The Prevention & Treatment of

Augmentation

M A R K J B U C H F U H RE R, M D

STANFORD UNIVERSITY SLEEP MEDICINE CENTER, REDWOOD CITY, CA

PRIVATE PRACTICE, DOWNEY, CA

©2017
What is Augmentation?
A worsening of RLS after an initial improvement with a dopamine
medication
◦ Levodopa (Sinemet)
◦ Pramipexole (Mirapex)
◦ Ropinirole (Requip)
◦ Rotigotine (Neupro patch)
◦ Cabergoline (Dostinex)
What is Augmentation?
A worsening of RLS after an initial
improvement with a dopamine medication

Also occurs with tramadol (Ultram)

◦ Pain pill related to opioids
When was Augmentation first
described?
Richard Allen – 1996
◦ “Augmentation of the restless legs syndrome with carbidopa/levodopa.”
◦ Occurred in 82% of RLS patients
◦ Worse with higher doses
◦ Resolved by stopping or decreasing the medication
 Augmentation – NIH Criteria
Worsening RLS symptoms after starting DA therapy (usually months
to years)
o Earlier onset by at least 2 hours
o Increase in intensity of symptoms
o Quicker onset of symptoms with rest
o Medication effect does not last as long
o Spread of symptoms to other body parts
o PLMW occur for the first time or are worse

Allen RP, Picchietti D, Hening WA, Trenkwalder C, Walters AS, Montplaisi J. Restless legs syndrome: diagnostic criteria, special considerations,
and epidemiology. Sleep Med 2003;4:101–19.
 Simplified Version
Consider that augmentation may be present whenever a patient
who has been on stable treatment for at least 6 months requests
more medication.
Rule out:
◦ Triggers
◦ Low iron
◦ Natural worsening

Garcia-Borreguero D1, Silber MH2, Winkelman JW3, Högl B4, Bainbridge J5, Buchfuhrer M6, Hadjigeorgiou G7, Inoue Y8, Manconi M9, Oertel W10, Ondo W11, Winkelmann J12, Allen
RP13. Guidelines for the first-line treatment of restless legs syndrome/Willis-Ekbom disease, prevention and treatment of dopaminergic augmentation: a combined task force of the
IRLSSG, EURLSSG, and the RLS-foundation. Sleep Med. 2016 May;21:1-11.
 Rule out other similar conditions

Garcia-Borreguero D1, Silber MH2, Winkelman JW3, Högl B4, Bainbridge J5, Buchfuhrer M6, Hadjigeorgiou G7, Inoue Y8, Manconi M9, Oertel W10, Ondo W11, Winkelmann J12, Allen
RP13. Guidelines for the first-line treatment of restless legs syndrome/Willis-Ekbom disease, prevention and treatment of dopaminergic augmentation: a combined task force of the
IRLSSG, EURLSSG, and the RLS-foundation. Sleep Med. 2016 May;21:1-11.
What is causing Augmentation?
Downregulation of the dopamine receptor?
◦ Similar to tolerance

Imbalance of Dopamine Receptor Subtypes

◦ D1, D2, D3, D4, D5

Early signs of changes in RLS with DA

How common is Augmentation?
Levodopa – 82%

Mirapex – 7-8%/year

Neupro – 5% after 5 years with 1-3 mg

◦ Less common with longer-acting DA?

Over 75% of referrals to national RLS experts

 Recommended Dopamine Drug
Doses

Garcia-Borreguero D1, Silber MH2, Winkelman JW3, Högl B4, Bainbridge J5, Buchfuhrer M6, Hadjigeorgiou G7, Inoue Y8, Manconi M9, Oertel W10, Ondo W11, Winkelmann J12, Allen
RP13. Guidelines for the first-line treatment of restless legs syndrome/Willis-Ekbom disease, prevention and treatment of dopaminergic augmentation: a combined task force of the
IRLSSG, EURLSSG, and the RLS-foundation. Sleep Med. 2016 May;21:1-11.
How do most doctors & specialists
treat Augmentation?
Typically, they increase the dose of the dopamine drug which
provides temporary improvement
◦ Mirapex up to 8 mg
◦ Ropinirole up to 24-48 mg
◦ Neupro up to 8-16 mg (often combined with other DA)
◦ Add gabapentin (alpha-2-delta) type drugs
 Task Force Article

