A recent study suggests that gabapentin can reduce both subjective and motor symptoms of RLS with significant improvements noted after 4 weeks of treatment.
Although restless legs syndrome (RLS) is common,1 the US Food and Drug Administration has not approved any therapy for this sensorimotor disorder. Current pharmacologic treatments that have been studied in randomized controlled trials include largely dopaminergic agents. A recent study by Diego Garcia-Borreguero, MD, and his colleagues at the Fundacion Jimenez Diaz in Madrid, Spain, however, shows that gabapentin, an anticonvulsant that is primarily used to treat seizures and neuropathic pain, is safe and effective in treating RLS.2
RLS can have a profound impact on sleep, and, indeed, people with severe RLS often endure the most extreme sleep deprivation seen with any sleep disorder. The creepy-crawly sensations of RLS and the compelling urge to move, which primarily affect the legs but can also involve the arms and, rarely, other body parts, are brought on by rest or inactivity and are relieved by movement. In addition, RLS has a circadian component, independent of the features that cause a worsening of symptoms in the evening and at night.3
Clinical Trial
Upon entering the trial, eight men and 12 women (who met the International RLS Study Group criteria for RLS (see sidebar, page 42) underwent overnight polysomnographic testing and physical and neurologic examinations and completed a validated RLS severity rating scale, a sleep questionnaire, and an hourly subjective assessment of their RLS symptom severity. Except for the neurologic examinations, all of these assessments were repeated at the end of each treatment period and subjects rated their pain level every 2 weeks. In this double-blind, crossover trial, participants were randomly assigned to receive either placebo or gabapentin (600 mg per day, with biweekly adjustments to a maximum of 2,400 mg per day) for 6 weeks. Following a 1-week washout period, they then received the alternative treatment for 6 weeks. Three participants dropped out of the trial due to lack of efficacy (placebo, 1), unspecified (gabapentin, 1), and arterial hypertension (placebo, 1). With gabapentin, 48% of participants experienced adverse effects; 21% of those taking placebo had adverse effects. Even though neurologic examination did not reveal evidence of clinical neuropathy in these patients, more than 50% indicated on the pain scale that they had pain.
The primary outcome measure was a change in the RLS rating scale (mild, moderate, or severe symptoms), and secondary measures included a self-reported change in symptoms, responses to the sleep questionnaire,4 and polysomnographic data—including periodic limb movements of sleep index (PLMI), total sleep time, sleep efficiency, sleep latency, and latency to rapid eye movement sleep.
International RLS Study Group Criteria A diagnosis of RLS requires that all four features be present at some point in the course of the disorder. 1. The desire to move the extremities arises in association with unpleasant sensations that occur spontaneously during wakefulness and are described using terms such as creeing, burning, tingling, cramping, aching, itching, pulling, crawling, or a sensation like “water flowing” deep within the affected limb or limbs. - Sensations are characterized as uncomfortable, usually not painful although a significant minority of patients report some sensations as painful.
- Sensations are typically deep-seated (not superficial) within the legs, most often in the calves; in some cases, sensations also occur in arms.
- Sensations may be present in the trunk or genital area.
- Sensations may be bilateral or unilateral.
2. Motor restlessness - Patients move to alleviate limb discomfort.
- Patients feel a compelling urge to move—these movements may be considered involuntary; however, since a patient chooses which type of movement to perform, these movements are voluntary.
- Movements are often stereotypical and repetitive.
- Movements may include walking or pacing, rocking, shaking, tossing and turning in bed, leg stretching, leg flexions, deep knee bends, marching in place, or cyclical body rocking.
- Movements may be mistaken for fidgetiness or nervousness.
3. Symptoms are worse or exclusively present at rest (lying or sitting) with at least partial and temporary relief by activity. - Sensorimotor symptoms generally occur during periods of inactivity.
- Sensorimotor symptoms may be provoked by more prolonged inactivity.
- Sensorimotor symptoms are usually substantially, if not completely, relieved by walking or other motor activities; however, they may recur after patient stops moving and rests.
4. Sensorimotor symptoms are worse in the evening or night. - Worsening of symptoms typically occurs during the evening or night, with a peak near midnight and with significant reduction in symptoms occurring during the early morning hours, usually sometime between 4 am and 10 am.
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Conclusion
Analysis showed that gabapentin significantly reduced both subjective (sensory) and objective (motor) symptoms of RLS at a mean dose of 1,855 mg at the end of the treatment period with significant improvements noted after 4 weeks of treatment at a mean dose of 1,391 mg. This amount was higher than that used in previous studies, including an open-label trial that also used polysomnography and did not show improvements in sleep parameters. PLMI decreased from 20.8 to 11.1 and total sleep time increased by 30 minutes. Sleep latency was not shortened with the use of gabapentin, a finding that the authors attributed to the medication’s effect on the PLMI rather than its soporific effects. Patients with higher scores on the pain scale showed a greater response to treatment with gabapentin.
In this short trial, none of the patients experienced the augmentation—a time shift of symptoms to a period that is earlier in the day than before the institution of treatment—that is common with the use of dopaminergic agents.5 This new research provides valuable information to the clinician who is dealing with this often-difficult-to-treat condition. If this work is validated in larger and longer-term trials, gabapentin may well prove to be a powerful agent in the treatment of RLS.
Catherine Friederich Murray is president of Morpheus Medical Communications, Ponte Vedra Beach, Fla; and Theresa Shumard is communications chair for the Association of Polysomnographic Technologists (APT); editor of the APT’s international news magazine, The A2Zzz; and a member of Sleep Review’s Editorial Advisory Board.
References
1. Chokroverty S, Jankovic J. Restless legs syndrome: a disease in search of identity. Neurology. 1999;52:907-910.
2. Garcia-Borreguero D, Larrosa O, de la Llave Y, Verger K, Masramon X, Hernandez G. Treatment of restless legs syndrome with gabapentin: a double-blind, cross-over study. Neurology. 2002;59:1573-1579.
3. Walters AS. Toward a better definition of the restless legs syndrome. The International Restless Legs Syndrome Study Group. Mov Disord. 1995;10:634-642.
4. Buysse DJ, Reynolds CF, Monk TH, Berman SR, Kupfer DJ. The Pittsburgh Sleep Quality Index: a new instrument for psychiatric practice and research. Psychiatry Res. 1989;28:193-213.
5. Allen RP, Earley CJ. Augmentation of the restless legs syndrome with carbidopa/levodopa. Sleep. 1996;19:205-213.
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