CASE REPORT

Mexiletine for Painful Alcoholic Neuropathy Kazutoshi Nishiyama and Manabu Sakuta*

Five patients suffering from painful alcoholic neuropathy showed severe painful sensory disturbance in their extremities. Although their pain was not ameliorated by the typical usual agents, oral mexiletine (MX) therapy was remarkably effective for the pain (especially tingling and aching sensation) without major side effects. This study indicated that the minimum effective dose was 300 mgper day and the effective concentration of MXin plasma was 0.66+0.15 |ig/ml in these patients. Thus, oral MXtherapy can be a reliable treatment for pain in alcoholic neuropathy. (Internal Medicine 34: 577-579, 1995) Key words: mexiletine, alcoholic neuropathy

Introduction demonstrated the presence of , which was characterized by axonal change with or without demyeli- Alcoholic polyneuropathy often shows severe painful sen- nating change. Sural nerve biopsy showed that there was both sory disturbance, which is often unresponsive to treatment. axonal degeneration and demyelination in cases 1 and 3. Conventional analgesic agents are only rarely responsive. Here, Etiological factors other than abuse could not be de- we describe five patients with painful alcoholic neuropathy and tected and the neurological diagnosis of alcoholic polyneuro- discuss the analgesic effect of a class Ib Na , pathy was madefor all five patients. mexiletine (MX), on painful alcoholic neuropathy. Mexiletine therapy Subjects and Methods The results of MXtherapy are shown in Table 2. Conven- tional analgesic including minor tranquilizer, ma- Report of five cases jor tranquilizer, anti-convulsant, anti-depressant and so on, The clinical findings of the five patients are given in Table 1. were not effective for the pain. An oral MXtherapy trial was All of the patients were Japanese menand their ages ranged performed with informed consent and all other drugs were from 45 to 68. They had a past history of chronic alcoholism. discontinued. For the clinical trial conducted with MX,four They complained of sensory disturbance with or without motor patterns of MXdose were tried for each patient: 150 mg, 300 involvement, with insidious onset following long-term alco- mg, 450 mg, and 600 mg per day. Each dose was administered holic abuse (intake of morethan 900 litre of ethanol over more orally three times daily and neurological complaints were than 27 years). All of their complaints demonstrated gradual examined twice a week. The dose was increased from 150 to progression of painful sensation. Bilateral ankle jerks were 600 mgper day. All the trials were continued for two weeks and absent in all five patients. Their neurological symptomswere the concentrations of MXin plasma were measured whenthe limited to the peripheral nervous system and a diagnosis of therapeutic effect was clarified for pain. Wemonitored for side sensory polyneuropathy or sensori-motor polyneuropathy was effects of the oral MXtherapy by following-up the patients for made. Painful sensation was noted as remarkable in the lower six months at their minimumeffective doses. After the follow- extremities. Details of sensory disorders including mexiletine up, with proper informed consent, the therapy was discontinued therapy are summarized in Table 2. Brain computed tomogra- after two weeks for three patients (cases 1, 2 and 3) after phy scan or magneticresonance imagingscan revealed no amelioration of pain in order to observe recurrence of pain abnormalities. Electrophysiological examinations including without MX. needle electromyogram (EMG)and nerve conduction study From the Department of Neurology, Institute for Brain Research, School of Medicine, University of Tokyo, Tokyo and *the Department of Neurology, Japanese Red Cross Medical Center, Tokyo Received for publication November 24, 1994; Accepted for publication February 17, 1995 Reprint requests should be addressed to Dr. Kazutoshi Nishiyama, the Department of Neurology, Institute for Brain Research, School of Medicine, University ofTokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 1 13

Internal Medicine Vol. 34, No. 6 (June 1995) 577 Nishiyama et al

Table 1. Clinical Data Pa ti en t Ag e Se x A lc o ho l ab us e le ve l N eu ro lo gi ca l fi nd in g N CV S ur al n er ve b io ps y D u ration * T o tal eth an ol** S ensory M otor

C ase 1 4 9 M 30 1,20 0 G S n .s. m ix ed m ixed C ase 2 56 M 35 1,40 0 S n .s. ax on al n .e . C a s e 3 4 5 M 2 7 9 0 0 S n . s . a x o n a l m i x e d C a s e 4 6 2 M 4 2 1 , 6 0 0 G S M A , M W m i x e d n . e . C a s e 5 6 8 M 5 0 2 , 0 0 0 G S M A , M W a x o n a l n . e .

