Carbamazepine

Two studies from 1983 and 1984 established carbazepine as useful for RLS. One study³ was a pilot study, but the second⁴ had the largest sample size of any published RLS study until the 21st century. Telstad and colleagues⁴ performed a 5-week double-blind study of 170 patients using carbamazepine and placebo. Both arms had significant benefit, but the carbamazepine arm showed significantly greater clinical benefit than the placebo arm. Although carbamazepine was recognized as a guideline in 1999¹ and endorsed by the European Federation of Neurological Societies (EFNS) as probably effective in 2006,⁵ it has not been widely used by RLS experts in the last decade.

Carbamazepine is metabolized in the liver and has an initial half-life of 25 to 65 hours, decreasing to 12 to 17 hours on repeated doses. Due to its metabolism by the cytochrome P450 system, it may interact with many other drugs. Carbamazepine can be started at 100 to 200 mg taken a few hours before symptoms onset and increased by 100 mg every 7 days until symptoms are relieved to a maximum of 1200 mg/day. The published studies, however, have used lower doses—one study limited the dose to a maximum of 300 mg/day. Depending on the preparation, carbamazepine can be taken up to 3 or 4 times daily (regular tablets) or twice daily (slow release tablets).

Common side effects of carbamazepine include dizziness, drowsiness, unsteadiness, nausea, and vomiting. Rare but severe dermatologic reactions, including toxic epidermal necrolysis and Stevens-Johnson syndrome, may occur. There have also been rare cases of pancytopenia or hepatic failure. During treatment, there should be frequent monitoring of relevant blood tests.

Gabapentin

Gabapentin is an anticonvulsant that has shown therapeutic activity for essential tremor, as well as for several pain-related syndromes such as trigeminal neuralgia, post-herpetic pain, and diabetic neuropathy.^2,6,7 Due to its effects on pain and other sensorial symptoms, in addition to the observation of an improvement of sleep in neuropathic pain, it has been suggested that gabapentin might be useful for the treatment of RLS. So far, two short to mid-term double-blind studies and several long-term open studies have shown therapeutic effects in RLS.^2,8–11

In one of the earlier studies, Adler and colleagues¹⁰ performed an open-label study for up to 6 months on eight patients with RLS. The dosage ranged from 300 to 2400 mg/day, with a mean of 1163 mg/day. The minimum period of treatment was 1 week, and four patients remained on medication for up to 6 months. Four of the eight patients had a beneficial response, and three of them had complete resolution of symptoms. Two patients discontinued the study due to side effects, which included dizziness, nausea, and drowsiness.

In another open-label case series,² 16 RLS patients were treated for a mean of 8 months with a mean dosage of 487 mg/day (SD, 199.6 mg). Based on the patient´s subjective estimation, RLS was relieved in 75% to 100% of the cases, with a mean improvement of 85% (SD, 16%). The drug was well tolerated with just dizziness being reported for two patients, as well as drowsiness and alcohol enhancement each for one patient.

Happe and colleagues⁸ performed an open study on nine patients diagnosed with idiopathic RLS and included polysomnography among the efficacy measurement. All patients were treated for 6 to 10 months with gabapentin at doses of 300 to 1200 mg, administered 2 hours before bedtime. Sleep studies were performed at baseline as well as 4 weeks after. After the first 4 weeks, all nine patients were still on gabapentin with a mean dose of 733 +/− 400 mg. Moreover, 6 to 10 months later, eight patients were still on gabapentin with a mean dose of 533 +/− 328 mg. There was a significant reduction of the International Restless Legs Syndrome Study Group (IRLSSG) Rating Scale (IRLS) score, both on short-term and on long-term treatment. Furthermore, indices of motor disturbance and sleep fragmentation, such as the PLM-index, the PLM-arousal index, and the arousal index, were reduced after 4 weeks of treatment. However, no similar improvement was seen on the other sleep parameters. There were only mild and mostly transitory side effects such as numbness, dizziness, sleepiness, and headache. Two patients reported persistent side effects, one with headache and one with sleepiness, but these side effects were only mild and did not lead to discontinuation of treatment with gabapentin. This study was the first to show an improvement in periodic leg movements during sleep (PLMS) during gabapentin treatment.

