By Ana Espino | Published on April 9, 2026 | 4 min readParkinson’s
disease is a chronic neurodegenerative disorder characterized by the
progressive worsening of motor symptoms. As the disease advances, a large
majority of patients treated with
levodopa develop
motor fluctuations, marked
by unpredictable alternations between “ON” and “OFF” periods. These
fluctuations lead to
significant clinical variability, have a lasting impact on
quality of life, and complicate therapeutic management.
Despite major
therapeutic advances, controlling these fluctuations remains a significant
challenge. Current strategies rely on optimizing dopaminergic treatments and
introducing targeted adjunctive therapies. However, the growing number of
available options, combined with the lack of a clear hierarchy based on robust
evidence, makes therapeutic decision-making particularly complex in clinical
practice.
In this
context, this international review provides a
structured update of
evidence-based recommendations for managing motor fluctuations in Parkinson’s
disease. It aims to critically assess the
efficacy, tolerability, and clinical
relevance of different therapeutic strategies in order to guide more rational
and personalized care.
Which
treatments truly reduce OFF time?
This systematic
review is based on the analysis of
102 randomized controlled trials, selected
using strict criteria including patients on levodopa experiencing motor
fluctuations. Data were evaluated using a methodology inspired by
GRADE,
incorporating both the quality of evidence and the clinical relevance of
outcomes.
The results
show that several treatments are considered effective, including certain
extended-release formulations of levodopa, dopamine agonists (pramipexole,
ropinirole, rotigotine), as well as agents such as opicapone and safinamide.
These interventions
significantly reduce OFF time—often by more than
one hour
per day—while increasing ON time without dyskinesia.
More advanced
approaches, such as
subthalamic nucleus deep brain stimulation (STN-DBS),
demonstrate major efficacy, with marked improvement in motor symptoms,
increased ON time, and enhanced quality of life.
Other
treatments are considered
probably effective, including continuous infusions of
levodopa or apomorphine, as well as certain classes such as
COMT inhibitors and
MAO-B inhibitors. These options provide clinical benefits, although with more
limited levels of evidence or consistency.
Conversely,
several interventions show insufficient evidence—or no demonstrated
efficacy—highlighting the heterogeneity of therapeutic responses. The findings
also underscore substantial variability in treatment effects and a limited
impact on certain outcomes, particularly quality of life.
Personalizing
treatment to better control Parkinson’s disease
Parkinson’s
disease, characterized by
complex motor fluctuations, requires continuous
adaptation of therapeutic strategies. This review confirms that multiple
options can
significantly reduce OFF time, while also emphasizing the
complexity of treatment selection in clinical practice.
Overall,
treatment optimization appears effective, with options ranging from oral
therapies to invasive approaches. However, several limitations remain,
including significant heterogeneity among studies, a lack of robust
head-to-head comparisons between strategies, and insufficient long-term data.
Future
perspectives rely on a more targeted approach, integrating the
patient’s
clinical profile, disease stage, and individual expectations. The development
of comparative studies and new therapeutic approaches may pave the way for more
personalized medicine, ultimately improving long-term management of motor
fluctuations.
Read next: Gene therapy: a turning point for parkinson’s disease?
About the author – Ana Espino
PhD in Immunology, specialized in Virology
As a scientific writer, Ana is passionate about bridging the gap between research and real-world impact. With expertise in immunology, virology, oncology, and clinical studies, she makes complex science clear and accessible. Her mission: to accelerate knowledge sharing and empower evidence-based decisions through impactful communication.