^Duration of alcohol abuse until symptoms ofpolyneuropathy appeared (yrs). **Total lifetime amount of ethanol consumed (1). GS: glove and stocking type sensory disturbance, S: stocking type sensory disturbance, n.s.: no symptom, MA:muscle atrophy, MW:muscle weakness, NCV:nerve conduction velocity, mixed: mixed type of axonal change and demyelination, axonal: type of axonal change, n.e.: not examined.

Table 2. Effects of Mexiletine (MX) Therapy P atie n t P r ic k lin e s s A c h i n g H y p e r e s t h e s i a B u r n i n g D o s e o f M X t h e r a p y * C o n c e n t r a t i o n o f M X ( u g / m l ) # B D A B D A B D A B D A (m g /d a y ) (m g /k g /d ay ) in p la sm a in liq u o r

C a s e 1 3 + 0 3 + 2 + 1 + 2 + 2 + 1 + 2 + 1 + 2 + 1 + 3 0 0 6 . 1 0 . 4 1 0 . 3 3 C a s e 2 3 + 1 + 3 + 3 + 1 + 3 + 3 + 2 + 3 + 2 + 2 + 2 + 4 5 0 0 . 7 6 C a s e 3 2 + 0 2 + 2 + 0 2 + 2 + 2 + 2 + 2 + 2 + 2 + 4 5 0 9 . 2 0 . 7 7 C a s e 4 3 + 1 + n . e . 3 + 1 + n . e . 2 + 2 + n . e . 2 + 2 + n . e . 3 0 0 7 . 5 0 . 7 2 C a s e 5 3 + 1 + n . e . 3 + 1 + n . e . 3 + 2 + n . e . 2 + 2 + n . e . 4 5 0 8 . 3 0 . 6 5

B: before MXtherapy, D: during MXtherapy, A: after cessation ofMXtherapy, n.e.: not examined, 0: no disturbance, 1+: mild, ^Minimum2+:dose of mexiletinemoderate,with sufficient analgesic effect. Concentration3+:of MXin severe.plasma and liquor when MXshows sufficient analgesic effect.

Results Discussion

The effects and details of oral MXtherapy are summarized Chronic alcoholism often demonstrates alcoholic neuropa- in Table 2. The trial of 150 mg per day did not show any thy with severe painful sensation. is generally influence on pain in any of the five cases. The trial of300 mgper unresponsive to treatment. Wereported five cases of alcoholic day revealed therapeutic effect on pain in cases 1 and 4, and 450 neuropathy in which conventional pain medications had been mg per day was effective forpain in cases 2, 3 and 5. This trial unsuccessful and oral MXtherapy was highly effective. Recur- indicated that the effective dose of MXtherapy required to rence of pain in their extremities was observed following improve the pain was 6.1 to 9.2 mg/kg/day (mean±SD: cessation of MXtherapy. Although MXtherapy did not reveal 8.00±1.24). The effective concentration of MXin plasma was objective alterations, it was proved to be a good therapy for 0.66±0. 15 J^ig/ml for these patients. Therapeutic doses amelio- painful alcoholic neuropathy without significant side effects. rated pain in a few days to a week. Objective findings, including The therapy seemed to be effective especially to tingling and deep tendon reflex, vibration sense and nerve conduction veloc- aching sensation. For the dose, 300-450 mg/day (6. 1-9.2 mg/ ity, did not show any significant changes. During MXtherapy, kg/day) was sufficient to obtain analgesic effects. tingling and aching sensation were remarkably diminished, MXis usually utilized for as a class Ib Na while hyperesthesia and burning sensation were decreased channel blocker. However, the effect of MXis not restricted to slightly. No major side effects were observed. The only side the cardiovascular system. MXtherapy has been reported to be effect seen wasdeterioration of the burning sensation in one excellent in reducing myotonic activity in EMG(1) and as an patient. All three patients with cessation of MXtherapy (cases anti-myotonic agent as well (2). 1, 2 and 3) developed recurrence of pain. The effects of MXon painful symptoms have been previ- ously reported in (3-5), and peripheral nerve injury (6). It has also been reported to be effective on the