Furthermore, in the only controlled study¹¹ performed on idiopathic RLS patients, 22 of the patients were treated for 6 weeks using a randomized, double-blind, placebo-controlled, crossover (gabapentin versus placebo) design. Patients were rated at scheduled intervals by the IRLS, and a sleep study was performed at the end of each treatment period. Compared with placebo, gabapentin was associated with a reduction of sensory and motor symptoms (Fig. 33-1). In addition, sleep studies showed a significant reduction in PLMS index and an improvement in sleep architecture (increased total sleep time, sleep efficiency, and slow wave sleep, and a decrease in stage 1 sleep). Patients whose symptoms included pain benefited most from gabapentin. The mean effective dosage at the end of the 6-week treatment period was 1855 mg, although therapeutic effects were already observed at the end of week 4 (at a mean of 1391 mg).

FIGURE 33-1. Severity of restless legs syndrome (RLS) symptoms, as reflected on the IRLS across treatment conditions. The graph shows the mean daily dosage of gabapentin at each stage of the study. *p < .1; **p < .01. GPB, gabapentin; PLB, placebo.

Reprinted with permission from Garcia-Borreguero D, Larrosa O, de la Llave Y, et al. Treatment of restless legs syndrome with gabapentin: A double-blind, cross-over study. Neurology 2002;59:1573-1579.

Gabapentin has been used in rare comparative trials of RLS treatments. One study has compared the therapeutic effects of gabapentin with a dopaminergic agonist: In a 4-week open clinical trial, eight patients with idiopathic RLS were treated with either 300 mg of gabapentin or 0.5 mg of ropinirole as the initial dose, with a subsequent uptitration until symptoms were relieved. The mean effective dosage of gabapentin was 800 (±397) mg versus 0.78 (±0.47) mg for ropinirole. In both groups, the IRLS scores improved significantly. Polysomnographic data showed a reduction of both periodic leg movements during sleep and the PLMS index in both groups. Side effects were only mild and mostly transient. After 6 to 10 months of follow-up, in most patients, RLS symptoms were still improved. The authors concluded that gabapentin and ropinirole provided a similarly well-tolerated and effective treatment of PLMS and sensorimotor symptoms in patients with idiopathic RLS.¹² Taken together with the previous studies suggest that gabapentin is a valid treatment for idiopathic RLS, although further systematized assessment of the long-term effects is necessary.

Two studies have investigated the therapeutic effects of gabapentin in uremic RLS. The first used a double-blind, placebo-controlled, crossover design on 16 patients with uremic RLS who were on hemodialysis.¹³ Following randomization, patients were treated with either gabapentin (300 mg) or placebo 3 times a week at the end of each haemodialysis session. Using a self-made rating scale based on each of the four RLS diagnostic criteria,¹⁴ 11 patients responded to gabapentin but not to placebo, 1 patient responded to placebo but not to gabapentin, and 1 patient did not respond to either one. The drug was in general well tolerated, but two patients dropped out during the gabapentin period study due to somnolence and lethargy, and a third patient died of myocardial infarction during treatment with placebo during the first treatment condition. No polysomnographic studies were performed.

Another study compared the therapeutic effects of gabapentin and L-DOPA in uremic RLS.¹⁵ Fifteen patients were treated for several weeks with gabapentin or L -DOPA. When both drugs were compared, the effect of gabapentin was superior to L -DOPA for the improvement of general health, body pain, and social functions. Moreover, gabapentin was also superior to levodopa for sleep quality, sleep latency, and sleep disturbance. Of these studies, it can be concluded that gabapentin is a useful treatment for the short-term management of uremic RLS. However, due to its significant renal excretion, caution is required in this type of population on hemodyalisis.

Two additional studies have investigated the effects of gabapentin on periodic leg movement disorder (PLMD). In an open study that was published as an abstract, seven patients who were diagnosed clinically with PLMD underwent sleep studies at baseline and were required to have a PLM index greater than 5 per hour.¹⁶