The Pharmacist's Perspective on Treatment of Early-Stage Parkinson's Disease

Jack J. Chen, PharmD, BCPS, CGP

The management of Parkinson's disease (PD) is complex and involves nonpharmacologic and pharmacologic interventions for motor and nonmotor symptoms (see accompanying article by Dr. Simuni). The aim of this article is to provide a greater understanding of PD, treatment risks and benefits, and new developments in treatment approach that will allow clinicians, pharmacists, and allied healthcare personnel to better educate and care for patients with PD.

As PD progresses from early to advanced stages, medication adjustments and increased numbers of medications should be expected. This article will focus on pharmacotherapy interventions for early-stage PD with an emphasis on safety and drug interactions. A discussion about early interventions in PD, outcomes, and healthcare costs is available elsewhere.[1] Discussions regarding advanced stage PD, management of motor complications, and pharmacotherapies for nonmotor symptoms of PD are beyond the scope of this article and are also available elsewhere.[2]
The Patient With Early-Stage PD

An individual with early-stage PD who has been recently diagnosed may present with motor symptoms and absence of functional impairment or mild functional impairment (eg, clumsiness of the hands, mild deterioration in performance of sports activities, a bothersome tremor, worsening of handwriting). An untreated patient with early-stage PD will have a Unified Parkinson's Disease Rating Scale (UPDRS) score of 20 to 30.

The current pharmacologic management paradigm for early-stage PD consists of initiating 1 drug (ie, monotherapy) to provide symptomatic benefit. Drug therapy is typically initiated to address functional impairment. However, with the publication of the Attenuation of Disease progression with Azilect Given Once-daily (ADAGIO) study data, initiation of rasagiline in recently diagnosed patients with early PD presenting without functional impairment is a plausible approach.

In early-stage PD, monoamine oxidase type B (MAO-B) inhibitors, dopamine agonists, and levodopa (with a decarboxylase inhibitor such as carbidopa) all provide a sufficient magnitude of therapeutic effect. In addition to providing relief of tremor, rigidity, and/or slowness of movement, pharmacotherapy can also improve nonmotor symptoms such as fatigue in early PD and can improve experiences of daily living. If other symptoms such as constipation, depression, sexual dysfunction, and sleep disorders are present, adjunctive therapies that specifically target the symptom should also be considered.
Pharmacotherapy for Early-Stage PD: Safety, Side Effects, Drug Interactions

Drug safety and treatment-emergent side effects play a major role in guiding the selection and adjustment of pharmacotherapy in PD. Healthcare professionals involved in the pharmacotherapy management and distribution spectrum of PD should be concerned about the overall safety of the medications in this population, the safety of polypharmacy regimens and their necessity (or lack thereof), drug interactions, and education of the patient and family about benefits and risks of the medication regimen. Pharmacists, in particular, are traditionally more focused on drug safety and interactions as well as on providing instructions on proper use of medications.

Levodopa

Levodopa provides a robust magnitude of symptom relief effects. In patients with early PD, common side effects of levodopa include nausea and somnolence. Of note, hallucinations and psychosis are more common in patients with advanced stage PD. There is concern about the gradual emergence of motor complications (such as dyskinesias and fluctuations) associated with dose escalation and treatment duration. Motor complications can arise quickly (within a few months) or slowly (after a year or more). Although there are risk factors (eg, levodopa dose and treatment duration, younger age), no method has been found to predict which patients will experience motor complications.

The development of levodopa-associated motor complications has a significant impact on clinicians, patients, and healthcare resources. Motor complications can be a challenge for clinicians to manage, can impair patient health-related quality of life, and can increase direct health costs. Independent researchers and pharmaceutical manufacturers have devoted time and resources toward understanding the pathophysiology of motor complications and developing interventions that have specific efficacy for motor complications (eg, apomorphine, entacapone, rasagiline, selegiline oral disintegrating tablets, and deep brain stimulation). Eventually all patients with PD will be prescribed levodopa; however, in patients with early PD, other medications are available to provide adequate symptom relief without the risk for motor complications.

Pramipexole, ropinirole, and rasagiline are also indicated as monotherapy for PD. Clinicians and patients should engage in discussions about the relative risks and benefits of levodopa therapy, and patients should be allowed to make informed decisions.

Dopamine Agonists

The dopamine agonists (pramipexole, ropinirole) provide sufficient symptomatic effects for patients with early-stage PD and are less likely to cause motor complications. Side effects that are encountered by patients with early PD include nausea, somnolence, edema of the extremities, orthostatic hypotension, and impulse control disorders (ICDs). Of note, hallucinations may occur in patients with early PD, but are more common in advanced stage PD or patients with cognitive impairment.

