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Tiagabine (Gabitril, Paris, France) is a new antiepileptic drug that acts as a selective inhibitor of the γ-aminobutyric acid (GABA) transporter, GAT-1.1 It has recently been reported to be effective in diseases other than epilepsy, such as stiff man syndrome2 and neuropathic pain,3 conditions in which GABAergic mechanisms are supposedly involved. In multiple sclerosis, painful tonic spasms affect approximately 10% of patients and are usually treated with GABAergic drugs such as baclofen or gabapentin.4,5
We undertook an open label pilot study of tiagabine, in a dose range of 5 to 30 mg/day, in a group of seven multiple sclerosis patients with painful tonic spasms who were non-responsive or intolerant to established drug treatment. The patients had previously been treated with gabapentin, baclofen, diazepam, or clonazepam, and were being followed in the department of neurology, PA Micone Hospital, Genoa, Italy. Four subjects were female and three were male, with a mean age of 45.1 years, mean disease duration of 7.1 years, and mean expanded disability status score (EDSS) of 4.0. Four patients had relapsing-remitting, one had secondary progressive, and two had primary progressive disease. Painful tonic spasms were defined as transient painful extensor or flexor spasms in the lower limbs, with abrupt onset and brief duration (from a few seconds to a few minutes), with repetitive and stereotypical features. The subjective level of the painful tonic spasms was scored using a three point scale previously described5: 0, no pain, no attack; 1, mild pain or discomfort, presents only a limited amount of time; 2, intermediate pain or discomfort: the duration moderately interferes with daily activities; 3, severe pain: intensity or frequency of symptoms seriously limiting normal daily activity. Spasticity level was scored using the Ashworth scale. Tiagabine was started at 5 mg daily and increased until spasms were relieved or to the maximum dosage of 30 mg. No other drugs with a potential influence on spasticity were allowed during the study period. The patients were clinically evaluated at baseline (T0), after pain relief was achieved (T1), and after three months from the beginning of the protocol (T2). The minimum follow up period was three months. All specific symptomatic drug treatments used previously were discontinued one week before treatment with tiagabine was begun.
The mean dose of tiagabine was 12.8 mg daily. Relief of painful tonic spasms was successful in four of the seven patients (minimum treatment period, three months). All four patients had complete and sustained recovery within one month of initiation of treatment (a reduction of two points on the pain scale); efficacy was maintained for a period of three months in all four subjects. The Ashworth score changed by one point in one subject. The clinical characteristics of the patients and the painful tonic spasm scores before and after treatment are given in table 1.
Two patients (Nos 2 and 5) dropped out of the study because of adverse effects: one with nausea and dizziness, the other with drowsiness and weakness. These subjects had a longer disease duration and higher EDSS scores, suggesting a possible correlation between disease severity and adverse effects.
Typically, antiepileptic drugs are effective for treating paroxysmal symptoms in patients with multiple sclerosis at doses that are lower than those used in epilepsy. For this reason, we arbitrarily set the maximum dose of tiagabine at 30 mg/daily, while in epilepsy the maximum dose is usually 56 mg daily. Moreover, patients with multiple sclerosis treated with antiepileptic drugs more often report central nervous system side effects than patients with other diseases such as seizures or mood disorders.
The results of this study suggest a possible new treatment for painful tonic spasms in multiple sclerosis and support the postulated GABAergic mechanism of action as the key factor in the choice of drug therapy. The spasticity level, measured with the Ashworth scale, did not change during the study period, as reported in trials of other antispasticity drugs such as tizanidine. This may reflect the inability of the scale to detect mild changes, or the different pathogeneses of painful tonic spasms and spasticity. The frequency of side effects of this agent in patients with multiple sclerosis and its efficacy in the treatment of painful tonic spasms or spasticity must be confirmed in a larger study.