By Steven Marsh

Patients who have been diagnosed with Parkinsons disease (PD) may have relief from symptoms associated with the condition in the near future, according to a study presented at the 2010 American Society for Stereotactical and Functional Neurosurgery.

In an effort to find potential treatments for individuals with the nervous system disorder, a team of researchers at Rhode Island Hospital conducted a series of exercises that stimulated the spinal cord on an animal model, which showed signs of PD. Because the findings displayed better motor function in the animal, the investigators tested the treatment with spinal cord simulation on a male patient aged 82 years.

While the individual wasn't receiving any form of medication as treatment for the disorder, researchers used different frequencies of stimulation to determine if a human would experience similar results compared to the animal model.

The researchers discovered that high stimulation frequencies made it easier for the patient to walk, while low frequencies worsened PD side effects.

While the results of thes tudy did give investigators some insight as to how to treat PD patients, clinical trials with a larger group of patients would be more beneficial to developing treatment.

Finding therapies for this disorder is growing in interest throughout the medical world, as QR Pharma and Massachusetts General Hospital have launched research to determine a way to block a protein associated the development of PD.ADNFCR-1960-ID-19845071-ADNFCR

Jack J. Chen, PharmD, BCPS, CGP

The management of Parkinson'sdisease (PD) is complex and involves nonpharmacologic and pharmacologicinterventions for motor and nonmotor symptoms (see accompanying articleby Dr. Simuni). The aim of this article is to provide a greaterunderstanding of PD, treatment risks and benefits, and new developmentsin treatment approach that will allow clinicians, pharmacists, andallied healthcare personnel to better educate and care for patients withPD.

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

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

Thecurrent pharmacologic management paradigm for early-stage PD consistsof 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 progressionwith Azilect Given Once-daily (ADAGIO) study data, initiation ofrasagiline in recently diagnosed patients with early PD presentingwithout functional impairment is a plausible approach.

Inearly-stage PD, monoamine oxidase type B (MAO-B) inhibitors, dopamineagonists, and levodopa (with a decarboxylase inhibitor such ascarbidopa) all provide a sufficient magnitude of therapeutic effect. Inaddition to providing relief of tremor, rigidity, and/or slowness ofmovement, pharmacotherapy can also improve nonmotor symptoms such asfatigue in early PD and can improve experiences of daily living. Ifother symptoms such as constipation, depression, sexual dysfunction, andsleep disorders are present, adjunctive therapies that specificallytarget the symptom should also be considered.
Pharmacotherapy forEarly-Stage PD: Safety, Side Effects, Drug Interactions

Drugsafety and treatment-emergent side effects play a major role in guidingthe selection and adjustment of pharmacotherapy in PD. Healthcareprofessionals involved in the pharmacotherapy management anddistribution spectrum of PD should be concerned about the overall safetyof the medications in this population, the safety of polypharmacyregimens and their necessity (or lack thereof), drug interactions, andeducation of the patient and family about benefits and risks of themedication regimen. Pharmacists, in particular, are traditionally morefocused on drug safety and interactions as well as on providinginstructions on proper use of medications.

Levodopa

Levodopaprovides a robust magnitude of symptom relief effects. In patients withearly PD, common side effects of levodopa include nausea andsomnolence. Of note, hallucinations and psychosis are more common inpatients with advanced stage PD. There is concern about the gradualemergence of motor complications (such as dyskinesias and fluctuations)associated with dose escalation and treatment duration. Motorcomplications can arise quickly (within a few months) or slowly (after ayear or more). Although there are risk factors (eg, levodopa dose andtreatment duration, younger age), no method has been found to predictwhich patients will experience motor complications.

Thedevelopment of levodopa-associated motor complications has a significantimpact on clinicians, patients, and healthcare resources. Motorcomplications can be a challenge for clinicians to manage, can impairpatient health-related quality of life, and can increase direct healthcosts. Independent researchers and pharmaceutical manufacturers havedevoted time and resources toward understanding the pathophysiology ofmotor complications and developing interventions that have specificefficacy for motor complications (eg, apomorphine, entacapone,rasagiline, selegiline oral disintegrating tablets, and deep brainstimulation). Eventually all patients with PD will be prescribedlevodopa; however, in patients with early PD, other medications areavailable to provide adequate symptom relief without the risk for motorcomplications.

Pramipexole, ropinirole, and rasagiline are alsoindicated as monotherapy for PD. Clinicians and patients should engagein discussions about the relative risks and benefits of levodopatherapy, and patients should be allowed to make informed decisions.

DopamineAgonists

The dopamine agonists (pramipexole, ropinirole) providesufficient symptomatic effects for patients with early-stage PD and areless likely to cause motor complications. Side effects that areencountered by patients with early PD include nausea, somnolence, edemaof the extremities, orthostatic hypotension, and impulse controldisorders (ICDs). Of note, hallucinations may occur in patients withearly PD, but are more common in advanced stage PD or patients withcognitive impairment.

Postmarketing recognition of the potentialfor dopamine agonist-induced ICDs has attracted much concern amongclinicians who treat PD. ICDs can be a source of financial and familialstrain for the patient. Common examples include excessive gambling,preoccupation with pornography, overindulgence in purchasing unnecessaryitems, excessive hobbyism, and preoccupation with Internet activities.The prospect of this potentially disruptive side effect should becommunicated to the patient and family. Dopamine agonist-associated ICDsare not dose related and can also develop in patients receiving lowdaily doses for restless legs syndrome.

