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INTRODUCTION

Among neurodegenerative disorders, Parkinson’s disease (PD) is second only to Alzheimer’s disease in terms of prevalence.¹ Worldwide, PD is estimated to affect more than 10 million individuals.² In addition to the primary motor symptoms associated with the disease (e.g., tremor, rigidity, bradykinesia, and postural instability), many non-motor symptoms may be present, including psychiatric disorders (e.g., psychosis/hallucinations, depression, dementia, impulse control disorder), autonomic disorders (e.g., postural hypotension, gastrointestinal slowing, excessive sweating, urinary urgency, loss of olfactory sensation), sleep disturbances, weight changes, pain, and fatigue. Such symptoms may be overlooked by clinicians.³ Additionally, the majority of PD patients are elderly and, as such, other comorbid conditions are often present. 

Treatment of PD often turns into a “kitchen sink” approach, with medication therapy becoming increasingly complex as the disease progresses. Treating comorbidities further complicates drug regimens. Pharmacists can play an important role in PD treatment by collaborating with prescribers, caregivers, and patients to promote safe drug selection, improve quality of life (QOL), and ensure optimal patient outcomes.

NON-ADHERENCE IN PATIENTS WITH PD

LG is a 74-year-old female with a 4-year history of PD. She is taking immediate-release (IR) carbidopa/levodopa 4 times daily. She experienced good symptom control when she was first diagnosed, but lately she has been having increasing difficulties completing her daily activities. At today’s visit, she has a noticeable tremor and she is tearful. What questions should be asked of LG?

Adherence to medication therapy has been described in many ways in the literature, and the definition remains somewhat ambiguous.⁴ Measurements of adherence are not always robust, as studies often rely on patient recall and surveys, which leads to an overestimation of adherence. However, non-adherence is frequently defined as any deviation from recommended dosing or timing, with an 80% threshold as the cutoff for appropriate adherence.¹ Theoretically, once-daily medication dosing should result in good adherence, but given that PD is progressive, and the fact that most medications used to treat the disease (including the gold standard, carbidopa/levodopa) are dosed multiple times per day, it is difficult to continually construct a simple regimen as time passes. Data suggest that more than half of PD patients take between 2 and 4 antiparkinson medications 3 to 4 times daily.⁵

In addition to poor outcomes for patients, non-adherence creates a substantial burden on the healthcare system due to greater utilization of resources, including hospitalization.⁶ Non-adherence in individuals with PD has been reported to be higher than 65%,⁷ but clinicians may overestimate rates of adherence in their patients. One study of 418 individuals revealed this discrepancy when physician perception of adherence was reported at 93.6%, while the study subjects self-reported an adherence rate of 60.4%.⁸ When patients arrive for follow-up visits and complain of uncontrolled symptoms, it is imperative to assess adherence and to verify that any changes suggested at a previous visit were, in fact, implemented. Factors associated with non-adherence include lack of social support, medication cost, forgetfulness, poor cognition, poor health literacy, polypharmacy/regimen complexity, low income, poor instructions at time of prescribing, unrealistic expectations with regard to the ability of medications to control symptoms, and poor disease state knowledge.^4,6,9,10

Age alone is generally not considered a risk factor for non-adherence, though comorbidities that are more common in the elderly may increase its prevalence.¹¹ For example, issues with vision, hearing, and manual dexterity may interfere with an older individual’s ability to take medications as prescribed. Gender can also be a factor in the type of non-adherence that patients experience. Women have been shown to be more likely to correctly estimate the frequency of missed doses, while men are more likely to report issues with timing of doses.¹² Cost may force individuals who take multiple medications or who are treating several ailments simultaneously to pick and choose which drugs to purchase or take as prescribed according to their perceptions of importance or ability to pay.¹³ 

Non-adherence to therapy may result in a flare of motor symptoms. In turn, this may decrease the patient’s ability to administer subsequent doses, resulting in a cycle of continued missed medication.¹⁴ For example, if a patient with a prominent tremor skips a dose and the tremor subsequently re-emerges or worsens, it may directly affect the patient’s ability to access medications if they need to open a bottle or another type of container. Also, swallowing difficulties may be exacerbated due to missed medication making the eventual administration of an oral dosage form difficult, if not dangerous, due to the possibility that the patient may choke or aspirate. Forgetting a dose and then trying to make up for it by doubling the amount of medication taken at one time may result in the emergence of dyskinesia or other intolerable side-effects.¹⁴ If a patient taking high doses of a dopaminergic medication decides to discontinue it without a pre-planned tapering schedule, there is a risk of a rare but potentially fatal disorder called parkinsonism-hyperpyrexia syndrome, which is characterized by rigidity, fever, and reduced consciousness.¹⁵

