Optimal management of Parkinson\u2019s disease requires timely recognition of progression, careful patient selection, and a coordinated multidisciplinary approach, writes Caroline McDermott<\/p>\n
Introduction
Parkinson\u2019s disease (PD) is a progressive neurodegenerative disorder marked by the gradual loss of dopaminergic neurons and an evolving mix of motor and non-motor symptoms.1 In the early stages, most patients experience a reliable and sustained response to oral levodopa. Over time, however, this response becomes less predictable, the therapeutic window narrows, and patients begin to experience increasing fluctuations in symptom control. In day-to-day clinical practice, this transition is rarely abrupt. Instead, it emerges gradually as patients report shorter durations of benefit, delayed responses to medication, or more variable symptom control. Recognising this shift is critical, as it often signals the need to reconsider treatment strategy and, in some cases, move beyond oral therapies.2<\/p>\n
Pathophysiology of progression and treatment complications
The clinical evolution of PD reflects a progressive loss of the brain\u2019s ability to buffer dopamine. Early in the disease, residual dopaminergic neurons can store and release dopamine in a relatively physiological manner. As this capacity diminishes, patients become increasingly dependent on exogenous dopamine delivery.1<\/p>\n
Intermittent oral levodopa results in pulsatile stimulation of dopamine receptors, which contributes to the development of motor complications, including fluctuations and dyskinesia. Levodopa-induced dyskinesia is strongly linked to non-physiological dopaminergic stimulation patterns over time.3 Non-neurological factors, particularly gastrointestinal dysfunction such as delayed gastric emptying, can significantly impair levodopa absorption and contribute to variability in clinical response.2<\/p>\n
Clinical challenges in advanced Parkinson\u2019s disease
Motor complications
Motor fluctuations are among the most recognisable features of advancing PD. A wearing-off effect, in which the benefit of each levodopa dose becomes progressively shorter, is commonly reported. Patients may also experience delayed ON periods, dose failures, or sudden and unpredictable OFF episodes.2 Levodopa-induced dyskinesias, ranging from mild to disabling, are a frequent complication of long-term therapy.3 These motor complications can substantially impair daily functioning and quality of life.2<\/p>\n
Non-motor symptoms
Non-motor symptoms are a major contributor to disability in PD, particularly in later stages.4 These include cognitive impairment, mood disorders, autonomic dysfunction, and sleep disturbances.1,4 Non-motor fluctuations often parallel motor OFF periods but are frequently under-recognised unless specifically assessed.2<\/p>\n
Increasing treatment burden
As PD progresses, treatment regimens often become more complex, with increasing reliance on multiple daily doses of levodopa,2 Adjunctive agents such as dopamine agonists, MAO-B inhibitors, and COMT inhibitors are commonly introduced to extend ON time. While these strategies can improve symptom control, they are associated with an increased risk of adverse effects and treatment burden.5 Complex regimens may also reduce adherence, particularly in patients with cognitive impairment.4<\/p>\n
Limitations of oral therapy
Oral therapy is associated with significant pharmacokinetic variability, particularly in advanced disease. Delayed gastric emptying, dietary protein interactions, and inconsistent intestinal absorption all contribute to fluctuating levodopa plasma levels.2 Intermittent dosing leads to pulsatile dopaminergic stimulation, which is associated with the development and progression of dyskinesia [3]. In many patients, a therapeutic ceiling is reached beyond which increasing doses provide limited additional benefit and may exacerbate adverse effects.2,5<\/p>\n
When to consider non-oral or advanced therapies
Treatment escalation should be guided by the overall clinical picture rather than a single metric.2 Key indicators include troublesome OFF periods, unpredictable fluctuations, disabling dyskinesia, and declining quality of life despite optimised oral therapy.2,6 Increasing dosing frequency and shortening duration of benefit from each dose are additional warning signs of advancing disease.2Treatment selection must be individualised, taking into account cognitive status, neuropsychiatric comorbidity, autonomic dysfunction, frailty, patient preference, and local expertise.4<\/p>\n
