Early Versus Delayed Diagnosis and Treatment of Parkinson’s Disease:
What You Need To Know

This CE program is supported by an educational grant from Teva Neuroscience.

FACULTY:

Michele A. Faulkner, PharmD
Associate Professor of Pharmacy Practice and Medicine
Creighton University
Omaha, NE

FACULTY DISCLOSURE STATEMENTS:

Michele A. Faulkner, PharmD reported the following relationships to products or devices she has commercial interests related to the content of this CE activity: member of the Speaker’s Bureau of Teva Neuroscience.

ACCREDITATION STATEMENT:

Pharmacy
Postgraduate Healthcare Education, LLC is accredited by the Accreditation Council for Pharmacy Education as a provider of continuing pharmacy education.
Program No.: 430-000-08-025-H01-P; 430-000-08-025-H01-T
Credits: 2.0 hours (0.20 ceu)

TARGET AUDIENCE:

This accredited program is targeted to pharmacists and pharmacy technicians. Estimated time to complete this monograph and posttest is 90 to 120 minutes.

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DISCLAIMER:

Participants have an implied responsibility to use the newly acquired information to enhance patient outcomes and their own professional development. The information presented in this activity is not meant to serve as a guideline for patient management. Any procedures, medications, or other courses of diagnosis or treatment discussed or suggested in this activity should not be used by clinicians without evaluation of their patients’ conditions and possible contraindications or dangers in use, review of any applicable manufacturer’s product information, and comparison with recommendations of other authorities.

GOAL:

To aid pharmacists in their understanding of the challenges associated with the diagnosis of Parkinson’s disease, the choice of initial drug therapy, and the timing of treatment initiation to ensure the best long-term patient outcomes.

OBJECTIVES:

After completing this program, participants will be able to:

1. Review the pathophysiology and clinical features of Parkinson’s disease;*
2. Describe the diagnostic process and confounding factors;*
3. Discuss current opinion regarding early versus delayed initiation of therapy;*
4. Review medications available for initial treatment;* and
5. Develop strategies for enhancing patient outcomes.

*Also applies to pharmacy technicians.

Controversy has existed for many years regarding the best approach for initiation of drug treatment for Parkinson’s disease (PD). Some practitioners adopt a “wait and watch” approach, questioning whether exposure to drug therapy carries a benefit that outweighs the risks unless the patient is experiencing symptoms that are interfering with functional ability. There is also concern that early drug exposure may render the efficacy of some treatment obsolete in later years, and a belief that delaying drug therapy, levodopa in particular, will protect a patient from the onset of motor complications. Other practitioners feel that treatment should be initiated immediately upon diagnosis, in the hope of preserving functional ability and staving off deterioration of quality of life (QOL). This monograph will attempt to address these issues.

ETIOLOGY AND PATHOPHYSIOLOGY

PD is a progressive disease with an insidious onset. It ranks second only to Alzheimer’s disease with regard to neurodegenerative disorder prevalence.¹ The underlying pathology is not completely understood, but death of nigrostriatal neurons and subsequent deficiency in dopamine cause a decrease in inhibitory output from the basal ganglia.² Normal dopamine activity as it relates to acetylcholine is diminished, and relative overactivity of cholinergic output results. This derangement of neurotransmitter function is believed to be the underlying cause of motor abnormalities that are the cardinal features of PD. In addition, Lewy bodies (disease-specific misfolded proteins) are easily identifiable in the brain cells of patients postmortem. These proteins are believed to result from the underlying pathology of PD rather than act as a cause.³ The rate at which cells die is unknown and is probably variable from person to person.⁴

There are two phases of PD that can be divided into the pre-symptomatic phase and the symptomatic phase.⁵ Only the second phase can currently be clinically assessed. PD appears to begin in the lower brainstem and the olfactory bulb, only affecting the nigrostriatal system about midway into its course.^6,7 At the time of diagnosis

up to 80% of susceptible neurons have been lost. In younger patients especially there appears to be a genetic predisposition.⁸ This genetic link is hypothesized to account for up to 20% of young-onset disease (PD that appears in persons under age 40). Several genetic mutations believed to have some role in the development of PD have been identified.⁸Besides a familial risk, toxins in the environment (including exposure to pesticides and well water) and the sequelae of infection have been implicated. Because we currently cannot identify with certainty which persons are at risk for PD development, early intervention continues to be a challenge.