MAO-B Inhibitors

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

Rasagilineis well tolerated in patients with early PD. Treatment-emergent sideeffects 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 thatrasagiline can be safely administered without regard to meal content oftyramine (eg, in foods such as aged cheeses, red wine, sauerkraut).Based on clinical pharmacology studies, tyramine restriction is nolonger required or advocated by the FDA when rasagiline is initiated.Likewise, sympathomimetic amines (eg, ephedrine, phenylephrine,phenylpropanolamine, pseudoephedrine) and local anesthesia withsympathomimetic vasoconstrictors can be administered concomitantly.Although the concurrent use of antidepressants (with serotonergicactivity) is not contraindicated, benefits should be weighed against thepotential for serotonin syndrome. The STACCATO study is underway tobetter define the potential occurrence of serotonin syndrome withrasagiline and antidepressants.[3]
Patient and Family Education

Patientand family education is critical for the safe and successful use ofmedications in patients with PD. The patient/family should be counseledabout the adverse effects that are most likely to occur and when toreport them to the prescriber. For example, ICDs such as Internetgambling could go undetected by family and unreported by patients andresult in serious financial complications. Nausea, common with levodopaand dopamine agonists, is uncomfortable for patients, and in somecircumstances, may cause discontinuation of therapy prematurely ifpatients are not informed in advance about how to manage the effect. Thesame is true for other adverse effects such as somnolence andorthostatic hypotension. Educating patients and family members aboutpotential treatment-emergent side effects and the importance of seekingassistance can mitigate premature abandonment of the therapy and preventthe side effect from becoming more severe.

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

Lack of awarenessregarding 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 yetresponded to the initial agent).

Patients and families should becounseled about the risks of self-discontinuing a drug for PD. Aworsening 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'sdisease is a lifelong neurologic disorder. Patients will be onpharmacotherapy for the rest of their lives and will have manyencounters with professionals in healthcare. Early-stage, mildlyimpairing PD will progress over time to advanced stages, with severemotor impairment and nonmotor deficits. For patients with early-stage PDand their families, dealing with the diagnosis, learning about PD andits prognosis, and accepting the need for lifelong therapy can beoverwhelming. Clinicians, pharmacists, and allied healthcare personnelcan help patients and families dealing with PD by ensuring that theyreceive adequate medication information at the time a new prescriptionis written and again when it is dispensed. Patients should be assessedfor side effects, and the need for ongoing monitoring of medicationefficacy and potential side effects should be discussed with the family.
Summary

Patientswith early-stage PD will have many encounters with healthcareprofessionals during their lifetime. A better understanding of the motorand 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 andmanage patients. Thoughtful consideration about the initiation ofpharmacotherapy for early-stage PD and information on realisticexpectations of efficacy and side effects can help prevent therapyabandonment and improve clinician-patient management of PD.


Supportedby an independent educational grant from Teva Neuroscience.

Bxarone P, Poewe W, Albrecht S, Debieuvre C, Massey D, Rascol O, TolosaE, Weintraub D.

Department of Neurological Sciences, Universityof Naples Federico II and IDC Hermitage Capodimonte, Naples, Italy.barone@unina.it

Abstract

BACKGROUND: Depression is commonin patients with Parkinson's disease, but evidence on the efficacy ofantidepressants in this population is lacking. Because depression inpatients with Parkinson's disease might be related to dopaminergicdysfunction, we aimed to assess the efficacy of the dopamine agonistpramipexole for treatment of depressive symptoms in patients withParkinson's disease. METHODS: We did a 12-week randomised, double-blind,placebo-controlled (1:1 ratio) trial of pramipexole (0.125-1.0 mg threetimes per day) compared with placebo in patients with mild-to-moderateParkinson's disease. Patients from 76 centres in 12 European countriesand South Africa were included if they were on stable antiparkinsoniantherapy without motor fluctuations and had depressive symptoms (15-itemgeriatric depression scale score > or =5 and unified Parkinson'sdisease rating scale [UPDRS] part 1 depression item score > or =2).Patients were randomly assigned by centre in blocks of four by use of arandomisation number generating system. Clinical monitors, the principalinvestigator, and patients were masked to treatment allocation. Theprimary endpoint was change in Beck depression inventory (BDI) score andall treated patients who had at least one post-baseline efficacyassessment were included in the primary analysis. We also did apre-specified path analysis with regression models to assess therelation between BDI and UPDRS part 3 (motor score) changes. This trialis registered with ClinicalTrials.gov, number NCT00297778, and EudraCT,number 2005-003788-22. FINDINGS: Between March, 2006, and February,2008, we enrolled 323 patients. Of 296 patients randomly assigned topramipexole or placebo, 287 were included in the primary analysis: 139in the pramipexole group and 148 in the placebo group. BDI scoresdecreased by an adjusted mean 5.9 (SE 0.5) points in the pramipexolegroup and 4.0 (0.5) points in the placebo group (difference 1.9, 95% CI0.5-3.4; p=0.01, ANCOVA). The UPDRS motor score decreased by an adjustedmean 4.4 (0.6) points in the pramipexole group and 2.2 (0.5) points inthe placebo group (difference 2.2, 95% CI 0.7-3.7; p=0.003, ANCOVA).Path analysis showed the direct effect of pramipexole on depressivesymptoms accounted for 80% of total treatment effect (p=0.04). Adverseevents were reported in 105 of 144 patients in the pramipexole group and101 of 152 in the placebo group. Adverse events in the pramipexolegroup were consistent with the known safety profile of the drug.INTERPRETATION: Pramipexole improved depressive symptoms in patientswith Parkinson's disease, mainly through a direct antidepressant effect.This effect should be considered in the clinical management of patientswith Parkinson's disease. Copyright 2010 Elsevier Ltd. All rightsreserved.