Interview Summary
Parkinson’s disease (PD) affects at least 1% of people aged over 60 years and 2–3% of those aged over 65 years. PD is reported to be the second most common progressive neurodegenerative disorder and the fastest-growing neurodegenerative condition globally. This article discusses the involvement of the gastrointestinal (GI) tract in PD, and the challenges associated with treating patients with PD whose disease has progressed and whose medication is no longer consistently effective. For this article, EMJ conducted interviews in December 2025 with two key opinion leaders, Vanessa Stadlbauer from the Division of Gastroenterology and Hepatology, Department of Internal Medicine, Medical University of Graz, and the Translational Precision Medicine Division, Centre of Biomarker Research in Medicine, Graz, Austria; and Bo Biering-Sørensen from the Movement Disorder and Pain Research Centre, Neurological Department, Rigshospitalet Glostrup, and Department of Public Health, Faculty of Health and Medical Sciences, University of Copenhagen, Denmark. The experts provided insights on overcoming GI challenges while treating OFF episodes in PD. First, Biering-Sørensen described the different types of OFF episode, the motor and non-motor symptoms of OFF episodes, how OFF episodes evolve, and how these episodes are recognised and tracked by patients and clinicians. Next, Stadlbauer and Biering-Sørensen discussed the involvement of the GI system in PD, the key challenges in recognising GI issues for patients and clinicians, strategies to encourage patients to disclose any GI issues during consultations, and the scientific rationale for bypassing the GI tract in PD management. Following this, the experts provided an evidence-based overview of the current therapeutic approaches for managing OFF episodes, starting with oral medications, and then exploring on-demand therapy and advanced treatments that bypass the GI tract. Finally, the experts outlined potential future developments in the management of OFF episodes in PD, as well as advances in research, clinical practice, or patient support they would like to see.
INTRODUCTION
PD has been estimated to affect at least 1% of individuals aged over 60 years and 2–3% of those aged over 65 years.1 It is the second most common progressive neurodegenerative disorder (after Alzheimer’s disease), and has been reported to be the fastest-growing neurodegenerative condition worldwide.1
This article discusses the involvement of the GI tract in PD, and the challenges associated with treating patients with PD whose disease has progressed and whose medication is no longer consistently effective.
OFF EPISODES IN PD
OFF episodes in PD are defined as periods during which the benefit of PD medication wears off, and motor and non-motor symptoms reoccur, substantially impacting quality of life.2
Motor symptoms, including tremor, rigidity, slowness, freezing, and difficulty in walking, are key phenomena in PD that may present during OFF episodes.3 Non-motor symptoms, such as anxiety, fatigue, pain, cognitive disorders, and depression, may also reoccur during these episodes,4 although Biering-Sørensen noted the reoccurrence of such symptoms is less well recognised.
Biering-Sørensen explained that, initially, PD medications are consistently effective, with the first few years of treatment often referred to as the ‘honeymoon phase’.5,6 Biering-Sørensen indicated that there is no typical pattern of PD progression and evolution of OFF episodes; however, patients usually start feeling the OFF episodes after approximately 2–5 years of PD treatment.
Research indicates that up to half of patients who have been treated for PD for around 5 years will experience OFF episodes,7 with at least two out of three patients who have received treatment for 10 years having motor fluctuations and OFF episodes.8,9
The non-motor symptoms observed in patients with PD have been suggested to be potentially more debilitating than the motor impairments associated with the disease.10 Indeed, in Biering-Sørensen’s experience, patients who have had PD for many years often find the non-motor symptoms more troublesome than the motor symptoms.
Biering-Sørensen summarised the different types of OFF episode, as outlined below. The first type of OFF episode that patients typically experience after the honeymoon phase is the ‘end-of-dose’, where the effect of the dose wears off and symptoms reoccur before the next dose is due or has time to be effective.2 Biering-Sørensen emphasised that this type of episode is usually associated with mild and manageable symptoms; however, it is important for patients to inform their clinicians about these symptoms straight away to enable timely adjustments to medications.
