Pregabalin Calms Restless Legs by Unknown Mechanism

Abstract

Oral pregabalin (Lyrica) significantly improved symptoms of moderate to severe restless leg syndrome (RLS), compared with both placebo and pramipexole, in an industry-sponsored, international randomized trial. Also, pregabalin was associated with significantly less worsening of symptoms than was pramipexole, Richard P. Allen, PhD, of the department of neurology at Johns Hopkins University, Baltimore, and his associates reported in the New England Journal of Medicine. Pregabalin also was associated with lower rates of nausea, vomiting, and headache than pramipexole, but patients taking pregabalin had higher rates of suicidal ideation, dizziness, somnolence, and weight gain – “factors that may limit its long-term use,” the investigators said. Dopaminergic drugs such as pramipexole are known to be associated with augmentation in which symptoms intensify and may involve more parts of the body and start earlier in the day than before treatment, so researchers have been searching for an alternative medication. Pregabalin is a nondopaminergic agent with analgesic and anticonvulsant activity. Dr. Allen and his colleagues assessed both agents in a study involving 719 adults with moderate to severe primary RLS who were treated and followed at 102 medical centers in the United States and Europe. In the double-blind trial sponsored by Pfizer, these patients were randomly assigned to receive 0.25 mg pramipexole, 0.5 mg pramipexole, 300 mg pregabalin, or matching placebo capsules every day for 12 weeks. At that time, all patients receiving placebo were randomly reassigned to one of the three active treatments for the remainder (40 weeks) of the 1-year study. At 12 weeks, patients who received pregabalin showed significantly greater improvement in International RLS (IRLS) Study Group Rating Scale scores than did those who received placebo. Patients who received pregabalin also reported greater improvement in waking after sleep onset, quality of sleep, number of nightly awakenings, and total sleep time. These measures also were significantly better for patients treated with 0.5 mg pramipexole when compared with placebo-treated patients, but not for those taking 0.25 mg pramipexole. In a noninferiority assessment, pregabalin outperformed both doses of pramipexole on reduction in IRLS score at both 12 weeks and 52 weeks. The finding that pregabalin is effective for RLS even though it has no direct effect on dopaminergic systems calls into question the rationale for dopaminergic therapies. Dopaminergic treatments have been predicated on the assumption that RLS results primarily from dopamine abnormalities, Dr. Allen and his associates noted (N. Engl. J. Med. 2014;370:621–631). A total of 50 serious adverse events occurred in 37 patients: 16 events in the pregabalin group, 22 events in the lower-dose pramipexole group, and 12 events in the higher-dose pramipexole group. This included 11 cases of suicidal ideation: 6 in the pregabalin group, 3 in the lower-dose pramipexole group, and 2 in the higher-dose pramipexole group. Editor's NoteLooks like Lyrica will be seeking Food and Drug Administration approval for restless leg syndrome, and it looks like it works reasonably well, with a different set of side effects from those seen with dopaminergic agents.It's a bit puzzling that a GABA-ergic drug would work for this condition. But benzodiazepines are often used with decent utility for restless legs. And if pregabalin works, maybe the much less expensive, noncontrolled, neurochemically similar drug gabapentin might be worth a try. That would be off label, of course, but for someone suffering with severe restless leg syndrome and limited response or intolerance of usual drugs, I'd consider it.— Karl Steinberg, MD, CMDEditor in Chief Looks like Lyrica will be seeking Food and Drug Administration approval for restless leg syndrome, and it looks like it works reasonably well, with a different set of side effects from those seen with dopaminergic agents. It's a bit puzzling that a GABA-ergic drug would work for this condition. But benzodiazepines are often used with decent utility for restless legs. And if pregabalin works, maybe the much less expensive, noncontrolled, neurochemically similar drug gabapentin might be worth a try. That would be off label, of course, but for someone suffering with severe restless leg syndrome and limited response or intolerance of usual drugs, I'd consider it. — Karl Steinberg, MD, CMD Editor in Chief