Managing OFF Times In Parkinson's Disease

If you or a loved one is living with Parkinson’s disease (PD), you know that daily life can be permeated with uncertainties, including fluctuations in medication-related symptom control commonly known as OFF episodes. During these times, Parkinson’s motor and/or non-motor symptoms will return or worsen, leading to functional disability and a significant impact on quality of life.

Generally, people define an OFF time as when their motor symptoms, like tremors or rigidity, re-emerge between medication doses. ON times are when symptoms are better controlled. Despite the attention paid to motor symptoms, it is worth noting that non-motor symptoms (i.e., GI issues, anxiety, and pain) will often worsen during an OFF episode, but may be disregarded because they seem to be present throughout the day and/or night. 

Recognizing the fluctuating symptoms (both motor and non-motor) that define OFF and ON is one of the most important aspects of managing OFF times in Parkinson’s. 

Why is this recognition important? For starters, in order to minimize OFF times, learning about the full spectrum of your OFF motor and non-motor symptoms and tracking them can help you identify patterns (i.e., dietary habits) and possible triggers (i.e., stress) that you can share with your healthcare provider. From this point, you can take steps to managing OFF by developing a strategic plan to help improve symptoms or decrease the duration of OFF (increase ON). 

Let’s take a closer look at the science behind OFF in Parkinson’s and consider some non-pharmacological interventions and coping strategies that can help you manage OFF times. 

What is an OFF episode?

OFF periods are times when motor and non-motor symptoms re-emerge or worsen in nature. Many individuals with Parkinson’s disease experience fluctuations in their symptoms: times when they are better controlled and times when they are not. The periods that the symptoms are better controlled are referred to as ON, and when they are not, as OFF. 

Table 1: Common motor and non-motor symptoms that may re-emerge or worsen during OFF in Parkinson’s disease.

OFF episodes often occur due to antiparkinsonian medications (i.e., levodopa) wearing off or at certain times of the day (i.e., the first dose or after eating). OFF times can also occur at unpredictable, random times for unknown reasons or due to medication failure.  Adjunctive medications (additional medications that help improve the efficacy of these primary medications) are often prescribed to help shorten the duration of OFF times.

The different types of OFF episodes attributed to medications that may occur in PD include: 

• Early morning OFF - occurs upon awakening and before the first dose 
• Delayed ON -  delayed symptom alleviation that occurs after the first dose or after eating
• Sudden OFF - a random, unpredictable switch from “ON” state to “OFF”
• Dose failure - medication failure, or medication unable to improve symptoms
• Wearing off - return of symptoms as medication wears off or gets close to the end of a dosing interval 

Why does wearing off occur in Parkinson’s?

One explanation why medications like levodopa wear off is linked to the progressive loss of dopaminergic neurons in PD that regulate dopamine storage as well as its release over time. As the disease progresses, these cells are lost, and the brain loses its ability to store and steadily release the extra dopamine provided by the medication. 

Further, early in the disease, the brain still has some naturally-produced dopamine in circulation to buffer the wearing-off period. But again, these levels decline as time passes due to the progressive nature of Parkinson’s disease. Food and digestion may also play a role. For example, high-protein intake shortly after taking the medication or slow digestion may impact medication transport and absorption.

Non-pharmacological interventions for managing OFF episodes

Motor symptoms, such as stiffness, reduced mobility, or tremors, are commonly recognized as hallmark symptoms of Parkinson’s disease. The impact of OFF is often focused around these motor symptoms, but the burden and frequency of non-motor symptoms can be just as significant, if not more disruptive. 

Fluctuating non-motor issues, including sleep disturbances, pain, mood-related symptoms, and GI issues, can emerge or worsen in OFF times. The unpredictability of OFF episodes, or not knowing when they will occur can also greatly affect mental health and overall well-being. Non-pharmacological interventions, such as diet and probiotics, and coping strategies may help. 

Diet

Studies have shown that taking antiparkinsonian medications with a meal high in dietary protein may contribute to fluctuations in motor symptoms by interfering with medication absorption. One underlying hypothesis as to why is that levodopa is absorbed using the same protein-transporters needed to absorb dietary proteins. 

Based on this information, some clinicians recommend not taking the medication soon before or after eating a protein-rich meal. Another recommendation, known as the protein-redistribution diet, involves limiting protein intake earlier in the day (i.e., breakfast and lunch), but compensating during dinnertime by eating the majority of protein at this time. Since medications are typically taken throughout the day (but not late at night), following this redistribution guideline, rather than eating the majority of daily protein before dinner, may improve daily ON time. 

However, current evidence is limited on the actual intestinal protein transporters involved, and studies of protein-restricted and protein-redistribution diets show conflicting results. Furthermore, strict adherence to these diets may have adverse effects, including weight loss and sarcopenia. Following your nutritionist and healthcare provider’s guidelines is always best. 

The digestive system itself, and not just what you eat, may also influence medication effectiveness. The absorption of some medications, including levodopa, depends on healthy functioning of the digestive tract as it passes through the small intestine. However, GI dysfunction, especially constipation and delayed gastric emptying, can disrupt the absorption of medications and lead to a delay in medication effectiveness (delayed ON) or medication ineffectiveness (no ON).

Probiotics

Gastrointestinal issues are common in Parkinson’s disease and can precede clinical symptoms of Parkinson’s disease by years, which may indicate a gut-first pathway in the pathogenesis of the disease. This discovery has prompted researchers to investigate the gut microbiome and the possibility that the gut-brain axis (the bidirectional communication system between the central nervous system and the gut) offers another pathway to improved symptom management in PD. 

