1.  RLS augmentation during long term treatment. Richard P Allen, PhD, DABSM Johns Hopkins Univ.

2. What do we know about augmentation What is augmentation Biological/theoretical considerations Clinical identification - criteria Why controversy Drug differences Dose considerations Time course: data needed over 5 - 10 years Significance- Why important Severe discomfort Limits dopamine treatment Actions Limit use of offending Rx Find Treatments to reduce or avoid augmentation

3. Discovery of dopamine treatment for RLS Akpinar S. Treatment of restless legs syndrome with levodopa plus benserazide. Arch Neurol 1982, 39:739. Also Montplaisir Clin Neuropharmacol 1986, 9:456

4. Low dose dopamine (Sinemet) more effective treatment than moderate dose opioid (propoxyphene) for treatment of PLMS and RLS Allen, et al, 1992

5. Recognition of augmentation with longer term treatment Levodopa dramatic relief to severely affected RLS patients seemed 100% effective in all RLS- 1986 - 1990: JHU using levodopa observed ‘time-shift’ in RLS symptoms to earlier in the day 1990: 2-year follow up study reported no problems with levodopa treatment of RLS for 26 of 30 patients (von Scheele C & Kempi V, Arch Neurol 47:1223-4, 1990) 1989-1995: JHU observed dramatic ‘augmentation’ cases 1996: Reported augmentation for about 80% of all RLS cases and offered 1st definition of augmentation (Allen R & Earley C, Sleep 19:205-13, 1996) 2003: NIH consensus workshop produced an operational definition of augmentation 2006:Munich consensus conference Improved dx criteria

6. Augmentation Concept Biological definition Drug treatment made a major aspect of the RLS disease process worse. Not a result of change in metabolism of treatment medication Not treatment medication failing to reduce RLS symptoms The Disorder is worse NOT the Rx less effective

7. Augmentation: RLS is worse with Rx treatment Disorder worse - requires All RLS symptoms become worse Augmentation symptom development follows the natural history of symptom progression Rx caused, not natural progression of RLS - requires Rate of progression of Sx faster than occurs naturally RLS symptoms less after withdrawal of Rx Rx caused, not change in life style, medical status or non-RLS Rx Occurs under conditions controlled for activity and alertness In theory would be revealed by repeated SIT tests

8. Clinical Features of Augmentation Compared to status just before treatment 1. Earlier onset of symptoms (AM ‘protected period’ less involved) 2. Shorter rest time to provoke symptoms 3. Increased intensity of symptoms 4. Involvement of more of the body (Usually arms but occasionally trunk) 5. Time course: treatment benefit slower and shorter 6. Degree of severity and stability: severe vs mild, continuing vs stable

9. One week in the life of an RLS patient

10. % of Augmentation by characteristics and % rebound for 30 patients treated with carbidopa/levodopa 0.00% 10.00% 20.00% 30.00% 40.00% 50.00% 60.00% 70.00% 80.00% Earlier onset Increased intensity Quicker rest onsetOther limbsAll AugmentationAM rebound Characteristics (Allen and Earley, Sleep, 1996)

11. NIH Consensus Workshop 2003 Operational definition of augmentation Earlier onset (>= 2 hours) Or two of the following 1.Intensity increase with increasing dose 2.Decreased intensity with decreasing dose 3.Shorter rest time to provoke symptoms than before Rx 4.RLS Sx occur in previously unaffected limbs or body parts 5.Shorter duration of Rx benefit than with initial treatment 6.PLMS or PLMW occur for the first time or are worse than either before treatment or after initial treatment

12. ROC: agumentation vs hours of symptom advance

13. Updated augmentation dx Max-Planck 2007 Compared to before treatment: Either A or B: A. Earlier onset of symtptoms with 1. Earlier by at least 4 hrs or 2. Earlier onset of any duration with one of the following (compared to before tx): A. Shorter latency to symptoms when at rest B. Expansion to other body parts C. Greater intensity of symptoms D. Shorter duration of relief from treatment

14. Clinical Relevance I: Clinically significant augmentation At least one of the following occurs: Change in daily activities and/or behavior (e.g. the patient stops riding in cars in the afternoon); Negative impact on the patient’s quality of life (sleep, mood, etc.); Need to change the treatment dose or the patient needs to take the dose earlier in the day (e.g., dividing the dose); Adjustments in concomitant medication are made to compensate for augmented RLS symptoms (e.g., an increased intake of analgesics or hypnotics to cover an increase in symptom intensity); Any other aspect as judged by the evaluator (should be specified). II: Not clinically significant augmentation None of the above mentioned criteria (a-e) are met.

15. What do we know about augmentation What is augmentation Biological/theoretical considerations Clinical identification - criteria Why controversy Drug differences Dose considerations Time course: data needed over 5 - 10 years Clinical significance (why important) Why important Severe discomfort Limits dopamine treatment Actions Limit use of offending Rx Find Treatments to reduce or avoid augmentation

16. 0% 10% 20% 30% 40% 50% 60% 70% 80% 90% 100% AllSevereMild- Moderate carbidopa/levodopa pergolide Percentage of Patients with RLS Augmentation for each medication by RLS severity.