Patients can also have ‘delayed ON’ episodes, in which the medication takes longer than it previously has to be effective.2 As the disease progresses, patients may also experience ‘dose failure’, where there is no defined benefit of the treatment (i.e., no ON period).2
Other types of OFF episode include ‘early morning OFF’, where patients wake up in the morning experiencing OFF symptoms.2 Biering-Sørensen described that patients who do not take medication during the night can wake up feeling stiff and have difficulty getting out of bed and completing their usual morning routine; it may take some time (an hour or so) after taking their medication to “feel like they are ON again.”
‘Unpredictable OFF’ episodes typically occur in patients who have had PD for several years; these episodes develop suddenly, are irregular and difficult to treat, and substantially impact quality of life.2
Biering-Sørensen explained that some patients may experience a sudden OFF episode that is directly followed by a dyskinetic episode, in which the sudden change from immobility to involuntary, dance-like movements is distressing for the patient and those around them. Also, patients may develop OFF episodes with dystonia, in which uncontrolled and sometimes painful muscle contractions further impact their gait and activity.11
Diving deeper into the impact of PD on quality of life, Biering-Sørensen highlighted that OFF episodes not only impact the patient, but also affect their caregivers, family, and friends, with the stress and burden increasing when patients have frequent OFF episodes. Social isolation is common and a major concern in the PD community.12 Biering-Sørensen highlighted that social isolation is prevalent among patients who have unpredictable OFF episodes, particularly those who have non-motor symptoms like anxiety, as they are concerned or scared about having an OFF episode or dyskinesia in public and dare not go outside the home.
Biering-Sørensen pointed out that it is important for clinicians to be aware of the different types of OFF episode to help them determine the optimal treatment strategy and provide personalised treatment, thus improving quality of life.
TRACKING OFF EPISODES AND SYMPTOMS
Biering-Sørensen acknowledged that tracking OFF episodes and symptoms is challenging, particularly as PD is not a stable disease and the symptoms can fluctuate from day to day or even from hour to hour. Patient diaries are a useful resource to help patients and clinicians recognise OFF episodes; however, filling in a diary is time-consuming, and patients may forget or be unwilling or unable to fill one out. In Biering-Sørensen’s experience, patients with newly diagnosed PD range from those who do not want to think too much about their disease or record their symptoms to those who regularly fill out a structured diary, including their symptoms and medication schedule. As PD progresses, patients who develop cognitive disorders may be less able to share any detail about the timing, nature, and symptoms of their OFF episodes. Poor reporting compliance and impaired cognitive ability impact the quality, precision, and reliability of the information the patients are disclosing. According to Biering-Sørensen, there is a lot of pressure on clinicians to interpret what the patients are actually saying about their current disease state and symptoms, and use this as a basis to provide precise, personalised treatment. Biering-Sørensen noted that digital health technologies to track OFF episodes and symptoms might be useful in the future to help reduce clinicians’ reliance on patient feedback for their treatment decision-making.
THE INVOLVEMENT OF THE GI SYSTEM IN PD
Stadlbauer explained that the GI system is heavily involved in PD.13-25 There is increasing evidence supporting the hypothesis that PD may originate in the GI tract.24 GI symptoms, such as constipation, gastroparesis (delayed gastric emptying), and dysphagia (difficulty swallowing), precede the onset of the motor symptoms by years, or even decades, in patients with a subsequent diagnosis of PD,13,19,21,25 and patients with clinically evident GI dysfunction tend to have worse motor symptoms.24,25
From a pathophysiological view, it is known that α-synuclein aggregates in the enteric nervous system can be detected in the entire GI tract, and transmit to the brain, thus supporting the involvement of the GI system in PD.13-16,18,19,24 In addition, gut microbiome dysbiosis, increased gut permeability, and chronic inflammation have been suggested to promote neuroinflammation and neurodegeneration.13-20
In Biering-Sørensen’s experience, many patients with PD in clinical practice have altered gut pathophysiology and experience GI issues long before they develop the motor symptoms characteristic of PD. Furthermore, Biering-Sørensen noted that the severity of GI dysfunction can change during any stage of PD.