DIAGNOSIS

We have learned much about PD, but the diagnosis is still made almost exclusively based on presenting symptoms and definitive response to the administration of levodopa. Although researchers are still looking to neuroimaging as a means by which patients may be diagnosed, at present it does not play a major role.³ Imaging may have a place in the study of medications for neuroprotection or disease modification, but at this time it is primarily useful in helping to rule out other diseases at diagnosis.

Cardinal Features

There are considered to be four cardinal features of PD: tremor, bradykinesia, rigidity, and postural instability. Tremor is the first and most common, and it usually begins unilaterally. The distal extremities, particularly the hands, are the most common site of early development, but the legs, lips, chin, and jaw may also be affected. Tremor motion in the hands is often described as “pill rolling,” since the fingers and thumbs move in opposition as though a small object was being rolled between them. Tremor typically is present at rest but early in the disease will disappear with purposeful movement or during sleep. Some patients do not demonstrate an outward tremor but complain of internal vibration.⁹ In younger patients, tremor may be intermittent and may be visible only during periods of stress or fatigue.⁸ Acetylcholine overactivity is thought to be the primary etiology of PD tremor.

Bradykinesia (or akinesia) is more likely to be found in older patients upon presentation. Bradykinesia is a generalized slowing of movement that poses difficulty with motions requiring fine motor control or repetition (such as brushing one’s teeth). Spontaneous gesturing may be reduced, and normal arm swing when walking may be absent.⁹ With unilateral involvement, patients may appear to be limping. Voice level and inflection are often diminished, and facial expression may be blunted. Early in the disease, generalized muscle weakness may be self-reported but may be absent upon examination. As the disease progresses, bradykinesia is often pinpointed by patients as their most troubling symptom. Movement becomes increasingly impaired and can make turning in bed, rising from a low chair, and even walking increasingly difficult.

Rigidity typically presents in older patients; it is much less common upon presentation in the young.⁸ It is distinguished by increased resistance of muscle throughout the range of passive movement. Rigidity may be proximal or distal and can be fixed, but more often is described as “cogwheeling” or “jerky.”⁹ Vague pain or aching, often due to stiffness in the shoulder or arm on the side where obvious symptoms will appear, may be an early manifestation.

Unlike the other features, postural instability is rarely present upon initial presentation. Therefore, it is not included as a criterion for diagnosis and if present early on may in fact be a clue that the patient has another disorder. Postural instability is the primary cause of falls associated with PD.⁹ Signs include flexion at the knees, hips, and waist and walking on the balls of the feet.

Variable Presentation

The diagnosis of PD is made when two of the four cardinal features are evident; however, patients may present with a variety of symptoms. It should be noted that symptoms associated with PD are not exclusively motor-related, but rather they exist in concert with a multitude of non-motor symptoms. In fact, non-motor symptoms may be the first to appear, suggesting that there may be a prodromal period associated with disease onset.⁴ Younger patients in particular may develop symptoms that are difficult to recognize as part of PD because the earliest manifestations of the disease may not be classic in their presentation, and because PD is less likely to be suspected in younger patients. Patients may feel cold, or they may complain of tingling or cramping, especially in the feet.⁸ Dystonias, some of which cause significant pain, may result in inward turning of an extremity or dorsiflexion of the big toe, plantar flexion of the foot, or adduction of the arm or elbow such that the patient carries the limb in front of the abdomen or chest. Symptoms may be intermittent rather than constant.⁴ In addition, loss of the sense of smell is also becoming increasingly recognized as an early symptom of PD and may in fact occur decades before a definitive diagnosis is made.¹⁰

Non-dopaminergic neurons can also be affected in patients with PD. This may ultimately lead to derangements in serotonin and norepinephrine concentrations. Such alterations may result in behavioral and psychiatric problems.⁸ In those patients who develop PD early, depression precedes the diagnosis in approximately one third of cases. It is not yet clear whether depression is part of the disease, a result of the disease, or simply shares the same pathology leading to concurrence. Depression becomes increasingly common as people continue to live with PD. In addition, anxiety, dementia, and sleep disorders are more common in patients with PD compared with the normal population and are likely directly connected to a common pathology. It is clear that PD is not bounded by the central nervous system.¹⁰ Lewy bodies have been identified in other tissues postmortem. There is evidence that sympathetic denervation of the heart is present in PD, as is involvement of the peripheral autonomic nervous system. These factors likely play a role in the fatigue; orthostatic hypotension; and esophageal, bowel, and bladder dysfunction that trouble many patients with PD (Table 1).

