Advanced Parkinson Disease: Treatment Approaches

Parkinson disease (PD) is a multisystemic neurodegenerative disorder associated with pathologic accumulation of misfolded α-synuclein in the central and peripheral nervous systems. Bradykinesia, rigidity, rest tremor, and postural instability are the cardinal motor symptoms. Nonmotor symptoms are myriad due to end-organ dysfunction caused by widespread neuronal degeneration. There is no universal definition of advanced PD (aPD), but individuals with aPD commonly develop complications of dopaminergic therapy and accumulate disability due to progression of both motor and nonmotor symptoms. In studies focusing on aPD, the most distressing symptoms reported were pain; neuropsychiatric manifestations; nighttime sleep disorders; impairments in gait, balance, and posture; and falls.¹

This review focuses on aPD, a clinical stage commonly characterized by significant motor fluctuations and/or dyskinesia despite optimized oral dopaminergic therapy, increasing functional disability, and a growing burden of non-motor symptoms. Although no universally accepted definition of aPD exists, this operational framework is consistent with descriptions endorsed by the International Parkinson and Movement Disorder Society and is widely used to guide escalation to device-aided and advanced therapies. When findings apply to PD across all stages, this is explicity stated.^1a

Motor Complications

As PD progresses, nigrostriatal dopaminergic neuronal loss increases the variability of plasma dopamine levels with oral levodopa dosing. This variability leads to fluctuations of motor and nonmotor symptoms, creating “off” (inadequately medicated) and “on” (medicated) states that become less predictable as the disease progresses. The presence of bothersome motor fluctuations requires an approach that maximizes “on” time without medication-related complications (good “on” time). See Table 1 for treatment guidance.

Pharmacologic Therapies
When motor fluctuations arise, increasing carbidopa/levodopa (C/L) dosing frequency can reduce wearing-off effects. However, more frequent dosing decreases adherence, interferes with natural mealtimes and sleep cycles, and increases the risk of peak-dose dyskinesia. Levodopa absorption may be reduced by competition with dietary protein; however, in those with aPD, timing of dosing relative to meals should be individualized to balance motor benefit, tolerability, nutritional status, and gastrointestinal symptoms.

Advanced formulations of oral C/L can deliver smoother and more sustained benefit. Crexont (C/L; Amneal Pharmaceuticals, Bridgewater, NJ) is a new capsule containing immediate release C/L and beads comprised of enteric coating, a mucoadhesive extended release C/L polymer, which enhances absorption, and sustained-acting C/L. Crexont was approved by the Food and Drug Administration (FDA) as a treatment for people living with PD complicated by motor fluctuations. Clinical trials demonstrated improved duration of good “on” time per dose and reduced dosing frequency compared with immediate-release formulations, supporting its use in patients with motor fluctuations.² Rytary (C/L; Amneal Pharmaceuticals, Bridgewater, NJ) is a capsule containing both immediate- and extended-release C/L beads that was approved by the FDA in 2015. Inbrija (levodopa inhalation powder; Merz Pharmaceuticals, Raleigh, NC) was approved by the FDA for the intermittent treatment of “off” episodes in patients with PD treated with C/L; it achieves peak effect within 15 minutes by bypassing enteric absorption. Inbrija can be used on-demand for sudden and severe “off” episodes.³

Nonlevodopa medications used as adjuncts to levodopa therapy may also reduce motor complications in people living with aPD. These include nonergot dopamine receptor agonists (oral pramipexole, oral ropinirole, Neupro [rotigotine transdermal patch; UCB, Atlanta, GA], and subcutaneous apomorphine for “off”-state rescue), selective monoamine oxidase B inhibitors (rasagiline, selegiline, and Xadago [safinamide; MDD, Rockville, MD]), and catechol-O-methyltransferase inhibitors (entacapone, tolcapone, and Ongentys [opicapone; Amneal Pharmaceuticals, Bridgewater, NJ]). Impulse control disorders and hallucinations are class-specific adverse effects related to activation of D2 receptor subtypes (D2, D3, and D4); concerns about these adverse effects may limit the use of dopamine agonists. Tavapadon (AbbVie, North Chicago, IL), a partial agonist of the D1 and D5 receptor subtypes developed to potentially reduce dopamine-related adverse effects, increases good “on” time compared to placebo as an adjunct to oral levodopa. It is under FDA review with a decision anticipated in 2026.^21a

Nourianz (istradefylline; Kyowa Kirin, Princeton, NJ), an adenosine A2A receptor antagonist, normalizes signaling in the indirect dopaminergic pathway and may reduce motor complications. Amantadine, which decreases glutamatergic tone through noncompetitive antagonism of striatocortical NMDA receptors, reduces peak-dose dyskinesias, and its extended-release formulation (Gocovri, Supernus Pharmaceuticals, Rockville, MD) can also reduce “off” time, although its downstream inhibition of cholinergic transmission can cause adverse effects that limit its use in older individuals.

Pump-Based Pharmacologic Therapies
Continuous subcutaneous administration of dopaminergic agents can reduce variability of plasma medication levels by circumventing gastrointestinal absorption and first-pass metabolism.

