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#275 A good sleep would be dop(aminergic) doc! Pramipexole in restless legs syndrome


CLINICAL QUESTION
Is pramipexole effective for the treatment of restless legs syndrome (RLS)?

BOTTOM LINE
Systematic review of twelve randomized controlled trials demonstrates 63% of patients using pramipexole report feeling much or very much better compared to 41% on placebo over 3-26 weeks. Lower doses (example 0.25/0.5mg) may have equivalent efficacy to higher doses with less risk of augmentation (paradoxical worsening of symptoms with treatment), although up to ~40% of patients may experience augmentation after 1 year.  


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EVIDENCE
Systematic review 12 randomized, controlled trials (RCTs), 3286 patients, average age 49-58 years, pramipexole 0.125 - 1.5mg/d versus placebo for 3 - 26 weeks.1 
  • Pramipexole significantly increased proportion of patients reporting: 
    • Improved symptoms (“very much better” or “much better”): 
      • 63% versus 41%; number needed to treat (NNT)=5. 
    • ≥50% reduction in International Restless Leg Score (IRLS): 
      • 62% versus 38%, NNT=5. 
Five RCTs report pramipexole dosing comparisons. 
  • Multiple outcomes assessed.2-6 
    • Patient Global Impression Improvement (“much or very much better”) at 3-6 weeks with:2,4 
      • 0.25mg: 73%, 
      • 0.5mg: 77-79%, 
      • 0.75mg: 57%-68%. 
Adverse events: 
  • Meta-analyzed by PEER, statistically significant increase versus placebo at 3-26 weeks for: 
    • Nausea: 8 RCTs, 2050 patients:2,7-13 
      • Pramipexole 14% versus placebo 5%, number needed to harm (NNH)=13. 
    • Fatigue: 6 RCTs, 1596 patients:2,7,8,10,11,13 
      • Pramipexole 10% versus placebo 6%, NNH=23. 
    • No statistically significant increase in dizziness, somnolence or headache compared to placebo.
Context: 
  • Non-pharmacologic treatment options should be tried first. Limited evidence supports options such as exercise, standard acupuncture, and compression devices.14 
  • If ferritin <50-75ug/L, iron supplementation may be beneficial.15,16 
  • Other dopaminergic drugs (example ropinirole) have demonstrated similar efficacy.15 
  • Augmentation may be difficult to identify (example a patient stable for 6 months asks for more medication).16 Risk increases with higher doses of pramipexole16 and duration of treatment:16-18 
    • <1 year: up to 8%, 
    • ≥1 year: up to 42%. 
  • Management of augmentation includes: Modified dosing (example split or earlier dose), alternate pharmacotherapies (example pregabalin or gabapentin), and minimizing exacerbating drugs (examples antihistamines, dopamine-receptor blockers, or serotonergic antidepressants).3,16 

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Author(s):

  • Christina Korownyk MD CCFP
  • Michael Wollin BSc
  • Rodger Craig MPH

1. Liu GJ, Wu L, Lin Wang S, et al. Clin Ther. 2016; 38(1):162-179.e6.

2. Partinen M, Hirvonen K, Jama L, et al. Sleep Med. 2006; 7(5):407-417.

3. Allen RP, Chen C, Garcia-Borreguero D, et al. N Engl J Med. 2014; 370(7):621-631.

4. Inoue Y, Kuroda K, Hirata K, et al. Neuropsychobiology. 2011; 63(1):35-42

5. Winkelman JW, Sethi KD, Kushida CA, et al. Neurology. 2006; 67(6):1034-1039.

6. Jama L, Hirvonen K, Partinen M, et al. Sleep Med. 2009; 10(6):630-636.

7. Ferini-Strambi L, Aarskog D, Partinen M, et al. Sleep Med. 2008; 9:874-881.

8. Hogl B, Garcia-Borreguero D, Trenkwalder C, et al. Sleep Med. 2011; 12:351-360.

9. Ma JF, Wan Q, Hu XY, et al. Sleep Med. 2012; 13:58-63.

10. Montagna P, Hornyak M, Ulfberg J, et al. Sleep Med. 2011; 12:34-40.

11. Inoue Y, Hirata K, Kuroda K, et al. Sleep Med. 2010; 11:11-16

12. Garcia-Borreguero D, Patrick J, DuBrava S, et al. Sleep. 2014; 37:635-643.

13. Oertel WH, Stiasny-Kolster K, Bergtholdt B, et al. Mov Disord. 2007; 22:213-219.

14. Harrison EG, Keating JL, Morgan PE. Disabil Rehabil. 2019; 41(17):2006-2014.

15. Winkelmann J, Allen RP, Högl B, et al. Mov Disord. 2018; 33(7):1077-1091.

16. Garcia-Borreguero D, Silber MH, Winkelman JW et al. Sleep Med. 2016; 21:1-11.

17. Lipford MC, Silber MH. Sleep Med. 2012; 13(10):1280-5.

18. Allen RP, Ondo WG, Ball E, Calloway, et al. Sleep Med. 2011; 12(5):431-9.

Authors do not have any conflicts of interest to declare.