DIFFERENTIAL DIAGNOSIS

A number of disorders share common features with PD, and differentiating among them can be challenging (Table 2). Available studies show nearly one third of patients diagnosed by primary care physicians as having PD in fact have another disorder.¹¹ The diagnosis can also pose challenges for neurologists. Disorders most commonly leading to misdiagnosis include essential tremor, progressive supranuclear palsy (PSP), multiple system atrophy (MSA), and dementia with Lewy bodies (DLB).¹² Unlike the tremor seen in patients with PD, essential tremor is often postural, increases with action, and is absent at rest.13 It is usually bilateral, may involve the head and voice (as opposed to the jaw and lips), and is not associated with a second cardinal feature of PD. The legs are not usually involved.

The median age of PSP onset is 55 to 70 years, which is consistent with PD. However, mean survival is only six years.¹⁴ Falls in patients with PSP are typical, even within the first 12 months. Since postural instability in early PD is rare, this may help to differentiate between the two diseases. Patients with PD tend to turn without twisting at the trunk (en bloc), whereas patients with PSP usually pivot.The most distinguishing feature of PSP is a prominent downgaze; there is no ocular involvement in PD.¹⁵ Rarely, patients with PSP respond to levodopa, but its effects wear off relatively quickly.

MSA is a degenerative disorder of the central and autonomic nervous systems. It typically strikes persons in their 50s, and death, often from bronchopneumonia, usually follows within 10 years.¹² Symptoms associated with MSA include autonomic failure, with frequent occurrence of urinary incontinence and male impotence. Both symptoms may also accompany PD in later stages. Parkinsonian features, including tremor at rest, unilateral akinesia, and rigidity, dominate in the majority of MSA cases.¹²

Symptomatic orthostatic hypotension is common in MSA but is uncommon in early PD unless it is drug induced.¹⁵ As with patients with PSP, a subset of patients with MSA (30%) may respond to levodopa, but the response is temporary.¹²

Parkinsonian symptoms are a primary manifestation of DLB. However, if symptom asymmetry is present, it is more suggestive of PD, as is the absence of cognitive disorders early in the disease. Dementia and recurrent hallucinations are qualities associated with DLB early, even within the first year of diagnosis.¹²

One other problem commonly mistaken for PD, particularly in younger persons, is drug-induced parkinsonism.^8,13 Medications often implicated include phenothiazine antiemetics, neuroleptics, and metoclopramide. Occasionally, symptoms may be unilateral, but more often they affect both sides. Postural tremor is more common with drug-induced disease, and there may be early choreoathetoid movements of the face and mouth. Drug-induced parkinsonism is completely reversible, typically fully resolving within weeks of drug discontinuation. However, in some cases the symptoms last a substantially longer time.¹³

STAGING

There are several rating scales used to stratify patients with PD into functional groups. The two most common are the Unified Parkinson Disease Rating Scale (UPDRS) and the Hoehn and Yahr scale. The UPDRS is the most well-established rating tool for assessing motor disability.⁹ It is subdivided into four sections:

1. mentation, behavior, mood;
2. activities of daily living;
3. motor function exam; and
4. the history of complication of therapy during the previous seven days.

A score of zero equates to no disability, and total disability is quantified by a score of 199.

In contrast, the Hoehn and Yahr scale is relatively simplistic and is meant to be a tool for overall assessment of disease advancement.⁹ It consists of five stages with symptoms grouped according to typical PD progression. With such scales, disease progression can be monitored, and determination of appropriate drug therapy at a given time can be accomplished.¹⁶

Hoehn and Yahr stage one corresponds to mild unilateral symptoms. Tremor, if present, will be confined to a single limb. Persons close to the patient will have begun to notice changes. The patient is typically able to remain independent despite impairment in functional ability.