578 Internal Medicine Vol. 34, No. 6 (June 1995) Mexiletine on Alcoholic Neuropathy central nervous system: painful tonic seizure in multiple scle- References rosis (7) and thalamic pain syndrome (8). Xuet al reported that Ceccarelli M, Rossi B, Siciliano G, Calevro L, Tarantino E. Clinical and systemically applied MXrelieves pain-related symptoms at electrophysiological reports in a case of early onset myotoniacongenita doses of 15 and 30 mg/kg in rats after ischemic spinal cord (Thomsen' s disease) successfully treated with mexiletine. Acta Paediatr injury. They speculated that systemic MXmedication may be .81: 453, 1992. useful in treating central nerve pain in patients with spinal cord Kwiecinski H, Ryniewics B, Ostrzycki A. Treatment of myotonia with injury (9). antiarrhythmic drugs. Acta Neurol Scand 86: 371, 1992. Dejgard A, Petersen P, Kastrup J. Mexiletine for treatment of chronic Kamei et al reported the effect of MXon the threshold for painful diabetic neuropathy. Lancet 1: 9, 1988. pain perception as determined by the application of mechanical Ackerman WE3rd, Colclough GW,Juneja MM,Bellinger K. The noxious stimuli in diabetic mice (10). MXproduced a pro- managementof oral mexiletine and intravenous to treat chronic painful symmetrical distal diabetic neuropathy. J Ky Med Assoc 89: 500, nounced analgesic effect in a dose-dependent manner. Their 1991. results suggest that a reduction in the release of substance P Stracke H, Meyer UE, Schumacher HE, Federlin K. Mexiletine in the from the nociceptive afferent terminal in the spinal cord is treatment of diabetic neuropathy. Diabetes Care 15: 1550, 1992. involved in the mechanismof MXanalgesia in diabetic mice. Chabal C, Jacobson L, Mariano A, Chaney E, Britell CW. The use of oral MXmay cause a reduction of painful sensations in painful mexiletine for the treatment of pain after peripheral nerve injury. alcoholic neuropathy in the manner proposed by Kamei et al Anesthesiology 76: 513, 1992. (10). Okada S, Kinoshita M, Fujioka T, Yoshimura M. Two cases of multiple sclerosis with painful tonic seizures and dysesthesia ameliorated by the The present study was limited to a open trial; MXtherapy administration of mexiletine. Jpn J Med 30: 373, 1991. should be checked again by a double-blind test on the effects on Awerbuch GI, Sandyk R. Mexiletine for thalamic pain syndrome. Int J pain alleviation. However it may be concluded that this therapy Neurosci 55: 129, 1990. is recommendablefor pain of alcoholic neuropathy. Xu XJ, Hao JX, Seiger A, Arner S, Lindblom U, Wiesenfeld HZ. Systemic mexiletine relieves chronic allodynialike symptomsin rats with ischemic spinal cord injury. Anesth Analg 74: 649, 1992. Kamei J, Hitosugi H, Kawashima N, Aoki T, Ohhashi Y, Kasuya Y. Antinociceptive effect of mexiletine in diabetic mice. Res Commun Chem Pathol Pharmacol 77: 245, 1992.

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