Expanding on the key GI symptoms in patients with PD, Biering-Sørensen explained that bowel dysmotility leads to slower transit time, which results in constipation, discomfort, and bloating.26 In gastroparesis, the stomach muscles do not work properly, leading to delayed gastric emptying, which can result in nausea, vomiting, loss of appetite, and bloating.27
Biering-Sørensen emphasised that patients should be informed that constipation and poor gastric emptying can reduce the absorption of their PD medication, and that they should be emptying their bowels daily or every other day. Changes to the diet and level of physical activity, as well as adding laxatives and promotility agents to treatment regimens, can be implemented to improve bowel emptying frequency and optimise the uptake and effectiveness of PD treatment.28,29
Oropharyngeal dysphagia, which is difficulties in swallowing due to uncoordinated throat muscles and slowed reflexes, can also impact nutrition and medication uptake. The swallowing dysfunction also results in hypersalivation (sialorrhea), which, although debilitating for patients with PD, is an under-recognised complaint.30 Biering-Sørensen commented that patients with PD can have saliva dribbling onto their clothes or into their dinner, which is “disabling and socially invalidating for these individuals.”
Biering-Sørensen pointed out that clinicians need to be aware of GI dysfunction and how it impacts nutrition, absorption, and therefore effectiveness, of medication, fluctuations in symptoms and OFF episodes, and quality of life in patients with PD.
THE KEY CHALLENGES IN RECOGNISING GI ISSUES
Stadlbauer and Biering-Sørensen acknowledged that GI symptoms such as constipation and bloating are common, non-specific problems that can overlap with other diseases, and could be considered to result from diet, medication, ageing, or other comorbidities. Stadlbauer proposed that clinicians should keep PD in mind when managing patients with one or more of the key GI symptoms (constipation, gastroparesis, dysphagia) and to arrange neurological screening if there is any suspicion of PD.
Patients who have GI symptoms, but have not (yet) developed any motor symptoms, are likely to present to gastroenterologists (constipation, gastroparesis) and/or ear, nose, and throat specialists (dysphagia) rather than to neurologists. Hence, Stadlbauer advocated for a multidisciplinary approach to identify patients who may develop PD and to diagnose the disease early.3
Stadlbauer indicated that patients diagnosed with PD may focus on their neurological symptoms during consultations and may not discuss what they consider to be minor GI problems: “It is important to educate patients and caregivers that GI symptoms are part of PD and should be disclosed. Clinicians need to remind patients to report their GI symptoms and bowel movements at each consultation to ensure they have the full clinical picture.”
Stadlbauer proposed that structured questionnaires to elicit information about GI symptoms would be useful in the context of a multidisciplinary approach involving dietitians, nurses, and speech therapists, with tablet computers and digital health tools a helpful resource for patients who have difficulty writing by hand. Standardised, validated questionnaires to assess GI dysfunction characteristics in patients with PD are available, including the Gastrointestinal Dysfunction Scale For Parkinson’s Disease (GIDS-PD),31 and the Gut Dysmotility Questionnaire (GDQ);32 however, Stadlbauer commented that using structured questionnaires is time-consuming and these resources tend to be used only in clinical studies rather than in routine clinical practice.
Biering-Sørensen observed that patients feel uncomfortable talking about their bowel movements. Strategies to encourage discussion, proposed by Biering-Sørensen, include creating a confidential atmosphere, educating patients about the importance of GI symptoms in their disease and the impact on quality of life, and normalising the conversation about constipation, hypersalivation, and bowel emptying. Biering-Sørensen remarked that some patients may feel more comfortable writing rather than speaking about their bowel movements, in which case questionnaires are useful.
THE RATIONALE FOR BYPASSING THE GI TRACT
Stadlbauer summarised that the GI tract is dysfunctional in PD, leading to problems with swallowing oral medications, unpredictable transit times, altered drug absorption, and erratic plasma levels of PD medication, thereby impacting the effectiveness of therapy. Hence, the oral route is not necessarily the optimal route for drug delivery in patients with PD.