Daytime subcutaneous infusion of the dopamine agonist Onapgo (apomorphine hydrochloride infusion; MDD, Rockville, MD) reduced “off” time, increased “on” time, and reduced the daily dose of oral levodopa compared with placebo.⁴ FDA labeling recommends using a low starting dose of 1 mg/h with careful titration to minimize nausea and vomiting typically associated with this medication. Common adverse effects leading to discontinuation of the medicine in the phase 3 clinical trial included skin nodules, nausea, and somnolence.⁴

Vyalev (continuous subcutaneous foscarbidopa/foslevodopa infusion; AbbVie, North Chicago, IL), which received FDA approval in 2024 for the treatment of motor fluctuations in those living with aPD, reduces “off” time and increases “on” time compared with oral C/L.⁵ In the pivotal phase 3 trial for this therapy, dermatologic side effects around the injection site were common but generally mild.⁵ However, 22% of participants in the treatment group discontinued therapy, mostly due to infusion site complications.⁵

These subcutaneous delivery systems eliminate the stoma-related side effects associated with gastrojejunostomy tube placement, which is required for continuous intrajejunal C/L enteral suspension (Duopa [intrajejunal carbidopa/levodopa suspension; AbbVie, North Chicago, IL]), which was the first infusion treatment approved as a treatment for those living with aPD in the United States (in 2015).

Surgical and Ablative Therapies
Deep brain stimulation (DBS) is the primary surgical treatment option for those living with PD with medication refractory motor complications and severe tremor at any stage of the disease.

Optimal candidate and target selection requires multidisciplinary collaboration and consensus.⁶ New developments in DBS include adaptive stimulation and imaging-guided programming, which can increase the therapeutic window through more temporally or spatially precise stimulation.^7,8

Magnetic resonance–guided focused ultrasound of the ventral intermediate nucleus of the thalamus (for tremor-dominant cases) and globus pallidus internus are noninvasive alternatives to DBS. Staged unilateral and bilateral magnetic resonance–guided focused ultrasound of the pallidothalamic tract was also recently approved by the FDA for patients with aPD with medication-refractory motor symptoms.⁹

Gait, Balance, and Postural Deformities
Postural deformities, impaired balance, and gait dysfunction reduce quality of life (QoL) and contribute to falls and related mortality in aPD. In addition, inactivity from fear of falling exacerbates motor and nonmotor symptoms in PD. Impaired balance in aPD is multifactorial and challenging to treat. See Table 2 for treatment guidance. Studies of levodopa and DBS in improving gait are mixed.¹⁰ Activity-based interventions demonstrate consistent benefits in balance, although their efficacy in reducing falls is less clear.¹⁰

As with balance, gait dysfunction in PD is multifactorial. Later symptoms include festination and freezing of gait (FoG), which occur in most people with aPD.¹¹

The evidence for pharmacologic and neuromodulatory treatment of gait dysfunction is mixed. In some cases, oral levodopa may improve gait dysfunction and FoG.¹¹ Regular exercise and targeted activity can improve gait and alleviate freezing episodes. Auditory or visual cuing with a metronome or a laser beam attached to a cane or walker can rescue an individual during a freezing episode and reduce FoG.¹¹ There are several specialized walkers available for PD-related gait impairment; however, the literature supporting these interventions has reported mixed results, and the walkers must be customized for each patient’s needs.^26a

People with PD can develop painful postural deformities, such as camptocormia or Pisa syndrome, which are due to axial dystonia causing forward or laterally bent postures, respectively. Dopaminergic medications may either cause or improve camptocormia. A small trial of botulinum toxin injections as treatment for this condition showed mixed results; however, targeted physical activity was beneficial.¹⁰ Pisa syndrome is multifactorial, and can co-occur with camptocormia. Risk factors include age, osteoporosis, arthritis, disease duration, and severity of PD. Pisa syndrome is associated with increased fall frequency and decreased QoL. The results of small trials of dopamine agonists, levodopa, and paraspinal muscle botulinum toxin injections have been negative.¹⁰ Botulinum toxin injections of the rectus abdominus done by an experienced clinician using ultrasound or fluoroscopic guidance may be beneficial in selected cases.

Nonmotor Complications

Nonmotor symptoms accumulate as PD progresses, making treatment in those living with aPD challenging for the clinician. Although PD-specific FDA-approved medications are not available for most nonmotor symptoms, there are several pharmacological options that are available for treatment. See Table 3 for treatment guidance.

Neuropsychiatric Symptoms
The primary neuropsychiatric manifestations of PD are affective disorders, neurocognitive disorders, and disorders of thought and perception. Affective disorders may occur prodromally; neurocognitive and thought disorders arise later in the disease.¹²

Symptoms of depression and anxiety occur in up to 35% of people with PD. The prevalence of depression increases with advancing disease, reaching up to 60% of those with aPD.¹² Cognitive-behavioral therapy (CBT) is the mainstay of nonpharmacologic treatment of depression, and CBT performed through telemedicine is noninferior to CBT performed in-person.¹² For individuals requiring pharmacologic therapy, meta-analyses have demonstrated safety of selective serotonin reuptake inhibitors, serotonin and norepinephrine reuptake inhibitors, and tricyclic antidepressants in those with PD.¹² Selective serotonin reuptake inhibitors are typically also used to treat generalized anxiety symptoms.