17. Medication type All dopaminergic medications Levodopa 50 - 80% rate Dopamine agonsits 9 - 35% rate Tramadol Limited clinical series45% rate Not reported for other RLS medications Gabapentin Oxycodone, hydrocodone Methadone

18. Rates and presentation by increasing Half-life 1. Earlier time of onset of symptoms 2. Reduced latency to symptoms at rest 3. Increased severity/decreased therapeutic effect at stable dose 4. Expansion of symptoms to upper limbs L-DOPA% Becker, 199336.21 Early, 1996691-4, being 1 the principal Trenkwalder, 200352%1, 3 Garcia-Boreguero, 200549-78,4% NIH, ASRS PRAMIPEXOLE: Montplaisir, 200001 Ferini-Strambi, 20018,8not specified Silber, 2003331 or 3 Winkelmann, 2004561, 3, 4 PERGOLIDE: Silber, 1997271 or 3 Stiasny, 200127,31 Early, 1996151-4, being 1 the principal Trenkwalder, 20040(1, 3) not specif. CABERGOLINE: Benes, 200431-4 Stiasny, 200491-4

19. % Augmentation for 30 RLS patients treated with carbidopa/levodopa by RLS severity and dose Carbidopa/levodopa dose 0.00% 10.00% 20.00% 30.00% 40.00% 50.00% 60.00% 70.00% 80.00% 90.00% 100.00% low <50/200High ≥50/200

20. Dose of levodopa and Augmentation with <= 6 months of treatment n% (of 49) 100 mg 0% 200 mg 14.3% 300 mg 50% 400 mg 28.6% 500 mg 7.1% Aver. dose: 329.81 + 105mg 85.7% of patients with AUG received dosages ≥ 300 mg/day! mg The only dose free of augmentation was 100 mg

21. Development of Augmentation Over 1 - 3 years (but data limited beyond 2 years) Pts without augmentation (%) (Silber et al., 2003) Months

22. What do we know about augmentation What is augmentation Biological/theoretical considerations Clinical identification - criteria Why controversy Drug differences Dose considerations Time course: data needed over 5 - 10 years Clinical significance (why important) Why important Severe discomfort Limits dopamine treatment Actions Limit use of offending Rx Find Treatments to reduce or avoid augmentation

23. Examples of severe augmentation

24. Mirapex 10-year survival curve

25. Percentage continuing on treatment discontinuing treatment each year ( 5 - 10 year follow-up) Mostly due to augmentation Note from year 2 on 90 - 100% discontinued Rx due to augmentation

26. Augmentation persists when dose is increased to maintain efficacy.

27. What do we know about augmentation What is augmentation Biological/theoretical considerations Clinical identification - criteria Why controversy Drug differences Dose considerations Time course: data needed over 5 - 10 years Why important Severe discomfort Limits dopamine treatment Actions Limit use of offending Rx Find Treatments to reduce or avoid augmentation

28. Minimize augmentation risk: Limit use of offending Rx L-dopa - risk:benefit consideration Use only for intermittent treatment ( <2 days/week) Increasing dose or the times covered by the dose delays but does not prevent augmentation Very long term use of very long acting DA not known Very long term consequences are unknown BUT Appears always reversible with d/c Rx Recovery after d/c Rx may take 4 or more days some cases may take much longer (2 weeks+)

29. Treatments to reduceAugmentation Low dose dopamine agonist Longer acting dopamine agonist? Low serum ferritin may contribute Consider oral or IV iron treatment ?

30. Treatments to avoid augmentation Alpha-2 delta Rx Gabapentin Gabapentin pro-drug Pregabalin Opioids and Morphine Short-acting oxycodone, hydrocodone, propoxyphene codeine Long-acting Methadone Alternate dopaminergics ?

31. Future needs Methods for clinical evaluation and early detection of RLS augmentation Afternoon SIT test Electronic diary Structured clinical interview Severity assessment Research on mechanisms of augmentation Animal analogs - effects of chronic DA use Theoretical models that can be tested

32. PLW/hr on Afternoon SIT after placebo for patients on dopaminergic Rx ConditionPLMW/hr mean ±sd Normal at NIGHT 9.0 ± 21.7 RLS not treated Night53.3 ± 62.8 (Michaud et al, Eur Neurol, 2002) Placebo for DA RLS afternoon95.3 ± 88.5 (Allen et al, abstract SfN 2008) DiphenhydramineLorazepam Cell Placebo Cell Mean Error Bars: ± 1 Standard Error(s)

33. ASRS validation study Validity Internal consistency: Cronbach`s alpha: 0,506 Internal consistency: Cronbach`s alpha: 0,506 Convergent validity: 0,23 (item 2) to 0,87 (item 1) Convergent validity: 0,23 (item 2) to 0,87 (item 1) Criterion validity: 0,59 Criterion validity: 0,59 Discriminant validity: 0,04+0,6 vs. 2,1+1,1 Discriminant validity: 0,04+0,6 vs. 2,1+1,1Reliability Inter-rater:0,906 + 0,05 Inter-rater:0,906 + 0,05 Test-retest:0,734 + 0,09 Test-retest:0,734 + 0,09

34. When is the ASRS total score clinically relevant?

35. L-dopa trial distribution of ASRS scores (Garcia-Borreguero et al Sleep med 2007) White bars: patients without augmentation, black bars: patients with definite augmentation according to experts. Range of the ASRS total score: 0 to 24

36. Augmentation is under-recognized Marvin has 4 limbs affected Intense symptoms All night - no relief Marvin severe augmentation? Maybe Marvin had too much Dopamine treatment