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By Timothy Tankosic, M.D.
The National Institute of Neurological Disorders and
Stroke describes restless legs syndrome (RLS; also known
as Ekbom's syndrome) as a common neurologic disorder
characterized by unpleasant sensations (e.g., burning,
creeping, tugging, or like insects crawling in the legs)
in the legs and an urge to move when at rest in an effort
to relieve these sensations. The paresthesias of RLS are
generally worse during periods of inactivity or rest,
while sitting or lying down, and during sleep. Movement of
the legs can temporarily relieve the symptoms, but the
combination of symptoms and movement to relieve them often
results in difficulty falling and staying asleep and
exhaustion and fatigue. RLS is a chronic and slowly
progressive disorder. Prevalence estimates vary widely,
from 12 million to more than 30 million adults in the U.S.
The higher prevalence estimates are based on RLS is
frequently misdiagnosed or remains undiagnosed.
It is estimated that only about 10% of those affected
by RLS receive treatment. Dopaminergic agents (e.g.,
dopamine agonists and levodopa-carboxylase inhibitors) are
considered to be the first line therapeutics for RLS.
Augmentation of the symptoms of RLS, particularly onset
occurring progressively earlier in the day, is a common
problem encountered with the long-term use of dopaminergic
drugs. The frequency appears to be less with dopamine
agonists than with other types. Benzodiazepines
(sedative-hypnotic agents), gabapentin and other
antiepileptic drugs (AEDs), and opiates are also used to
treat RLS. AEDs and opiates may be preferred when the
condition is painful.
Dopamine agonism is the most common mechanism of action of
drugs in development for RLS. Many of the drugs in
development for RLS (or used off-label to treat it) are
also in development or approved for Parkinson's disease.
In May 2005, the dopamine agonist, Requip® (ropinirole;
oral tablet; GlaxoSmithKline) became the first drug to
receive FDA approval for RLS. The tables below list select
drugs that are approved (one drug) or in development for
RLS. New classes of drugs may soon be evaluated for RLS.
The partial D2 (and D3) receptor agonist, aripiprazole (Abilify™;
Bristol-Myers Squibb/Otsuka) is an atypical antipsychotic
that acts principally at the dopamine receptor that has
demonstrated activity against RLS (see Sleep. 2004 Aug
1;27(5):1022).
Suggested reading:
- Earley, CJ. Restless Legs Syndrome. NEJM.
2003;348:2103-9. (clinical review)
- Happe S, Trenkwalder C. Role of dopamine receptor
agonists in the treatment of restless legs syndrome.
CNS Drugs. 2004;18(1):27-36.
- Schapira AH. Restless legs syndrome: an update on
treatment options. Drugs. 2004;64(2):149-58.
Table 1
|
Select
Drugs Approved or in Development for Restless Legs
Syndrome |
|
Compound |
Company |
Mechanism of Action |
Development Status |
Comments |
| Requip®
tablets (ropinirole) |
GlaxoSmithKline (London, U.K.) |
D2/D3
agonist |
Approved |
First
drug to be FDA approved for RLS; For
moderate-to-severe primary RLS in adults;
Previously approved for Parkinson's d. |
| ReQuip
CR (ropinirole, controlled release) |
GlaxoSmithKline (London, U.K.) |
D2/D3
agonist; Once daily administration |
Phase
III |
U.S. and
E.U. regulatory submissions for RLS anticipated in
2006; Anticipated in 2005 for Parkinson's d. |
|
Rotigotine (SPM-962) |
Schwarz
Pharma (Monheim, Germany) / Aderis
Pharmaceuticals, Inc. (Hopkinton, MA) |
DA
agonist |
Phase
III |
Phase
III initiated in May 2005; First results expected
in Q1 2007; Schwarz submitted NDA and MAA
applications for transdermal rotigotine (Neupro™)
early Parkinson's d. in Sep 2004 |
| Mirapex®
/ Sifrol® (pramipexole) |
Boehringer Ingelheim (Ingelheim, Germany) |
DA
agonist |
Phase
III |
Phase
III for Parkinson's d.; Phase II for epilepsy |
|
SEP-226330 |
Sepracor,
Inc. (Marlborough, MA) |
NE + DA
reuptake inhibitor |
Phase II |
Also
under evaluation for Parkinson's d. |
|
Radafaxine (353162) |
GlaxoSmithKline, Plc (London, England) |
NE/DA
reuptake inhibitor; Bupropion metabolite |
Phase II |
Also
Phase II for depression |
| XP13512 |
XenoPort,
Inc. (Santa Clara, CA) |
Gabapentin prodrug; Designed for improved GI tract
absorption |
Phase II |
Phase II
for post-herpetic neuralgia |
|
Safinamide |
Newron
Pharmaceuticals SpA (Bresson, Italy) |
Mechanisms include Na+ channel blocking, Ca++
channel and glutamate modulation, RIMA, DA
reuptake inhibition |
Phase II |
Phase
III for Parkinson's d.; Phase II for epilepsy |
| Lisuride
TTS (transdermal patch) |
NeuroBiotec GmbH (Berlin, Germany) |
DA
agonist |
Clinical |
No
recent RLS news; Phase II for Parkinson's d. |
|
Dorsiflex (mephenoxalone) |
Will-Pharma
(Wavre, Belgium) |
Muscle
relaxant; Anti-spasmodic |
Available |
|
|
Sumanirole |
Pfizer,
Inc. (New York, NY) |
D2
agonist + 5-HT1A activity |
Discontinued (U.S.) |
DC'd in
Phase III, July 2004; Was in development for
Parkinson's d. and restless legs syndrome; No
significant therapeutic advantage |
|
Source: D&MD
This review of
emerging drugs for the treatment of restless legs syndrome
was written by Timothy Tankosic, M.D. He may be contacted
via e-mail at
tt888@aol.com |