Garcia-Borreguero D1, Silber MH2, Winkelman JW3, Högl B4, Bainbridge J5, Buchfuhrer M6, Hadjigeorgiou G7, Inoue Y8, Manconi M9, Oertel W10, Ondo W11, Winkelmann J12, Allen RP13. Guidelines for the
first-line treatment of restless legs syndrome/Willis-Ekbom disease, prevention and treatment of dopaminergic augmentation: a combined task force of the IRLSSG, EURLSSG, and the RLS-foundation. Sleep
Med. 2016 May;21:1-11.
 Prevention of Augmentation
Do not use dopamine drugs
Choose an alpha-2-delta drug as first line therapy unless
contraindicated, side effects occur or they are not effective

Garcia-Borreguero D1, Silber MH2, Winkelman JW3, Högl B4, Bainbridge J5, Buchfuhrer M6, Hadjigeorgiou G7, Inoue Y8, Manconi M9, Oertel W10, Ondo W11, Winkelmann J12, Allen
RP13. Guidelines for the first-line treatment of restless legs syndrome/Willis-Ekbom disease, prevention and treatment of dopaminergic augmentation: a combined task force of the
IRLSSG, EURLSSG, and the RLS-foundation. Sleep Med. 2016 May;21:1-11.
 Prevention of Augmentation
When using dopamine drugs
◦ Use the lowest possible dose (but may occur with the lowest dose)
◦ Consider intermittent use (up to 3/week)
◦ Do not increase the dose more than once
◦ Do not change to another short-acting DA
◦ Consider using longer acting DA – Neupro
Keep ferritin levels as high as possible

Garcia-Borreguero D1, Silber MH2, Winkelman JW3, Högl B4, Bainbridge J5, Buchfuhrer M6, Hadjigeorgiou G7, Inoue Y8, Manconi M9, Oertel W10, Ondo W11, Winkelmann J12, Allen
RP13. Guidelines for the first-line treatment of restless legs syndrome/Willis-Ekbom disease, prevention and treatment of dopaminergic augmentation: a combined task force of the
IRLSSG, EURLSSG, and the RLS-foundation. Sleep Med. 2016 May;21:1-11.
 Approved Dopamine Drug Doses

Garcia-Borreguero D1, Silber MH2, Winkelman JW3, Högl B4, Bainbridge J5, Buchfuhrer M6, Hadjigeorgiou G7, Inoue Y8, Manconi M9, Oertel W10, Ondo W11, Winkelmann J12, Allen
RP13. Guidelines for the first-line treatment of restless legs syndrome/Willis-Ekbom disease, prevention and treatment of dopaminergic augmentation: a combined task force of the
IRLSSG, EURLSSG, and the RLS-foundation. Sleep Med. 2016 May;21:1-11.
 Dr. Buchfuhrer’s Maximum Dopamine
Drug Doses
Pramipexole (Mirapex) .25 mg

Ropinirole (Requip) 1 mg

Rotigotine (Neupro) 3 mg
 Augmentation Treatment Algorithm

Eliminate exacerbating factors

(serum ferritin < 50-75 μg/mL], lifestyle changes, exacerbating drugs)

Mild augmentation (all of the below) Severe augmentation

1. Temporal shift mainly 1. Not mild, OR
2. Dopaminergic dose is ≤ maximum recommended dose 2. Does not respond to treatment for mild augmentation
3. Symptoms cause mild distress
4. There has been no prior increase in dose above what
was previously therapeutically effective The objective is to reduce, and, if possible eliminate the short acting
dopamine agonist and to begin treatment with rotigotine or a long acting
dopamine agonist or an α2δ ligand
Keep the same OR Complete switch Two strategies are available for doing this:
dopamine agonist to one of the options
below OR OR
Cross titration Switch 10-day washout
Add an alpha-2-delta Switch patient from
One of the below two An α2δ calcium-channel
ligand and then a short-acting
options: ligand Evaluate if any drug
gradually reduce the dopamine agonist to
1. Split with same dose; treatment is
dose of the dopamine rotigotine or a
2. Advance the dose OR agonist with the long-acting needed.
earlier. If symptoms
objective of eliminating dopamine
If options 1 and 2 fail Rotigotine or a long-acting continue, introduce
it altogether, agonist if this is not
consider increasing the dopamine agonist at an α2δ ligand or
understanding that this already the case.
dose but keeping it at/ ≤ approved dose an opioid
may not be possible in
below approved daily dose
all cases

If this strategy fails If this strategy fails

consider a complete consider “severe • If these strategies fail or if the patient has severe, round-the-clock
switch of medication augmentation” options symptoms, then treatment with low doses of an opioid (long-acting
oxycodone or methadone) should be considered.
• If serum ferritin < 50-75 μg/mL then treatment with intravenous iron,
according to availability, should be strongly considered.