According to Stadlbauer, patients with GI dysfunction (particularly gastroparesis or dysphagia), and those with severe fluctuations in motor function who need a rapid onset treatment for OFF episodes, are the individuals most likely to benefit from treatment via non-oral routes. Biering-Sørensen added that PD medications that bypass the GI tract are also an important option for patients undergoing surgery.
Biering-Sørensen specified: “Delayed gastric emptying, reduced or slow intestinal absorption, and impaired gut motility impact drug uptake and effectiveness, meaning that medications are less reliable. If we cannot solve the GI issues, we need to consider bypassing the GI tract.”
ORAL TREATMENTS FOR MANAGING OFF EPISODES
Oral medications, such as levodopa–carbidopa, are the foundation of therapy for PD.9,33 These treatments control motor symptoms effectively in the early stages of disease, but may not be sufficient to manage non-motor symptoms or advanced disease.5,33,34
Biering-Sørensen outlined that the therapeutic options for patients who develop OFF episodes include optimising their current treatment through altering the dose or frequency, adding medications to the regimen, or changing the type of medication, depending on the type of OFF episode, as follows.
Strategies for OFF episodes during the day include increasing the dose frequency or adding a catechol-O-methyltransferase (COMT) inhibitor, such as opicapone, entacapone, or tolcapone, to extend the levodopa effect.2
Options for early morning OFF episodes include adding a slow-release dopamine agonist (pramipexole, ropinirole) or COMT inhibitor in the evening or during the night, or administering a fast-acting medication, such as a levodopa combined with benserazide (a peripheral decarboxylase inhibitor), in the morning.2
Other oral medications that can be used to treat OFF episodes include monoamine oxidase Type B inhibitors (rasagiline, safinamide, selegiline), which reduce dopamine catabolism.2
Biering-Sørensen emphasised that treating patients with unpredictable OFF episodes is challenging, and on-demand therapy and advanced treatment may need to be considered when oral PD medications are no longer consistently effective.2
MEDICATIONS THAT BYPASS THE GI TRACT
Treatments for PD that bypass the GI tract include transdermal patches, inhaled and sublingual on-demand therapies, subcutaneous treatments (injection and infusion pumps), intrajejunal infusion, and deep brain stimulation.2,35-39
Transdermal patches are widely used as an adjunctive therapy in PD management to bypass the GI tract and provide continuous, slow-release administration of dopamine agonists (rivastigmine or rotigotine), thus circumventing the peaks and troughs associated with oral drug delivery.2,36,38,39
On-demand therapies, such as inhaled levodopa and sublingual apomorphine, provide rapid relief from symptoms during OFF episodes.2,35 Stadlbauer highlighted: “On-demand therapy is used when patients need quick delivery of the drug, but you cannot rely on the GI tract, and the transit time is unknown.”
Biering-Sørensen pointed out that inhaled levodopa acts quickly, with relief observed after 10 minutes,40 thus offering an effective treatment solution for patients out in public who suddenly develop OFF symptoms. However, Biering-Sørensen noted that on-demand therapies are “not an instant fix,” and the effects can wear off quite quickly.
Stadlbauer stated: “I think the recent advances in inhaled medication are very promising because this route is non-invasive, and there is a very fast onset. Patients and caregivers will require training on this type of medication to ensure they are administering it in the correct way.”
The experts depicted that, in cases where OFF episodes and symptoms are not being adequately controlled by a combination of oral and on-demand therapies, more complex, device-aided therapies or surgery (collectively known as advanced treatments) should be considered.2
Subcutaneous treatment options include apomorphine via a multidose pen or infusion pump, and foslevodopa–foscarbidopa via a pump.2,35 Self-administering a subcutaneous injection can be difficult for patients who are experiencing motor fluctuations during OFF episodes; hence, apomorphine multidose pens tend to be underused in clinical practice.2 Patients who find self-injection challenging and/or who require an increase in dosing frequency could be switched to continuous subcutaneous apomorphine infusion.2
Intrajejunal administration is used to deliver levodopa–carbidopa intestinal gel or levodopa–carbidopa–entacapone intestinal gel continuously, via a pump, through a percutaneous jejunostomy tube directly to the jejunum (part of the small intestine).2,35,36 Biering-Sørensen noted that this type of continuous therapy leads to more stable disease, with fewer fluctuations in symptoms and OFF episodes, and may also reduce the occurrence of dyskinetic episodes.