Postmarketing recognition of the potential for dopamine agonist-induced ICDs has attracted much concern among clinicians who treat PD. ICDs can be a source of financial and familial strain for the patient. Common examples include excessive gambling, preoccupation with pornography, overindulgence in purchasing unnecessary items, excessive hobbyism, and preoccupation with Internet activities. The prospect of this potentially disruptive side effect should be communicated to the patient and family. Dopamine agonist-associated ICDs are not dose related and can also develop in patients receiving low daily doses for restless legs syndrome.

MAO-B Inhibitors

The MAO-B inhibitors (rasagiline, selegiline) provide modest symptomatic relief in patients with early PD. Of the available MAO-B inhibitors, rasagiline is the only one with labeling approved by the US Food and Drug Administration for monotherapy in PD. In addition, data from the ADAGIO study (a large, randomized, controlled trial) suggest that early initiation of rasagiline in patients with PD and the absence of functional impairment confer more benefit than delaying therapy.

Rasagiline is well tolerated in patients with early PD. Treatment-emergent side effects are nonspecific and include flulike weakness and asthenia. Overall, rasagiline is notable for its lack of dopaminergic side effects (eg, nausea, orthostasis, somnolence). Postmarketing data indicate that rasagiline can be safely administered without regard to meal content of tyramine (eg, in foods such as aged cheeses, red wine, sauerkraut). Based on clinical pharmacology studies, tyramine restriction is no longer required or advocated by the FDA when rasagiline is initiated. Likewise, sympathomimetic amines (eg, ephedrine, phenylephrine, phenylpropanolamine, pseudoephedrine) and local anesthesia with sympathomimetic vasoconstrictors can be administered concomitantly. Although the concurrent use of antidepressants (with serotonergic activity) is not contraindicated, benefits should be weighed against the potential for serotonin syndrome. The STACCATO study is underway to better define the potential occurrence of serotonin syndrome with rasagiline and antidepressants.[3]
Patient and Family Education

Patient and family education is critical for the safe and successful use of medications in patients with PD. The patient/family should be counseled about the adverse effects that are most likely to occur and when to report them to the prescriber. For example, ICDs such as Internet gambling could go undetected by family and unreported by patients and result in serious financial complications. Nausea, common with levodopa and dopamine agonists, is uncomfortable for patients, and in some circumstances, may cause discontinuation of therapy prematurely if patients are not informed in advance about how to manage the effect. The same is true for other adverse effects such as somnolence and orthostatic hypotension. Educating patients and family members about potential treatment-emergent side effects and the importance of seeking assistance can mitigate premature abandonment of the therapy and prevent the side effect from becoming more severe.

Patients and families should be counseled about the drug's expected time to onset and response. Levodopa symptomatic benefit will be noted almost immediately (within a few doses or days). Dopamine agonists require initiation at a low (subtherapeutic) dose with gradual titration to a maintenance dose. This is done to minimize side effects. Thus, onset of a noticeable improvement usually takes more than 2 weeks. The onset of noticeable improvement with rasagiline may take several weeks, and the full effect may not be seen for up to 8 to 12 weeks.

Lack of awareness regarding a realistic onset of effect can lead to medication abandonment (because of the belief that the drug is ineffective) and polypharmacy (if other agents are prescribed to treat symptoms that have not yet responded to the initial agent).

Patients and families should be counseled about the risks of self-discontinuing a drug for PD. A worsening of motor symptoms would occur, and in some cases, discontinuation effects such as agitation, anxiety, diaphoresis, dysphoria, insomnia, or neuroleptic malignant syndrome may occur.

Parkinson's disease is a lifelong neurologic disorder. Patients will be on pharmacotherapy for the rest of their lives and will have many encounters with professionals in healthcare. Early-stage, mildly impairing PD will progress over time to advanced stages, with severe motor impairment and nonmotor deficits. For patients with early-stage PD and their families, dealing with the diagnosis, learning about PD and its prognosis, and accepting the need for lifelong therapy can be overwhelming. Clinicians, pharmacists, and allied healthcare personnel can help patients and families dealing with PD by ensuring that they receive adequate medication information at the time a new prescription is written and again when it is dispensed. Patients should be assessed for side effects, and the need for ongoing monitoring of medication efficacy and potential side effects should be discussed with the family.
Summary

Patients with early-stage PD will have many encounters with healthcare professionals during their lifetime. A better understanding of the motor and nonmotor symptoms of PD, risks and benefits of PD medications (Table), and drug-related complications will allow clinicians, pharmacists, and allied health professionals to better educate and manage patients. Thoughtful consideration about the initiation of pharmacotherapy for early-stage PD and information on realistic expectations of efficacy and side effects can help prevent therapy abandonment and improve clinician-patient management of PD.


Supported by an independent educational grant from Teva Neuroscience.