Some probiotics have been shown in studies to improve GI issues like constipation in Parkinson’s disease. However, other probiotics have also been studied for their potential to improve non-GI-related motor and non-motor symptoms by exerting neuroprotective benefits via the gut-brain axis. These types of probiotics, known as psychobiotics, may help support management of Parkinson’s disease beyond gut health. The psychobiotic PS128, for example, has been shown to benefit gut-brain health in Parkinson’s disease-like models and pilot studies.

Psychobiotic PS128 may improve quality of life and akinesia in ON and OFF states

In a 2021 clinical pilot study, PS128 was studied as a nutritional add-on therapy for Parkinson’s disease. For 12 weeks, 25 individuals with PD took 60 billion CFUs of PS128 alongside their usual medications, including levodopa. Patients in the study had been diagnosed with Parkinson’s disease an average of ten years and reported at least 3 hours of daily OFF times in self-reported diaries. 

The study was conducted as a single-arm, baseline-controlled study - which means there was no separate placebo group and researchers recorded a starting measurement, or baseline, for each participant before the intervention began. In this case, the primary baseline measures were the Unified Parkinson’s Disease Rating Scale part III (UPDRS-III) motor scores and changes in the participants’ ON-OFF diary recording of symptoms. 

At the end of the study (12 weeks), researchers observed a significant reduction in UPDRS motor scores and akinesia (difficulty or freezing in movement) subscores as compared to baseline in the OFF state. In their diaries, the participants reported a significant reduction in OFF period duration as well as a significant increase in the duration of the ON period. Additionally, 68% of participants taking PS128 reported a noticeable improvement in their quality of life, with 20% reporting feeling much or very much improved. While these changes occurred alongside other therapies and were compared to baseline and not to placebo, the study shows promise for PS128 as a nutritional add-on to existing approaches to PD.  

Lived experience study of OFF periods: Triggers and coping strategies

In a clinical study, individuals shared their lived experience, including triggers and coping strategies, of OFF periods in Parkinson’s disease. Via a free-text survey, participants stated that stress, anxiety or depression, and tiredness/fatigue were common triggers for OFF periods. Other triggers included social situations, cold or heat exposure, family issues, anger, driving, and food intake (i.e., food delay and hunger). 

Individuals also free-texted their response to the question:“Other than taking medication, what do you do during your OFF periods to help manage your PD symptoms?” Responses included the following: 

• Exercise: Stretching, walking, yoga, hiking, physical therapy exercises, vigorous exercise
• Relaxation or mindfulness exercises: Calming or relaxing exercises, quiet time, slowing down, avoiding stress, breathing exercises, massage, relaxation exercises, mindfulness music
• Sleep: Rest or sleep as a recharge, bed rest or laying down, taking a nap
• Eating and/or drinking: Hydration, water, following diet designed for Parkinson’s, protein, carbonated beverage
• Activities: Crossword puzzles, word searches, gardening, making art, cleaning, singing, reading a book, listening to music
• Focus on movements: Deliberate movement to oppose dystonia (uncontrolled muscle movements), flexion/extension, focusing on not falling while walking
• Animals: Walking the dog, holding pets (i.e., cat), going to the barn
• Social: Being socially engaged, conversation, talking with friends

Participants in the study reported OFF episodes that averaged 3.5 hours a day, or a quarter of their waking hours. However, keep in mind that this is the average out of all the participants and does not necessarily reflect a standard. 

In another real-world lived experience of OFF time study, researchers gathered information via questionnaires from a large pool of participants (n=6,757) about the frequency, duration, and severity of episodes. Approximately half of the participants (n=3,470) reported having OFF episodes and the average time since diagnosis was six years. 

Of those stating they experienced OFF times, 67% reported 1-2 OFF episodes a day, with 90% reporting a duration of more than 15 minutes per episode. Only 18% reported episodes lasting one hour or more. In terms of severity, over half (55%) stated that the OFF periods were mild to moderate and a small percentage (6%) indicated that the episodes severely impacted their activities. According to the authors, prevalence of OFF times based on disease duration was consistent with the literature - that is, within 4-6 years of initiating antiparkinsonian medication treatment, about 40% of people with PD report motor symptoms from wearing off. 

Developing a strategic plan that works for you

The frequency and unpredictability of OFF periods can be one of the most challenging aspects of living with Parkinson’s disease. Developing a strategic plan for managing OFF times involves not just flexibility and vigilance, but also creating an environment where symptoms are less likely to escalate. 

Some different strategies that may be helpful include logging symptoms regularly to identify patterns and triggers, reducing sensory overload, and keeping a medication schedule with precise timing. Daily habits, including exercise, stress management, sleep, and diet, can play a central role in how individuals experience and cope with OFF periods.

Probiotics, specifically psychobiotics like PS128, have also been shown to exert neuroprotective benefits in preclinical models and shorten the duration of OFF times in a clinical pilot study. Individuals with PD who took PS128 also reported less motor symptoms in the same clinical study. Supporting health using probiotics may offer options that improve quality of life and overall well-being in Parkinson’s.  

Recommended reading

Dance for Parkinson's Disease

PS128 Probiotic & Parkinson’s - How Does it Work?

Parkinson’s: Foods to Eat and Avoid