Biering-Sørensen pointed out that the practicalities of wearing a pump for 16 or 24 hours a day to deliver medication either subcutaneously or directly to the jejunum have to be considered.2 Patients who wear a pump for 16 hours a day do not have the difficulty of wearing them at night, but may have night time or early morning OFF episodes. In contrast, patients who wear a pump for 24 hours may have no or few OFF episodes, but they have to manage to sleep while wearing the pump.
Deep brain stimulation of the subthalamic nucleus and globus pallidum internus2 has been shown to substantially improve OFF episodes and motor symptoms, but its use is typically limited to younger patients with disabling mid-to-late stage PD who have no or little cognitive impairment, and should not be offered to individuals with early PD without fluctuations.37
Biering-Sørensen summarised that the purpose of these advanced treatments is to try to remove a lot of the fluctuations in motor symptoms, as well as the non-motor symptoms, OFF episodes, and dyskinetic episodes associated with PD. He commented that there is debate about when to incorporate advanced therapies into treatment plans.37,41 According to Biering-Sørensen, many centres implement the ‘5-2-1 rule’, which is a tool used in clinical decision making to help identify when a patient’s disease is advanced and their current treatment is not sufficiently controlling symptoms and may need adjusting.41,42 The key indicators for this rule are: the patient takes PD medication at least 5 times per day; they experience at least 2 hours of OFF time, when their symptoms are not adequately controlled; and at least 1 hour of dyskinesia (involuntary movements) per day.41 Patients who meet these criteria should be considered for advanced treatment.41
FUTURE PROSPECTS
Biering-Sørensen would like to see digital health technologies that improve patient awareness of OFF episode symptoms and help guide clinicians to provide more personalised treatment. He suggested that a pump delivery system with continuous measurement of symptoms and relevant adjustments to the amount of medication delivered could help to reduce the OFF episodes and periods of dyskinesia. Biering-Sørensen suggested: “In the future, alongside the clinical assessments of the patients and patient-reported information, we need to have objective measurements, like wearables or other digital health technologies, that can help us look at the OFF episodes and dyskinesias that arise when the therapeutic window narrows.”
According to Stadlbauer, gut permeability and the composition of the microbiome play a role in the development of PD; therefore, microbiome-based therapies could be an adjunct treatment to slow the disease progression in the future.13-15,18,21 Stadlbauer commented that probiotics have been shown, in small studies, to alleviate GI symptoms, particularly constipation,16,18,43,44 and have neuroprotective effects.16,18 Stadlbauer advocated for further research into the value of probiotics in PD, particularly next-generation probiotics that improve gut permeability and decrease inflammation, and thereby potentially modify the course of the disease.
KEY TAKEAWAY
Biering-Sørensen summarised that non-motor symptoms of PD are currently under-recognised, and the identification and assessment of OFF episodes need to improve, particularly as PD progresses and these episodes become more pronounced. Digital health technologies could play a part in recognising OFF episodes and non-motor symptoms, thereby enabling personalised treatment for patients with PD. He concluded: “We have to stay ahead of the OFF episodes.”
Stadlbauer stated that clinicians should be aware that GI symptoms can precede the diagnosis of PD, and these symptoms substantially impair quality of life. Patient education and a multidisciplinary care approach are important, ideally using standardised questionnaires to help identify GI and other non-motor symptoms. Stadlbauer suggested: “Non-oral routes are valuable for the treatment of OFF episodes. Inhaled, sublingual, subcutaneous, and intrajejunal therapies are a way forward to bypass the GI tract and improve the symptoms and quality of life of patients with PD.”
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