Garcia-Borreguero D. et al. Available at: http://irlssg.org/wp-content/uploads/2015/05/Summary-of-recommendations-RLS-Augmentation-May-2015.pdf

 Augmentation Treatment Algorithm

Eliminate exacerbating factors

(serum ferritin < 50-75 μg/mL], lifestyle changes, exacerbating drugs)

Garcia-Borreguero D. et al. Available at: http://irlssg.org/wp-content/uploads/2015/05/Summary-of-recommendations-RLS-Augmentation-May-2015.pdf

 Augmentation Treatment Algorithm

Eliminate exacerbating factors

(serum ferritin < 50-75 μg/mL], lifestyle changes, exacerbating drugs)

Mild augmentation (all of the below) Severe augmentation

1. Temporal shift mainly 1. Not mild, OR
2. Dopaminergic dose is ≤ maximum recommended dose 2. Does not respond to treatment for mild augmentation
3. Symptoms cause mild distress
4. There has been no prior increase in dose above what
was previously therapeutically effective

Garcia-Borreguero D. et al. Available at: http://irlssg.org/wp-content/uploads/2015/05/Summary-of-recommendations-RLS-Augmentation-May-2015.pdf

 Augmentation Treatment Algorithm

Eliminate exacerbating factors

(serum ferritin < 50-75 μg/mL], lifestyle changes, exacerbating drugs)

Mild augmentation (all of the below)

1. Temporal shift mainly
2. Dopaminergic dose is ≤ maximum recommended dose
3. Symptoms cause mild distress
4. There has been no prior increase in dose above what
was previously therapeutically effective

Keep the same OR Complete switch

dopamine agonist to one of the options
below

One of the below two An α2δ calcium-channel

options: ligand
1. Split with same dose;
2. Advance the dose OR
earlier.
If options 1 and 2 fail Rotigotine or a long-acting
consider increasing the dopamine agonist at
dose but keeping it at/ ≤ approved dose
below approved daily dose

If this strategy fails If this strategy fails

consider a complete consider “severe
switch of medication augmentation” options

Garcia-Borreguero D. et al. Available at: http://irlssg.org/wp-content/uploads/2015/05/Summary-of-recommendations-RLS-Augmentation-May-2015.pdf.

 Augmentation Treatment Algorithm

Eliminate exacerbating factors

(serum ferritin < 50-75 μg/mL], lifestyle changes, exacerbating drugs)

Severe augmentation
1. Not mild, OR
2. Does not respond to treatment for mild augmentation

The objective is to reduce, and, if possible eliminate the short acting

dopamine agonist and to begin treatment with rotigotine or a long acting
dopamine agonist or an α2δ ligand
Two strategies are available for doing this:
OR OR
Cross titration Switch 10-day washout
Add an alpha-2-delta Switch patient from
ligand and then a short-acting
gradually reduce the dopamine agonist to Evaluate if any drug
dose of the dopamine rotigotine or a treatment is
agonist with the long-acting needed.
objective of eliminating dopamine If symptoms
it altogether, agonist if this is not continue, introduce
understanding that this already the case. an α2δ ligand or
may not be possible in an opioid
all cases

• If these strategies fail or if the patient has severe, round-the-clock

symptoms, then treatment with low doses of an opioid (long-acting
oxycodone or methadone) should be considered.
• If serum ferritin < 50-75 μg/mL then treatment with intravenous iron,
according to availability, should be strongly considered.
Garcia-Borreguero D. et al. Available at: http://irlssg.org/wp-content/uploads/2015/05/Summary-of-recommendations-RLS-Augmentation-May-2015.pdf. .
 Question & Answer

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