In stage two, symptoms have become bilateral, and gait and posture have become involved. Medication response usually remains robust. Hoehn and Yahr stages one and two generally equate to a UPDRS score under 20, signifying that the patient is experiencing difficulty with daily tasks but has remained relatively independent.¹⁶

Hoehn and Yahr stage three represents significant slowing of movement and moderately severe functional impairment. Balance may now be involved. Patients may experience wearing off of medication effect and abnormal motor symptoms related to treatment. The corresponding UPDRS score is 30 to 40, indicating the patient can still accomplish most activities of daily living without help but may need some assistance at times of more impaired function.¹⁶ At this point the patient begins the transition from impaired to disabled.⁶ Stage four represents severe symptoms, with diminished ability to walk and pronounced rigidity and bradykinesia. The patient will be unable to live independently.

Stage five represents wheelchair-bound patients needing constant care. When patients reach a UPDRS score of 40 to 60, cognitive abilities become affected, and the patient will find tasks such as managing money and medications difficult without help. Disability continues from that point up the scale.

DISEASE PROGRESSION

As stated previously, PD is a progressive disease. Prior to the discovery of levodopa, the diagnosis meant an early death. Now the lifespan of patients approaches that of the unaffected population.⁸ Progression of PD varies by individual patient, much as the presenting symptoms do. In a single individual, disease progression may be monitored using the UPDRS, which is more relevant than surrogates such as imaging, since function is the ultimate measure of treatment success. A specific time course for disease evolution is not feasible using direct observation alone, because virtually all patients receive medication that alters presentation.¹⁷

As patients continue to live with PD and are treated with dopaminergic medications, motor complications materialize. They include wearing off, on-off phenomenon, and dyskinesias. Wearing off occurs when patients experience reemergence of symptoms before the next dose of medication is due despite continuing a regimen that previously controlled symptoms. Disease modeling shows that the effects of dopamine replacement do not decline with PD progression, nor does levodopa speed disease progression.¹⁷ One currently accepted belief for why wearing off occurs is that neuronal ability to store dopamine diminishes over time. Ultimately, this leads to insufficient receptor stimulation and symptom reemergence. Strategies for combating wearing off include decreasing the dosing interval, adding a receptor stimulating medication in an effort to “spare” existing dopamine, or adding a medication that inhibits the breakdown of dopamine via enzymes in the brain.

On-off phenomenon, unlike wearing off, is unpredictable. Symptoms may be controlled in one moment, and then break through without warning only to come under control once again as suddenly as they appeared. This process typically occurs within seconds to minutes.¹⁸ Because there is no warning, on-off phenomenon is particularly distressing to patients. If off time becomes increasingly severe, the drug apomorphine may be used. However, the inconvenience of multiple injections, the high incidence of nausea, and the potential for severe hypotension have somewhat limited its use.

Dyskinesias are involuntary movements that emerge in patients after exposure to dopaminergic medications. They usually appear after five to ten years of drug use.¹⁹ There are different types, with the most common being the peak-dose variety, which affects 80% of patients.²⁰ Their occurrence is simultaneous with the achievement of peak dopamine levels supplied through medication, resulting in optimal control of PD motor symptoms. A definitive cause of dyskinesia development has not been identified, although the most constant risk factor appears to be younger age at disease onset.²⁰ Early theories about the mechanism included dopamine receptor overstimulation, a supposition made more credible by the fact that dyskinesias sometimes appear when patients are given drugs to prevent dopamine degradation. However, an increasingly accepted theory is that dyskinesias are related to pulsatile stimulation of dopamine receptors.²⁰ Fewer nerve terminals and insufficient storage of dopamine blunt the brain’s ability to buffer fluctuations in dopamine levels altered by medication delivery.^19,20 If this supposition is correct, then providing dopaminergic medication via a delivery system that limits plasma fluctuation could delay or prevent the emergence of dyskinesias.

There is currently no formulation of levodopa in the US market that has been found to prevent this unwanted pulsatile stimulation. The controlled-release and immediate-release formulations of levodopa have been studied, and each has been assessed for the development of dyskinesias or emergence of symptom breakthrough.²¹ After five years, no difference between the two therapies was identified. (It is possible that the controlled-release formulation was not dosed often enough to prevent pulsatile stimulation and that more frequent dosing might have resulted in a different outcome.) It has been suggested that giving a liquid formulation of levodopa at one-hour intervals, thus avoiding the erratic absorption noted with other oral formulations, would result in less fluctuation of levels. Alternatively, a gel formulation given directly into the small intestine via a permanently placed tube is available in Europe and is currently being studied for use in the US.

