An open-lebel trial of gabapentin treatment of paroxysmal symptoms in multiple sclerosis patients

Paroxysmal symptoms (PS) occur frequently in multiple sclerosis (MS) patients and are often the cause of relevant discomfort and suffering. PS include trigeminal neuralgia (TN), painful tonic spasms (PTS), dysesthetic or paresthetic symptoms, episodic ataxia, dysarthria, or akinesia. PS are likely due to abnormal transient electric discharges spread by an ephaptic mechanism throughout demyelinated axons. PS are often treated with antiepileptic drugs such as carbamazepine and phenytoin, diazepam, amitriptiline, and bromocriptine.¹ Nevertheless, these medications may not be effective or tolerated because of their adverse effects. Gabapentin (GBP) is a new well-tolerated antiepileptic drug² found to be effective for several neurologic symptoms, including neuropathic pain, idiopathic TN, postherpetic neuralgia, restless leg syndrome, hemifacial spasm, and acquired nystagmus.^3,4 GBP has been reported to induce an amelioration of spasticity in MS⁵ and to improve refractory dysesthetic limb pain in a single MS patient.⁶

We treated 21 MS patients having PS with GBP, with most experiencing complete resolution or a relevant and sustained amelioration of symptoms without significant adverse effects.

Subjects and methods. We included in an open study 21 patients with clinically definite MS who were experiencing PS and were being followed up as outpatients at the MS Center of the Department of Neurological Sciences and Neurorehabilitation, University of Genova. PS were defined as transient symptoms with an abrupt onset and brief duration (a few seconds to a few minutes), with repetitive and stereotyped features.¹ The 21 patients (10 men, 11 women) had a mean age of 42.8 and an average disease duration of 10.8 years. At study entry, mean Expanded Disability Status Scale(EDSS) was 5.2 and PS mean duration was 22.4 months. Six patients had TN and all had been previously treated with either phenytoin or carbamazepine, up to 1200 mg/d. These treatments were interrupted because of poor clinical response or adverse effects. Of 21 patients, 11 had PTS, three experienced paroxysmal paresthetic disturbances, and one had ocular ataxia with severe nystagmus (table). In these patients, conventional therapies including amitriptiline, diazepam, and baclofen were ineffectual or poorly tolerated.

Before initiating therapy and at each visit, pain level, discomfort, and frequency of attacks were scored by the same examining physician. Subjective symptoms and impairment in performing daily activities were rated using a three-point scale,⁷ as follows:

0: No pain, no attack.

1: Mild pain or discomfort. Does not seriously interfere with facial or other movements and is restricted to a limited area, present only during waking hours, and lasts for a limited time.

2: Intermediate pain or discomfort. In TN, pain is easily evoked by facial movements or light touch and spreads to more than one division; in PS, duration, frequency, and degree of discomfort moderately interferes with daily activities.

3: Severe pain. In TN, significantly interferes with eating or speaking and is severe enough to awaken the individual; intensity or frequency of symptoms seriously limits normal daily activity.

GBP, 300 mg, was administered daily at bedtime to avoid possible food interactions. After 3 days, dosage was increased to 300 mg twice a day. After phone contact after 7 to 10 days, dosage was titrated to 1200 mg if no response was obtained with the previous daily regimen. Because of the rapid onset of improvement after therapy was started, no concomitant medications were administered during the study, with the exception of one patient who needed association with lamotrigine, 200 mg/d, to reach a partial improvement(Patient 20). One month after therapy initiation or when a steady clinical condition (optimal dosage) was obtained, patients were clinically evaluated. At this point, GBP plasma levels were measured in 10 patients by capillary electrophoresis. The main outcome was the amelioration of symptoms within 3 months after medication initiation. At this time, a final neurologic examination was performed and a second subjective score of symptoms was assigned. A longer follow-up (6 to 9 months) for treatment efficacy was possible in seven patients. Statistical analysis was performed, applying Wilcoxon's signed rank test.

Results. Of 21 patients with PS, 18 achieved the main outcome(minimum treatment period of 3 months). Fourteen patients experienced a complete and sustained recovery within 1 month from treatment initiation, and four patients had a consistent amelioration of symptoms. Three patients dropped out of the study after 2 weeks because of poor compliance (two patients) and side effects (nausea). Of six patients with TN, five experienced complete remission of pain at progressively increasing doses (two patients at 600 mg/d, two patients at 900 mg/d, and one patient at 1200 mg/d); partial recovery was obtained in one patient at a dose of 1200 mg/d. Improvement typically began 3 to 5 days after therapy initiation. The mean pretreatment pain score was 2.67; it was 0.17 at the time when the optimal dosage was reached, which was unchanged after a period of 3 months(p = 0.027). Most patients with PTS experienced a dramatic improvement within the first 3 days of treatment, leading to complete resolution of symptoms within the first month. The mean pretreatment score was 2.09, which dropped to 0.10 when the optimal dosage was achieved and remained stable after 3 months, suggesting a significant pharmacologic effect of GBP (p = 0.005). In two of three patients with paroxysmal paresthetic disturbances, it was necessary to titrate to the maximum study dosage (1200 mg/d) to ameliorate symptoms. In one patient, another medication was administered to further control symptoms.

Adverse effects were limited to two patients and were characterized by a mild decrease in daytime alertness in one patient and severe nausea in another (who dropped out). Major adverse effects previously reported (e.g., incontinence, coreoathetosis, ataxia, and imbalance) were not observed.⁸

Increasing the dose of GBP resulted in higher plasma levels within the dosage range. Remarkably, when GBP was effective at 600 mg/d, plasma concentrations remained nearly undetectable (less than 1.5 µg/mL). A clear relation between dosage and plasma concentration was not detected.

Discussion. In this report, we observed that in all patients with TN and PTS, GBP at the dosage of 600 to 1200 mg/d induced a relevant reduction or complete resolution of PS within 3 months of therapy, which was sustained for subsequent months. For patients with paroxysmal paresthetic disturbances, improvement was less consistent. In six patients with a longer follow-up (three with TN, four with TPS), complete recovery from PS was stable, persisting for up to 6 months. Clinical effects of GBP were typically experienced within the first few days after therapy at 600 mg/d, although in some patients it was necessary to increase the dosage to 1200 mg and in one patient to add lamotrigine (patient 20) to obtain clinical improvement. As previously reported,⁹ no directly proportional correlation between dosage and plasma level of GBP was observed. Therefore, for each patient, an optimal dosage must be reached empirically after a gradual titration of GBP until clinical response is evident. Overall, GBP was well tolerated, and effective dosages were lower than those typically used in epilepsy patients. Adverse effects were limited to nausea and mild decrease in daytime alertness.

Although GBP mechanisms of action remain undetermined, experimental evidence demonstrates that GBP enhances gamma aminobutyric acid (GABA) synthesis and inhibits GABA degradation, increasing GABA levels in the brain.¹⁰ GBP has been indicated as an effective treatment for several neurologic disorders and more recently for various symptoms in MS, including acquired nystagmus,⁴ hypertonia,⁵ and dysesthetic limb pain.⁶ This study demonstrates that GBP may be an effective and well-tolerated therapy for MS patients in whom conventional therapies are ineffective or poorly tolerated. A randomized double-blind study comparing either carbamazepine or baclofen with GBP may be relevant to identifying the first-choice therapy for PS in MS.