The symptom spectrum of wearing-off in Parkinson’s disease

In a satellite symposium held at the 2019 EAN Congress, the speakers discussed the spectrum of motor and non-motor fluctuations associated with the wearing-off of levodopa treatment for Parkinson’s disease, and steps to prevent and manage these troublesome symptoms.

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.

Our correspondent’s highlights from the symposium are meant as a fair representation of the scientific content presented. The views and opinions expressed on this page do not necessarily reflect those of Lundbeck.


1. Fahn S et al. Does levodopa slow or hasten the rate of progression of Parkinson's disease? J Neurol. 2005 Oct;252 Suppl 4:IV37-IV42.

2. Rascol O et al. Development of dyskinesias in a 5-year trial of ropinirole and L-dopa. Mov Disord. 2006;21(11):1844-50.

3. Parkinson Study Group CALM Cohort Investigators. Long-term effect of initiating pramipexole vs levodopa in early Parkinson disease. Arch Neurol. 2009;66(5):563-70.

4. Stocchi F et al. Early detection of wearing off in Parkinson disease: the DEEP study. Parkinsonism Relat Disord. 2014;20(2):204-11.

5. Kerr C et al. Health-related quality of life in Parkinson's: impact of 'off' time and stated treatment preferences. Qual Life Res. 2016;25(6):1505-15.

6. Chaudhuri KR, Poewe W, Brooks D. Motor and nonmotor complications of levodopa: Phenomenology, risk factors, and imaging features. Mov Disord. 2018;33(6):909-19.

7. Storch A et al. Nonmotor fluctuations in Parkinson disease: severity and correlation with motor complications. Neurology. 2013;80(9):800-9.

8. Rizos A et al. Characterizing motor and non-motor aspects of early-morning off periods in Parkinson's disease: An international multicenter study. Parkinsonism Relat Disord. 2014;20(11):1231-5.

9. Politis M et al. Parkinson's disease symptoms: the patient's perspective. Mov Disord. 2010;25(11):1646-51.

10. Dafsari HS et al. EuroInf 2: Subthalamic stimulation, apomorphine, and levodopa infusion in Parkinson's disease. Mov Disord. 2019;34(3):353-65.

11. Seppi K et al. Update on treatments for nonmotor symptoms of Parkinson's disease-an evidence-based medicine review. Mov Disord. 2019;34(2):180-198.


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