Oral pregabalin significantly improved symptoms of moderate to severe restless leg syndrome, compared with both placebo and pramipexole, in an industry-sponsored, international randomized trial.

Just as important, pregabalin was associated with significantly less iatrogenic worsening, or augmentation, of symptoms than was pramipexole, Richard P. Allen, Ph.D., of the department of neurology at Johns Hopkins University, Baltimore, and his associates reported Feb. 12 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, and was recently reported to be effective against restless leg syndrome.

Dr. Allen and his colleagues assessed both agents in a study involving 719 adults with moderate to severe primary restless leg syndrome who were treated and followed at 102 medical centers in the United States and Europe. The patients did not undergo an objective assessment of sleep.

In the double-blind trial sponsored by Pfizer, the manufacturer of pregabalin, 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. The mean age of the patients ranged from 54 to 57 years in the groups, and 32%-45% in each group were men.

Periodically, the study participants reviewed with clinicians their daily symptom logs and completed the International RLS (IRLS) Study Group Rating Scale, which measures subjective symptom severity on a 0-40 scale, with higher scores indicating worse symptoms. They also reported on limb pain, sleep quality and quantity, and quality of life.

Clinicians also objectively assessed patients’ symptoms using the Clinical Global Impression of Improvement (CGI-I) scale, and they assessed possible augmentation using their clinical judgment, scores on the Augmentation Severity Rating Scale, and scores on the Structured Interview for the Diagnosis of Augmentation instrument.

At 12 weeks, patients who received pregabalin showed significantly greater improvement in IRLS scores than did those who received placebo, improving from 22.3 to 10.9 for pregabalin-treated patients and from 22.4 to 15.5 for placebo-treated patients. Pregabalin-treated patients also were more likely to have "very much improved" or "much improved" ratings on the CGI-I, compared with placebo (71.4% vs 46.8%).

Patients who received pregabalin also reported greater improvement in several sleep parameters, including waking after sleep onset, quality of sleep, number of nightly awakenings, and total sleep time, compared with those who received placebo. 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 Feb. 12 [doi:10.1056/NEJMoa1303646]).

Pregabalin was associated with significantly less augmentation than the 0.5-mg dose of pramipexole, but not the 0.25-mg dose. "Among patients receiving active treatment over the entire 52-week study period, augmentation occurred in 3 of 176 patients receiving pregabalin (1.7%), 11 of 167 receiving 0.25 mg of pramipexole (6.6%), and 16 of 178 receiving 0.5 mg of pramipexole (9.0%)," the investigators wrote.

Augmentation occurred more often among patients on higher-dose pramipexole than in those on the lower dose. Longer exposure to the medication also raised augmentation rates. "For participants who received active therapy for the full 52 weeks of the study (not 40 weeks), augmentation rarely occurred until the second half of the study," they wrote.

The rate of discontinuing the study because of adverse events was higher for the patients receiving pregabalin (27.5%) than for those receiving pramipexole at either the lower dose (18.5%) or higher dose (23.9%).

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.

Dr. Allen reported ties to Pfizer, UCB Pharma, Impax Pharmaceuticals, Luitpold Pharma, Xenoport, GlaxoSmithKline, and Pharmacosmos. His associates reported ties to Pfizer and numerous industry sources. Four authors are employees of Pfizer.

Pregabalin improves restless leg syndrome with less symptom augmentation