Another option for the control of dyskinesias is amantadine. This drug is occasionally used for early PD treatment, but it is now recognized as a means to help control motor fluctuations due to its affinity for N-methyl-D-aspartate (NMDA) receptors. Via these binding sites, the primary excitatory neurotransmitter in the brain, glutamate, is inhibited by amantadine administration.²⁰ It is believed that glutamate has increased activity due to dopaminergic denervation.¹⁹ Studies have demonstrated that after three weeks of amantadine therapy, the frequency of dyskinesias can be cut in half.^22,23

Initiating early therapy with a dopamine agonist rather than with levodopa has been associated with a low risk of causing motor fluctuations.⁸ However, it has yet to be determined whether the sequence of medication initiation has a long-term effect on the prevalence of fluctuations after several years have passed and exposure to both drugs has occurred. A comparison of the dopamine agonist ropinirole with levodopa demonstrated that dyskinesias could be delayed when patients were given ropinirole first. However, once levodopa was given to patients originally taking ropinirole, dyskinesias emerged at a rate similar to the group started on levodopa monotherapy. Thus, dyskinesias were delayed, but not prevented, by postponing levodopa use.²⁴ A second study, this time with the dopamine agonist pramipexole, confirmed the ability to delay the onset of dyskinesias by waiting to start levodopa.²⁵

Pramipexole was compared with levodopa as initial therapy and was given for a period of four years. Over the course of the study, patients taking levodopa were twice as likely to develop dyskinesias.

INITIATION OF DRUG THERAPY

A number of agents are used for the control of PD symptoms. Most have action at dopamine receptors or affect dopamine levels. A smaller number of agents target acetylcholine overactivity.

Levodopa

Levodopa remains the workhorse of the PD medication arsenal. To date, no treatment has proven more efficacious.²⁶ Levodopa is converted into dopamine in the brain. Due to continued neuron loss, exogenous administration of dopamine becomes necessary for virtually all patients at some point.²⁶ The medication must be delivered in conjunction with a dopa decaboxylase inhibitor. Carbidopa is the inhibitor used in the US. Without carbidopa, levodopa would be converted in the periphery, causing significant nausea and hypotension and resulting in subtherapeutic levels of CNS dopamine. Patients can usually get by on 600 mg of levodopa or less per day given with 75 to 100 mg of carbidopa for the first few years (extra doses of carbidopa may be administered if necessary). ²⁶

Levodopa is best taken on an empty stomach, but if given with food to prevent nausea, the protein load should be low to avoid competition for transport into the brain. Abrupt levodopa withdrawal is not recommended due to the risk of neuroleptic malignant syndrome, a potentially life-threatening disorder characterized by delirium, rigid muscles, fever, and autonomic nervous system instability.

Dopamine Agonists

There are currently four dopamine agonists used for PD in the US. The oldest of these agents is apomorphine, which is not used for general symptom control. Two medications, pramipexole and ropinirole, are non-ergolines, whereas the remaining medication, bromocriptine, is an ergot derivative. Dopamine agonists directly stimulate post-synaptic receptors, thereby bypassing degenerating nigrostriatal neurons.²⁷ The non-ergolines have a greater affinity for inhibitory D2 and D3 receptors, as opposed to excitatory D1 receptors. Certain side effects such as pleuritis, pulmonary fibrosis, and pericarditis tend to be associated only with the ergot derivatives. Head-to-head trial data are lacking, making drug choice a practitioner and patient preference. As demonstrated by clinical trial data and UPDRS scores (five to seven points sustained over time), dopamine agonists are less efficacious than levodopa but also less likely to induce dyskinesias.^24,25 However, many patients are able to obtain adequate benefit for up to three years with a dopamine agonist alone.²⁷

A fifth dopamine agonist, rotigotine, is unavailable in the US at the time of this writing due to issues related to manufacturing of the transdermal patch. Primary advantages of this delivery system include more stable concentrations, leading to continuous receptor stimulation, which may decrease motor complications.²⁸

Dopamine agonists in general are useful for treating wearing off, and their use may result in the ability to give lower levodopa doses.²⁹ Some patients taking dopamine agonists experience uncontrollable sudden-onset sleep. In addition, recent observations of dopamine dysregulation syndrome and increased impulsivity in the form of gambling, buying, and sexual behavior have been noted.^3,30

Impulsivity can occur with levodopa as well, but it is significantly more common with the dopamine agonists.

