEh (90–100 ms) = threshold change between the specified latencies after the start of hyperpolarizing current; SDTC = strength-duration time constant; NS = not significant.
Axonal degeneration/regeneration is usually accompanied by remodeling of Na+ channels on the axolemma, which would be associated with pain (Devor et al., 1989, 1993; Matzner and Devor, 1994; Cummins and Waxman, 1997; Cummins et al., 2007). However such changes have never been demonstrated in patients with neuropathic pain, largely because of the lack of non-invasive technique to test axonal ionic conductances. Multiple excitability measurements using computerized threshold tracking are innovative strategies to investigate human ionic currents and membrane potential of the axons (Bostock et al., 1998; Burke et al., 2001; Nodera and Kaji, 2006). This is the first study that demonstrates a significant relationship of pain and nodal Na+ currents, and the effects of mexiletine on sensory axonal excitability in vivo. There are a number of limitations in this study. First, as mentioned in Section 1, neuropathic pain arises from small myelinated or unmyelinated fibers rather than large myelinated fibers tested in this study. In fact, there was no significant correlation between the reduction rate of threshold changes at 0.2 ms in latent addition, and the reduction rate of visual analogue scale score in our patients. The findings indicate that latent addition measured in large fibers is not a direct measure of neuropathic pain, that arises from small fibers, and future studies will be necessary to directly estimate persistent Na+ currents in small fibers, for example, using microneurography. In large myelinated nerve fibers, the sodium channel, Nav1.6, was expressed at the nodes of Ranvier. After nerve injury, Nav1.3 or other subtypes of Nav channel are significantly upregulated (Rogers et al., 2006). There are multiple isoforms, TTX-sensitive and resistant with different gating behavior, expressed differently on small myelinated and unmyelinated axons. The channel expression and gating behavior in axonal injury would also differ in these fibers. Interactions between multiple Na+ channel isoforms would contribute to increase Na+ currents and thereby, generation of neuropathic pain (Rogers et al., 2006). Our findings cannot be directly applied to small fiber properties. However, pain and paresthesias usually coexist, and both could be suppressed by Na+ channel blockade. Secondly, neuropathic pain predominantly affects the distal lower limbs. Therefore, our results might not directly reflect the ionic pathophysiology in patients with neuropathy. Further studies investigating small fibers in the lower limb nerves will be necessary. An overview of the clinical trials in neuropathic pain suggests that a single agent offers clinically important relief in only 40–60% of patients at best (Rowbotham, 2002). Surprisingly in this study, the large proportion of patients showed substantial
response to mexiletine. Placebo effects could not be excluded. Moreover, there might be some sampling bias that most patients included in the present study had mild-to-moderate neuropathy with relatively short duration, because sensory nerve action potentials >10 lV at least are necessary for stable recording. Our findings raise the possibility that early therapeutic intervention could result in favorable responses to Na+ channel blockade, probably because sustained ectopic impulse generation would lead to central sensitization later. However, this should be clarified in placebo-controlled trials involving a larger number of patients. We believe that monitoring the axonal ionic pathophysiology of neuropathic pain in individual patients could be the basic and significant step towards development of new therapeutic approach. Funding This study is supported in part by Research Grant from the Ministry of Education, Culture, Sports, Science, and Technology of Japan (S.M., Kakenhi-21790834). Competing interests None. Copyright license statement I certify that all the authors have made significant contribution on the manuscript and agree with the content. Neither the entire paper nor any part of its content has been published or is being submitted for publication elsewhere. References Bostock H, Rothwell JC. Latent addition in motor and sensory fibres of human peripheral nerve. J Physiol (Lond) 1997;498:277–94. Bostock H, Cikurel K, Burke D. Threshold tracking techniques in the study of human peripheral nerve. Muscle Nerve 1998;21:137–58. Burke D, Kiernan MC, Bostock H. Excitability of human axons. Clin Neurophysiol 2001;112:1575–85. Campbell JN, Meyer RA. Mechanisms of neuropathic pain. Neuron 2006;52:77–92. Chabal C, Jacobson L, Mariano A, Chaney E, Britell CW. The use of oral mexiletine for the treatment of pain after peripheral nerve injury. Anesthesiology 1992;76:513–7. Cummins TR, Waxman SG. Downregulation of tetrodotoxin-resistant sodium currents and upregulation of a rapidly repriming tetrodotoxin-sensitive
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