Comparison of Pregabalin with Pramipexole for Restless Legs Syndrome

Article Citation

Allen R, et al. “Comparison of Pregabalin with Pramipexole for Restless Legs Syndrome” . The New England Journal of Medicine. 2014. 370(7):621-631

Clinical Question

In patients with restless leg syndrome, is pregabalin as, or more effective for symptom improvement such as urge to move the legs, quality of sleep, and reduction in IRLS score as compared to pramipexole?

Bottom Line

In patients with restless leg syndrome pregabalin is preferred over pramipexole to reduce the urge to move the legs, increase quality of sleep, and in reducing total IRLS score.

Major Points

Restless leg syndrome is a condition that causes the nocturnal urge to move the legs disrupting sleep and impacts quality of life. Usually, this condition requires treatment for over the course of the patient's life. This treatment is often short acting dopamine agonist such as pramipexole and ropinirole, however in patients treated with these drugs RLS can worsen over the lifetime.

In 2014 a randomized double blinded trial was conducted to compare the current treatment of pramipexole to pregabalin, an alpha-2 anticonvulsant agent. A total of 719 patients were randomized at 102 centers within the United States and Europe. Over a period of twelve weeks, patients taking pregabalin,both 0.25mg and 0.5mg of pramipexole, and placebo were analyzed for a reduction in the International RLS study group rating scale scores (0-40, 0 indicating little or no symptoms) as well as a reduction in CGI-I scores. Pregabalin showed a statistically significant reduction in IRLS scores in comparison to 0.25mg pramipexole after 52 weeks. The study also showed that pregabalin provided improved secondary treatment outcomes when compared to a placebo or pramipexole and pregabalin also significantly lowered augmentation rates.

Guidelines

As of November 2016, there is an indication within the guidelines from the American Academy of Neurology indicating this trial provides insufficient evidence. Currently, pramipexole is still considered a first line treatment in preventing Restless leg syndrome symptoms, however pregabalin is shown to have a moderate level of evidence backing for symptom improvement.

Design

• Multicenter/national, randomized, double blinded, placebo-controlled
• N=719 RLS patients randomized
  • Pramipexole 0.25mg (n=178)
  • Pramipexole 0.5 mg (n=180)
  • Pregabalin 300 mg (n=182)
  • Standard control (n= 179 placebo patients for 12 weeks, then re-randomized to get one of the three above treatments)
• Setting: 102 sites across the United States and Europe
• Enrollment: December 2008 - June 2011
• Follow-up: Every 2-4 weeks for the duration of the trial (52 weeks from start of treatment)
• Analysis: Intention-to-treat
• Primary Outcome: Reduction of RLS symptoms measured by the IRLS Rating Scale and the Clinical Global Impression of Improvement

Population

Inclusion Criteria

• Adults. Age 18 years or older.
• Idiopathic RLS with the presence of all four clinical manifestations of RLS

• RLS symptoms must occur predominantly in the evening (between the hours of 17:00 to 07:00).
• A history or the presence of RLS symptoms for at least 6 months.
• An International Restless Leg Scale (IRLS) total score ≥15 at beginning of placebo run-in (1 week prior to Baseline) and end of ::placebo run-in (Baseline).
• Have ≥15 nights with RLS symptoms in the month prior to Screening. Subjects receiving RLS therapy at the time of Screening are to :: have had ≥15 nights per month with RLS symptoms prior to initiation of this treatment. Have ≥2 nights with RLS symptoms during the :: week of placebo run-in.

Exclusion Criteria

This trial excluded any adult with RLS secondary to other conditions, such as end stage renal disease or iron-deficiency anemia, or any other serious health conditions not related to RLS. In addition patients who had current augmentation due to RLS treatments, or pramipexole-caused clinically significant augmentation within 6 weeks of the screening visit, any symptomatic neuropathies, or employment that caused a change in circadian rhythm were also excluded.

Baseline Characteristics

There were no significant differences among the study groups at baseline based on sex, age, BMI, and interval since RLS onset.

Pregabalin

Sex

• Female: 123
• Male: 59

Age

• Range: 20-79
• Mean: 54.3

BMI

• Range: 18.8- 49.5
• Mean: 28

Interval Since RLS onset (years)

• Range: 0-52.5
• Mean: 5

0.25 mg Pramipexole

Sex

• Female: 108
• Male: 70

Age

• Range: 25-82
• Mean: 56.5

BMI

• Range: 19.5- 43.5
• Mean: 28.6

Interval Since RLS onset (years)

• Range: 0-35.1
• Mean: 4

0.5 mg Pramipexole

Sex

• Female: 99
• Male: 81

Age

• Range: 24-80
• Mean: 54.2

BMI

• Range: 18.8- 49.6
• Mean: 28.2

Interval Since RLS onset (years)

• Range: 0-47.9
• Mean: 4.9

Placebo

Sex

• Female: 111
• Male: 68

Age

• Range: 19-79
• Mean: 53.5

BMI

• Range: 18.5- 49.2
• Mean: 28.4

Interval Since RLS onset (years)

• Range: 0-35.1
• Mean: 5.9

Interventions

Randomization to pramipexole, pregabalin, and placebo

• 0.25mg pramipexole per day
• 0.5 mg pramipexole per day
• 300 mg pregabalin per day

• All medication forms were identical in appearance

• Patients receiving placebo were randomly assigned to one of the three active treatments after week 12
• Medication doses were increased over the first 2 weeks to fixed dose
• Prior to randomization, patient discontinued all RLS therapy for at least 1 week or five half-lives. Followed by 1 week single-blinded placebo run in.