Monoamine Oxidase Inhibitors

There are two types of monoamine oxidase (MAO). Type A is found primarily throughout the gastrointestinal system and the liver. Type B is responsible for the majority of activity in the basal ganglia.³¹ MAO inhibitors act to increase the availability of the monoamine transmitters norepinephrine, dopamine, and 5-hydroxytryptamine, via irreversible inhibition of MAO-B. Common side effects include nausea, dizziness, and abdominal pain.

The first MAO-B inhibitor to be used in patients with PD was selegiline, which is approved as an adjunctive therapeutic option. Selegiline is given at a dose of 5 mg twice daily. The latest the drug should be given in a day is early afternoon to prevent insomnia, which can result from amphetamine metabolites. A newer formulation of selegiline, a rapidly dissolving tablet, is absorbed through the buccal mucosa and avoids first-pass metabolism through the liver. As a result, patients experience a more rapid onset of action and a much lower amphetamine metabolite concentration.²⁹ This formulation has shown promise for combating wearing off.³¹

Because MAO-A is mostly unaffected by the selective inhibitors at normal doses, concern for interaction with tyramine (sometimes called the “cheese effect”), which causes elevated levels of norepinephrine and potentiation of sympathomimetic effects such as hypertension and tachycardia, is low. Selegiline has been associated, although rarely, with tyramine sensitivity in certain patients. Tyramine is found in many pickled, fermented, and aged foods, such as herring, wine, and cheeses. Some persons may be more predisposed to the cheese effect. It is important to understand that selectivity for MAO-B is dependent on dose and individual patient parameters. As such, even though the risk is minimal, the consumption of these foods should probably be limited by patients taking an MAO-B inhibitor as a precautionary measure.

The newest MAO-B inhibitor is rasagiline, which can be dosed once daily (1 mg alone or 0.5 mg when added to levodopa), has no amphetamine metabolites, and is approved for monotherapy and adjunctive therapy alike. Rasagiline is an option for treatment initiation as well as for when symptom control wanes with other agents.²⁹ Adverse events reported in clinical studies include headache, nausea, and joint pain.

Amantadine

Amantadine is an antiviral agent that has been found to have activity in patients with PD through an unknown mechanism. Its mild effects make it useful early but limit its role in later stages.³² This drug has anticholinergic properties, making it a viable option for patients with tremor. However, side effects, particularly constipation, limit the drug’s use, especially in older patients. Patients may develop leg edema and hallucinations.²⁹ Rebound symptoms are possible with abrupt withdrawal, so tapering is recommended. As described previously, a resurgence in the use of amantadine for the treatment of dyskinesia has occurred. The usual dose of amantadine is 100 mg twice a day.

Anticholinergics

Similar to amantadine, anticholinergic agents (primarily benztropine, diphenhydramine, and trihexyphenidyl) are used in the early treatment of patients with PD for the control of tremor. Adverse effects associated with these agents have significantly limited their use, particularly in older patients, who tend to be more susceptible.³²

Common adverse effects include dry mucous membranes, tachycardia, memory impairment, and orthostatic hypotension. Rebound symptoms may occur if anticholinergics are discontinued abruptly.

Catechol-O-Methyltransferase Inhibitors

Catechol-o-methyltransferase (COMT) inhibitors are formulated to inhibit the secondary pathway of peripheral levodopa conversion. This pathway predominates when carbidopa is being administered.²⁹ COMT inhibitors are only indicated for adjunctive therapy.

There are two available agents. The first, tolcapone, is the more potent of the two, but due to associated liver toxicity it is rarely used. Tolcapone dosing is three times daily (starting at 100 mg) at six-hour intervals.