On-demand therapies
On-demand therapies are useful for managing sudden or unpredictable OFF episodes. Subcutaneous apomorphine injections provide rapid dopaminergic stimulation with a fast onset of action.2 These therapies are particularly beneficial in patients with intermittent but disabling OFF periods. However, frequent reliance on rescue treatments should prompt consideration of continuous dopaminergic strategies.6 Alternative options, including inhaled levodopa and sublingual apomorphine, may be appropriate in selected settings.2<\/p>\n
Infusion therapies
Continuous dopaminergic stimulation is a key principle in advanced PD management.2 Continuous subcutaneous apomorphine infusion has been shown to reduce OFF time and improve motor stability in appropriately selected patients.6\u00a0Levodopa\u2013carbidopa and levodopa\u2013carbidopa-entacapone intestinal gels provide continuous jejunal delivery of levodopa and are effective in reducing motor fluctuations.2\u00a0Subcutaneous levodopa formulations such as foslevodopa\/foscarbidopa offer continuous delivery without the need for enteral access and represent a newer therapeutic option.7<\/p>\n
Device-aided and surgical therapies
Deep brain stimulation (DBS) is an established treatment for patients with refractory motor complications. In appropriately selected individuals, DBS can significantly reduce OFF time and dyskinesia while allowing reduction of medication burden. Careful patient selection is essential, particularly regarding cognitive and psychiatric comorbidity. MR-guided focused ultrasound may be considered in highly selected cases, particularly for tremor-dominant disease, although its use remains more limited.8<\/p>\n
Clinical decision-making
Treatment decisions are guided by the dominant clinical problem. Occasional OFF episodes may be managed with on-demand therapies.2 Frequent or unpredictable fluctuations often warrant consideration of infusion therapies.6 Persistent, disabling motor complications may prompt referral for device-aided therapies such as DBS.8 These decisions are best made within a multidisciplinary framework involving neurology, specialist nursing, and allied health professionals.4<\/p>\n
Challenges associated with advanced therapies
Advanced therapies can provide substantial symptomatic benefit but are associated with potential adverse effects, device-related complications, and procedural risks.8 Access to these therapies may be limited by cost, infrastructure, and service availability.6 Importantly, current treatments remain symptomatic and do not modify the underlying neurodegenerative process.1<\/p>\n
Role of primary care
Primary care clinicians play a central role in the longitudinal management of PD. Early recognition of motor fluctuations, monitoring of treatment tolerability, and timely referral to specialist services are essential for optimising outcomes.4<\/p>\n
Future directions
Research is focused on improving continuous drug delivery systems, developing adaptive neuromodulation strategies, and integrating digital monitoring tools into routine care.2 The long-term goal remains the development of disease-modifying therapies.1<\/p>\n
Conclusion
As Parkinson\u2019s disease progresses, the limitations of oral therapy become increasingly evident.2 Non-oral, device-aided, and surgical therapies offer opportunities to improve symptom control and quality of life.2,4 Optimal management requires timely recognition of disease progression, careful patient selection, and a coordinated multidisciplinary approach.4 ![\"\"\/](\"https:\/\/www.newsbeep.com\/ie\/wp-content\/uploads\/2025\/11\/imt_end6.jpg\" "\\"\\"")
<\/p>\n
References:<\/p>\n
Sayyaed A, et al. A detailed review of pathophysiology, epidemiology, cellular and molecular pathways involved in the development and prognosis of Parkinson\u2019s disease with insights into screening models. Bull Natl Res Cent. 2023;47(70). doi:10.1186\/s42269-023-01047-4<\/a>.
\nde Bie RMA, et al. Update on Treatments for Parkinson\u2019s Disease Motor Fluctuations \u2013 An International Parkinson and Movement Disorder Society Evidence-Based Medicine Review. Mov Disord. 2025;40:776-794. doi:10.1002\/mds.30162<\/a>.
\ndi Biase L, et al. Levodopa-Induced Dyskinesias in Parkinson\u2019s Disease: An Overview on Pathophysiology, Clinical Manifestations, Therapy Management Strategies and Future Directions. J Clin Med. 2023;12(13):4427. doi:10.3390\/jcm12134427<\/a>.