• All patients had discontinued RLS therapy for at least 2 weeks prior to trial
• Medications administered PO 1-3 hours prior to bedtime
• Patients visits were scheduled at week 2,6,10,12, and 14 of treatment and monthly until week 52
• Patients documented symptoms daily for one week following each visit
• Trial lasted 52 weeks

Outcomes

Primary Outcomes

Reduction in IRLS Score: (Baseline vs. 12 weeks)

Pregabalin

• P<0.001
• Improvement in score: 22.3 vs. 10.9 (11.4 difference)
• Mean change from baseline vs. Placebo: -4.5
• -5.9 - -3.2 (95% CI)

0.25 mg Pramipexole

• P=0.36
• Improvement in scores: 22.4 vs. 14.6 (7.8 difference)
• Mean change from baseline vs. Placebo: -0.6
• -2.0 - 0.7 (95% CI)

0.5 mg Pramipexole

• P<0.001
• Improvement in scores: 22.1 vs. 12.0 (10.1 difference)
• Mean change from baseline vs. Placebo: -3.2
• -4.5 - -1.9 (95% CI)

Pregalbalin vs. 0.25mg Pramipexole

• P<0.001
• Improvement in score: 71.4% vs. 51.2% (20.2% difference)
• -4.0 - -2.8 (97.5% CI)
• NNT=5

Pregalbalin vs. 0.5mg Pramipexole

• P=0.08
• Improvement in score: 71.4% vs. 62.7% (8.7% difference)
• -1.7 - -0.5 (97.5% CI)

CGI-I Rating for symptom improvement

At 12 weeks:

Placebo vs. Pregabalin

• P<0.001
• Improvement in score: 46.8% vs. 71.4% (24.6% difference)
• NNT= 4

Placebo vs. 0.25mg Pramipexole

• P=0.439
• Improvement in scores: 46.8% vs. 51.2% (4.4% difference)

Placebo vs. 0.5mg Pramipexole

• P=0.002
• Improvement in score: 46.8% vs. 62.7% (15.9% difference)
• NNT= 6

At 52 weeks:

Pregalbalin vs. 0.25mg Pramipexole

• P<0.001
• Improvement in score: Not provided
• -3.8 - -2.7 (97.5% CI)

Pregalbalin vs. 0.5mg Pramipexole

• P=0.36
• Improvement in score: Not provided
• -3.1 - -2.0 (97.5% CI)

Secondary Outcomes

Lower rate of Augmentation (Worsening of RLS)

Overall:

Pregabalin vs. 0.25mg Pramipexole

• P=0.08
• 5/235 (2.1%) vs. 12/225 (5.3%)

Pregabalin vs. 0.5mg Pramipexole

• P=0.001
• 5/235 (2.1%) vs. 18/235 (7.7%)
• NNH= 18

Limb Pain

At 12 weeks: ( visual analogue scale)

Placebo vs. Pregabalin

• 3.3 vs 2.3
• Mean change from baseline -1.0
• -1.6 - -0.5 (95% CI)

Placebo vs.0.25mg Pramipexole

• 3.3 vs 3.1
• Mean change from baseline -0.43
• -1.0 - 0.1 (95% CI)

Placebo vs. 0.5mg Pramipexole

• 3.3 vs. 2.9
• Mean change from baseline -0.55
• -1.1 - 0.0 (95% CI)

Quality of Life

At 12 weeks:

Placebo vs. Pregabalin

• 73.2 vs 77.8
• Mean change from baseline 3.9
• 1.9 - 5.8 (95% CI)

Placebo vs.0.25mg Pramipexole

• 73.2 vs 73.3
• Mean change from baseline 0.5
• -1.5 - 2.4 (95% CI)

Placebo vs. 0.5mg Pramipexole

• 73.2 vs. 75.5
• Mean change from baseline 2.1
• 0.1 - 4.1 (95%CI)

Sleep Assessments

At 12 weeks:

Placebo vs. Pregabalin

• 52 vs 42.5
• Mean change from baseline -17.2
• -25.8 - -8.7 (95% CI)

Placebo vs.0.25mg Pramipexole

• 52 vs 62
• Mean change from baseline -1.1
• -9.7 - 7.6 (95% CI)

Placebo vs. 0.5mg Pramipexole

• 52 vs. 50.3
• Mean change from baseline -4.6
• -13.1 - -3.9 (95% CI)

Adverse Events

The majority of adverse events were mild to moderate in severity

50 serious adverse events were reported in 37 patients

• 11 were in patients receiving pregabalin
• 20 in patients receiving 0.25mg pramipexole
• 12 in patients receiving 0.5 mg pramipexole
• 5 in patients who switched from placebo to pregabalin
• 2 in those who switched from placebo to 0.25mg pramipexole

Percentages of patients who discontinued therapy due to adverse effects

• 18.5% for 0.25mg pramipexole
• 23.9% for 0.5mg pramipexole
• 27.5% for pregabalin
• Common reasons for discontinuation
• Dizziness
• Somnolence

The most common adverse effects for pramipexole:

• Nausea
• Headache
• Fatigue

The most common adverse effects for pregabalin:

• Dizziness
• Somnolence
• Fatigue
• Headache.

Criticisms

• Pfizer is the drug company that creates and owns the patent for the drug Lyrica (pregabalin).
• The authors had edited drafts with the assistance of a medical writer paid by Pfizer, and made the final decision to submit the :manuscript for the publication.
• Authors were involved in both study designs and results (review board consisted of 3 experts, all authors of the articles)
• The study only studied one strength of pregabalin (highest available strength).
• A major issue with this journal article was the major involvement of the drug company Pfizer, who produces the brand name pregabalin, :Lyrica. At the time of this study and until June of 2019 Lyrica will remain the only available pregabalin product on the market.

Funding

This article is supported and funded by Pfizer.