The second drug, entacapone, is available alone as a 200-mg tablet and in a formulation containing levodopa/carbidopa. Entacapone is administered simultaneously with levodopa, although some patients respond better when dosing is separated by 30 minutes, since rates of absorption may be different between the two agents. Side effects include orange body fluids and severe diarrhea, which may not coincide with treatment initiation.²⁹

BARRIERS TO TREATMENT INITIATION

Traditionally, treatment of PD has been delayed until patients experience symptoms that interfere with their day-to-day ability to function.³³ Lack of data supporting any agent as able to slow or stop disease progression, coupled with the knowledge that the sooner levodopa therapy is initiated the sooner motor fluctuations emerge, meant many practitioners were not eager to expose their patients to drug therapy. In addition, since the disease most often strikes persons in their later years, most are near or past retirement age, and the risk of devaluing a perceived need to function at capacity may be a reason for treatment delay. Even when patients report declines in self-perceived health status, the potential for motor complications often takes precedence.³³ Fears about drug toxicity, particularly with levodopa, have added to the problem.

The ELLDOPA trial was undertaken to determine whether levodopa was toxic to neurons.³⁴ Patients enrolled were given variable doses of levodopa or placebo for nine months followed by a two-week washout period. They then underwent imaging using beta-CIT SPECT. There was an increase in the reduction of this marker in patients taking active drug, thus suggesting toxicity. However, after the washout, patients taking levodopa had better UPDRS scores than those given placebo. Imaging data did not correlate with clinical endpoints. Results of this study led to a new question. Was levodopa neuroprotective, or were the effects evident at two weeks due to insufficient washout?³⁴

In addition to clinicians, patients and families can pose barriers to treatment. This is especially true for younger patients. With the advent of the Internet, patients and caregivers have unlimited resources at their fingertips. This can be beneficial but can also pose a problem, since available information may be erroneous or alarming. For instance, patients diagnosed with PD at a younger age may read that levodopa works well, but for only a short time. Patients then may choose to delay treatment, thinking they can target which years they want the drug to be efficacious because they do not understand the progressive nature of the disease as it relates to drug therapy.³⁵ Additionally, there may be disbelief that PD has struck someone at a younger age, since it has been considered a disease of the aged. However, denial as a barrier to treatment is not exclusive to the young.

QOL studies clearly favor drug treatment. A study assessment of patients taking rasagiline demonstrated improvement in scores for patients on active drug in comparison with placebo.³⁶ Another study evaluated changes in self-reported health status when treatment with any anti-PD drug was delayed at the time of diagnosis.³³

Multiple visits took place, and drug treatment could have been initiated at any time. After 18 months (visit two), all eight domains of the QOL scale used were significantly decreased from baseline in those who had not been started on medication. In contrast, those who received medication at visit one were stable in all but two domains. A third study evaluating treatment with any anti-PD drug versus delay demonstrated that mobility scores, activities of daily living (ADL) scores, and measurement of disease stigma were all worse in drug-naïve patients after two years.³⁷

EARLY VERSUS DELAYED START

When to initiate treatment is a question at the forefront of PD research. As previously discussed, one school of thought is that treatment should be delayed until symptoms are interfering with functional ability. Using this approach, unnecessary drug exposure and side effects are avoided, and motor complications are delayed. However, more practitioners are favoring early intervention to maintain QOL, but also because there is evidence that some available medications have disease-modifying potential. Even in the absence of definitive data, the benefits of drug exposure might outweigh the risks. Additionally, there are data from imaging and neuropathological studies that suggest disease progression may be more rapid at diagnosis, so early intervention might be optimal.^38,39

Few would argue that neuroprotection (strategies to protect neurons from injury or degeneration) and disease modification (alteration of the molecular processes that lead to progression of disease) are the most important PD goals. The benzyl ring contained within dopamine agonist structures suggests potential for free radical scavenging.¹ Several studies assessing medication neuroprotection and disease modification have been conducted (Table 3). The CALM-PD-CIT trial used beta-CIT SPECT to measure transporter loss in patients taking pramipexole or levodopa for four years.⁴⁰ There was a 40% reduction in loss with pramipexole. However, UPDRS scores were consistently better with levodopa. REAL-PET investigators noted a reduced loss of cell density in patients taking ropinirole compared with levodopa.⁴¹ Flaws associated with these trials include the fluorodopa imaging measure of surrogate markers and inconsistency with clinical function, as well as the fact that the trials were not designed for the delayed start of medication. This made both levodopa toxicity and dopamine agonist protection viable scenarios.¹

The primary outcome in the DATATOP trial was the ability to delay the need for levodopa administration in patients treated with selegiline.⁴² Compared with placebo, selegiline delayed the need for levodopa, thus suggesting neuroprotection. It can be assumed that after adequate drug washout, protective effects will remain and symptomatic effects will cease, providing a true comparison of medication timing as it relates to PD progression.³⁹