\nNational Institute for Health and Care Excellence (NICE). Parkinson\u2019s disease in adults (NG71). London: NICE; 2017 (updated Dec 2024). Available from: https:\/\/www.nice.org.uk\/guidance\/ng71<\/a>.
\nSako W, et al. Comparative efficacy and safety of adjunctive drugs to levodopa for fluctuating Parkinson\u2019s disease: a network meta-analysis. npj Parkinsons Dis. 2023;9:143. doi:10.1038\/s41531-023-00589-8<\/a>.
\nArias-Carri\u00f3n O, Ortega-Robles E. Treatment strategies for motor fluctuations in Parkinson\u2019s disease: a systematic review of efficacy, functionality, and drug accessibility with a focus on Latin America. Front Pharmacol. 2025;16:1725248. doi:10.3389\/fphar.2025.1725248<\/a>.
\nNational Institute for Health and Care Excellence (NICE). Foslevodopa\u2013foscarbidopa for treating advanced Parkinson\u2019s with motor symptoms (TA934). NICE; 2024. Available from: https:\/\/www.nice.org.uk\/guidance\/ta934<\/a>.
\nDeuschl G, et al. European Academy of Neurology\/Movement Disorder Society-European Section Guideline on the Treatment of Parkinson\u2019s Disease: I. Invasive Therapies. Mov Disord. 2022;37:1360-1374. doi:10.1002\/mds.29066<\/a>.<\/p>\n","protected":false},"excerpt":{"rendered":"Optimal management of Parkinson\u2019s disease requires timely recognition of progression, careful patient selection, and a coordinated multidisciplinary approach,…\n","protected":false},"author":2,"featured_media":391951,"comment_status":"","ping_status":"","sticky":false,"template":"","format":"standard","meta":{"footnotes":""},"categories":[10],"tags":[173636,173637,103,61,60,173638,26910,6458,3262],"class_list":{"0":"post-391950","1":"post","2":"type-post","3":"status-publish","4":"format-standard","5":"has-post-thumbnail","7":"category-health","8":"tag-apomorphine","9":"tag-dyskinesia","10":"tag-health","11":"tag-ie","12":"tag-ireland","13":"tag-levodopa","14":"tag-neurodegenerative-disorder","15":"tag-neurology","16":"tag-parkinsons-disease"},"_links":{"self":[{"href":"https:\/\/www.newsbeep.com\/ie\/wp-json\/wp\/v2\/posts\/391950","targetHints":{"allow":["GET"]}}],"collection":[{"href":"https:\/\/www.newsbeep.com\/ie\/wp-json\/wp\/v2\/posts"}],"about":[{"href":"https:\/\/www.newsbeep.com\/ie\/wp-json\/wp\/v2\/types\/post"}],"author":[{"embeddable":true,"href":"https:\/\/www.newsbeep.com\/ie\/wp-json\/wp\/v2\/users\/2"}],"replies":[{"embeddable":true,"href":"https:\/\/www.newsbeep.com\/ie\/wp-json\/wp\/v2\/comments?post=391950"}],"version-history":[{"count":0,"href":"https:\/\/www.newsbeep.com\/ie\/wp-json\/wp\/v2\/posts\/391950\/revisions"}],"wp:featuredmedia":[{"embeddable":true,"href":"https:\/\/www.newsbeep.com\/ie\/wp-json\/wp\/v2\/media\/391951"}],"wp:attachment":[{"href":"https:\/\/www.newsbeep.com\/ie\/wp-json\/wp\/v2\/media?parent=391950"}],"wp:term":[{"taxonomy":"category","embeddable":true,"href":"https:\/\/www.newsbeep.com\/ie\/wp-json\/wp\/v2\/categories?post=391950"},{"taxonomy":"post_tag","embeddable":true,"href":"https:\/\/www.newsbeep.com\/ie\/wp-json\/wp\/v2\/tags?post=391950"}],"curies":[{"name":"wp","href":"https:\/\/api.w.org\/{rel}","templated":true}]}}