Impact of wearing-off on motor symptoms
As Parkinson’s disease (PD) progresses over time from a stable treated disease to an advanced state there is a recurrence of motor symptoms during wearing-off (time when symptoms get worse between doses of oral medication) including tremor, dystonia, muscle spasms, postural instability, slowness and gait difficulties. Wearing-off occurs frequently in about 80% of patients within 4 years from therapy initiation (especially during levodopa therapy).1-3
Wearing-off during levodopa treatment may be detected even at the early stages of PD and is underestimated by routine neurological clinical evaluation. The number of symptoms, both motor and nonmotor, increases along with disease duration and unsurprisingly has a negative impact on patient’s quality of life.4
Patients with PD rate wearing-off as the greatest challenge with their levodopa therapy. Activities of daily living are rated as most bothersome by patients, because they are most limited during OFF time.5 Patients would prefer treatments that increase the amount of ON time, and for which they are able to predict the occurrence of OFF time to within 30 minutes.
Wearing-off is the greatest challenge of levodopa therapy, which occurs within 4 years of therapy initiation, and may be detected even earlier
Impact of non-motor symptoms
The characteristic OFF periods develop over time in subjects with PD on chronic levodopa therapy. During OFF periods patients are experiencing re-emerging of motor and non-motor symptoms of PD. Both are negatively affecting patients’ well-being.
Non-motor fluctuations occur almost inevitably alongside motor fluctuations and vary from sensory and autonomic to disabling neuropsychiatric symptoms including for example dysphagia, anxiety, depression, fatigue, excessive sweating, inner restlessness, pain, concentration/attention, dizziness, bladder urgency.6
Non-motor symptoms occur frequently alongside motor symptoms in PD and are heterogeneous and complex
The patterns of non-motor symptom fluctuations are heterogeneous and complex: Non-motor symptoms may be present in ON and more severe in the OFF state while some may occur exclusively during OFF- or ON-periods. Psychiatric non-motor symptoms (anxiety, depression, pain) fluctuate more frequently and severely and have greatest impact on health-related quality of life.7
Psychiatric non-motor symptoms –anxiety, depression, pain – fluctuate frequently and severely and have greatest impact on quality of life
Early morning OFF-related non-motor symptoms can be very disabling in addition to having a negative impact on quality of life.8 Early morning OFF periods are common and occur in 60% of subjects across all disease stages, the majority of which (88%) are associated with non-motor symptoms, predominantly urinary urgency, anxiety, dribbling of saliva, pain, low mood, limb paresthesia and dizziness.
Steps to manage treatment fluctuations
Patients rate response fluctuation to medication as the “most bothersome” problem in their lives. Drugs that prolong dopamine bioavailability and mimic continuous drug delivery may be an effective strategy to prevent and manage non-motor fluctuations.10 Currently, treatment of nonmotor symptoms is limited and the development of new treatments targeting nonmotor symptoms in PD is a research priority.11
This article highlights information presented during a satellite symposium at the 2019 EAN Congress, “Beyond motor wearing-off: What have we learned?” sponsored by BIAL.