However, in this trial a symptomatic effect from selegiline could not be ruled out, as washout time may have been inadequate. Furthermore, after 35 months of observation, there was no lasting effect on motor complications or disability, nor were mortality rates between groups different through eight years.⁴³

The DATATOP trial clearly demonstrated the need for a trial design that ruled out symptomatic effects. A delayed-start trial design allows for comparison of two groups on the same medication initiated at different points in time (essentially a “wash-in” trial design). Rasagiline is a more potent MAO inhibitor than is selegi-line, with pre-clinical evidence of disease modification associated with both the parent compound and its metabolite.¹ The TEMPO trial compared 404 patients with early PD taking placebo or rasagi-line (1 or 2 mg).⁴⁴ UPDRS scores were measured over six months. Patients on placebo were then converted to rasagiline 2 mg. After six additional months, patients starting with rasagiline early had better overall UPDRS outcomes. Since all patients received rasagi-line, this difference cannot be explained by symptomatic effects alone. However, some have argued that the observed two-point difference on the UPDRS was not clinically significant.

A recently completed trial, ADAGIO, was designed to demonstrate disease modification.⁴⁵ This also was a delayed-start design trial. Patients with early PD (n=1,176) were given rasagiline (1 or 2 mg) for 72 weeks versus 36 weeks of placebo followed by 36 weeks of active drug. Three UPDRS endpoints were chosen as primary outcomes, and the 1-mg dose met all of them with significance. During the placebo-controlled phase, rasagiline showed superiority of slope when comparing UPDRS progression. Symptoms worsened from baseline up to week 72 in the patients who delayed the start of rasagiline compared with those who were given the drug from the outset. Finally, compared with those who experienced a delay in active drug treatment, UPDRS changes in subjects who were given rasagiline for the entire study were non-inferior from weeks 48 to 72. The trial design suggested disease modification, in that patients started on rasagiline earlier had better motor outcomes than patients who had therapy delayed.

ENHANCING PATIENT OUTCOMES

Logically, adherence to medication is necessary for maximum clinical benefit. In order for patients to be adherent, several aspects must be true. Addressing expectations of both patients and their families and caregivers is essential. There is no cure for PD, and patients must understand that current approaches are aimed at maximizing function at any point in the disease process. Medication choice should be based on evidence-based medicine including the potential for neuroprotection/disease modification, but patient/caregiver preferences cannot be ignored. Side effects are a primary reason for nonadherence, and it is incorrect to assume that patients will always be forthcoming when they are having difficulty. Patients must be told what they may expect without causing alarm. In particular, side effects such as impulsivity must be discussed at the outset, since they are unlikely to be recognized by laypersons as medication-related. Caregivers may be more likely to inquire about and discuss patients’ impulsive behaviors due to embarrassment or denial on the part of the patients.

It is important that all involved must understand that PD is more than just derangement of movement. Comorbidities include psychosocial diagnoses such as depression, dementia, and psychosis. Depression in particular is an undertreated problem in PD, in part because there is substantial symptom overlap. A conversation about depression must be initiated with families and care-givers, since patients with depression are not as likely to be active participants in their care. Constipation, sleep disorders, hypotension, urinary dysfunction, and sexual dysfunction can all be associated with PD but can also be associated with medications. It is important to differentiate between the two etiologies and treat accordingly to maintain QOL.

Given the propensity for the occurrence of falls in patients with PD, prevention of fractures should be accomplished with calcium and vitamin D supplementation along with prescription medications where applicable. Motor fluctuations may require the addition of medication or a change in dose or interval.

Dosage forms should also be tailored to the needs of patients. Swallowing difficulties, common in patients with PD, may necessitate changes to liquid or rapidly dissolving preparations. Patients must also be told which products can and cannot be altered to make taking them easier.

CONCLUSION

Increasing evidence suggests that earlier initiation of medications for the treatment of Parkinson’s disease results in better patient outcomes. Delaying medication use may postpone the onset of motor fluctuations; however, the trade-off may be a decrease in quality of life. Additionally, recent trial data suggest that disease modification may be possible, thus preserving functional ability. Ultimately, it is only with a team approach, with both patients and caregivers being members, that patients with PD will achieve optimal outcomes.

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