One-third of people with PD have mild cognitive impairment, and a majority will eventually develop dementia. Addressing modifiable risk factors for cognitive issues, such as cardiovascular health, sleep apnea, social isolation, auditory function, and orthostatic hypotension, is imperative when treating individuals with PD. Evidence for the benefits of acetylcholinesterase inhibitors and memantine on cognition in PD is mixed.²³ Rivastigmine remains the only medication approved by the FDA for mild-to-moderate dementia associated with PD.²³

Disorders of thought and perception in aPD vary widely in severity. Psychosis manifests as persistent and distressing hallucinations or delusions, typically in the setting of cognitive decline. Up to 60% of people with aPD experience psychosis, which confers increased risk of both institutionalization and mortality.¹² After toxic, metabolic, and iatrogenic contributors to psychosis are investigated and treated, pharmacologic antipsychotic treatment may be necessary if symptoms persist. Pimavanserin (Nuplazid; Acadia Pharmaceuticals, San Diego, CA), an inverse agonist and antagonist of the 5-HT2A receptor, received FDA approval to treat hallucinations and delusions associated with PD psychosis in 2016.¹³ The second-generation antipsychotic drug clozapine is an effective treatment for PD psychosis. As of 2025, the FDA no longer requires patient or provider participation in the centralized Risk Evaluation and Mitigation Strategy (REMS) program when using clozapine, easing its accessibility as a treatment for PD psychosis.^29a Another second-generation antipsychotic agent, quetiapine (Seroquel; AstraZeneca, Wilmington, DE) is often used off-label to treat PD psychosis in part due to its known sedating effects despite limited evidence for efficacy. All second-generation antipsychotics, including quetiapine and pimavanserin, include an FDA boxed warning due to a potential increase in mortality when used in older patients with behavioral disturbances.^29b

Autonomic Symptoms
In PD, both central and peripheral autonomic dysfunction contribute to substantial disability. Common autonomic manifestations include decreased gastrointestinal motility, constipation, detrusor overactivity, neurogenic orthostatic hypotension, sialorrhea, and sexual dysfunction. Appropriate management should account for individual comorbidities and disease-related sensitivities to certain adverse effects of medications. Both nonpharmacologic and pharmacologic treatment options were reviewed in detail in a previous issue of Practical Neurology.¹⁴ Some autonomic symptoms, such as constipation, may appear in the prodromal stage; all symptoms invariably worsen over time.

Pain
In one meta-analysis, pain was cited as the most bothersome symptom by those living with aPD.¹ Although between 40% and 85% people with PD experience pain, only ~50% receive appropriate analgesia.¹⁵

The treatment of pain in those living with PD depends on its quality and etiology. Possible causes include both “on” and “off” motor symptoms, postural deformities, sensory neuropathy, painful dystonia unresponsive to PD medications, or central pain. Escalating treatment should begin with nonpharmacologic or topical modalities to minimize adverse effects of systemic analgesics.

Sleep
Insomnia and excessive daytime sleepiness are common in PD and tend to worsen as motor symptoms progress.¹⁶ Possible etiologies of insomnia include nocturnal motor symptoms, REM sleep behavior disorder, restless legs syndrome, periodic limb movements of sleep, mood disorder, vivid dreams, sleep-disordered breathing, and nocturia. Appropriate treatment should be tailored to the underlying disturbance.

Providers should screen for “sleep attacks”, which are characterized by an abrupt and unavoidable transition from wakefulness to sleep, particularly in individuals who take dopamine receptor agonists.

Palliative and Hospice Care

Palliative care in aPD focuses on symptom management, psychosocial support, and improving health-related QoL. Providers with the appropriate skills also should provide caregiver support, facilitate conversations around advanced care planning, and administer goal-congruent end-of-life care.¹⁷

The 2 most common causes of death in aPD are aspiration pneumonia and complications from hip fractures. Dysphagia also contributes to malnutrition and reduced adherence to oral medication regimens. Gastrostomy tubes do not improve QoL or reduce mortality risk, and are associated with increased hospitalizations.¹⁷

Hospice enrollment increases access to home assistance, certain medications, and inpatient facilities, if necessary. Individuals enrolled in hospice are more likely to receive care aligned with their wishes and less likely to die in a hospital.¹⁷

Conclusion

The functional impairment resulting from the accumulation of motor and nonmotor symptoms leads to substantial disability and reduced QoL and presents unique therapeutic challenges in people with aPD that warrant comprehensive, multidisciplinary treatment. Continuity of care builds trust among patients, caregivers, and providers, facilitating difficult conversations regarding treatments and potential side effects. Treatment options vary widely and should be selected based on accessibility, side effect profile, and best practices when available. Appropriate involvement of palliative care specialists can support goal-congruent care and reduce caregiver burden.