Non-motor symptoms associated with PD may further contribute to non-adherence. For example, rates of adherence have been inversely associated with the incidence of depression.¹⁶ Overall, patients with depression have 3 times the rate of non-adherence than individuals without depression.¹⁷ The diagnosis of depression, which is estimated to be present in approximately 40% of the PD population, is frequently missed. In part, this occurs because of the similarity of symptoms between the 2 diagnoses, such as lack of expression, sleep disturbances, appetite changes, and avoidance of social interaction.¹⁸ It has been suggested that targeted monitoring for and treatment of depression may result in fewer negative outcomes associated with non-adherence.¹⁹ Further, non-adherence to antidepressant therapy in patients with PD has been linked with an increased risk of mortality.²⁰ Therefore, targeted monitoring of adherence to antidepressant use is warranted if prescribed. Hallucinations and psychosis are also negatively correlated with adherence rates.⁸ In fact, individuals with these diagnoses incur double the risk of inappropriate medication use.

Some patients may deliberately take their medication in opposition to the directions they have been given. For instance, the maintenance of employment often leads patients to modify their medication dosing schedules to coincide with times they feel their symptoms need to be under the best control.²¹ Others decrease or skip doses out of fear that side effects, particularly dyskinesias, may develop.¹⁴ Some patients have been expressly told to avoid ingestion of protein with levodopa due to competition for absorption and the ability to cross into the central nervous system (CNS) for conversion to dopamine. As such, they must alter dosing to fit around meal times, which creates uneven intervals.¹⁴ Whether deliberate or unintentional, self-adjustment of dosing times is the most common form of non-adherence, especially when more than 1 dose per day is necessary.¹⁹

While non-adherence is generally thought of in terms of taking less medication than prescribed, there is a subset of patients who may use more than instructed by the prescriber. Dopamine dysregulation syndrome, characterized by addictive, compulsive, or risky behavior (e.g., gambling, overeating, compulsive shopping, hypersexuality) in individuals who have been taking dopaminergic medications may lead to overconsumption of medication.²²

Some data suggest that targeted adherence therapy (i.e., interventions aimed at improving insight into illness, motivation for treatment, and self-management skills) may help improve medication-taking behaviors in patients with PD. One study found that patients had poor disease state knowledge prior to therapy and did not understand that an increase in symptoms was not necessarily due to a failure of medication but, rather, advancing disease.²³ Adherence therapy in this cohort led to an increase in disease acceptance and taught patients coping mechanisms for symptom fluctuations. A second study compared 38 patients who underwent 7 one-on-one adherence therapy sessions at home with 38 patients who received traditional treatment.¹⁰ After 12 weeks, the adherence therapy group demonstrated a 60.5% increase in adherence compared with a 15.8% increase in the control group. The intervention group displayed better mobility, improved ability to participate in activities of daily living (ADL), less body discomfort, and a general increase in emotional well-being. The practicality of such a treatment model may prevent implementation, but the results do demonstrate that increasing patient knowledge about PD and reinforcing strategies for dealing with symptoms can improve patient outcomes and QOL through increased medication adherence.¹⁰ Other strategies, such as the use of mobile phone applications, have been suggested for PD patients to help them track their symptoms and medication use and improve the retention of disease state information.²⁴ However, while some patients may find this helpful, many individuals in the age group most affected by PD are not as technologically savvy as would be necessary for routine implementation of such a model.

It is important to find out if LG is taking her medications as prescribed to determine if the tremor is due to non-adherence, so that strategies for resolution can be offered, or to disease progression, in which case medication changes may be warranted. Her tearfulness may be an indicator of depression and screening should be offered or suggested to assess if that is contributing to poor disease control.

MOTOR FLUCTUATIONS

Under normal circumstances, dopamine acts at D₁ receptors resulting in an excitatory response in direct pathways to facilitate movement. Conversely, its activity in indirect pathways is inhibitory and is facilitated via D₂ receptors resulting in movement inhibition.²⁵ The driver of both pathways is glutamate input from the cortex and the thalamus. PD-related dopamine loss causes a decrease in thalamocortical glutamatergic output and, subsequently hypokinetic movement.²⁶

The 2 most common motor fluctuations noted in patients with PD are wearing-off and peak-dose dyskinesia. Both are common hallmarks of moderate disease.²⁷ When levodopa is chosen for treatment early after diagnosis, the response is usually extremely robust. Typically, in the earliest stages of therapy, even if a patient misses a dose the benefits of the drug continue and motor symptoms may remain stable.²⁷ However, during the first 5 to 10 years of levodopa therapy, 50% to 88% of patients will develop motor complications.²⁸ While dyskinesias are generally considered to be more significant, possibly due to their sometimes dramatic presentation, it is wearing-off that has a greater effect on QOL.²⁹ The pathophysiologies of wearing-off and dyskinesia are not well understood.

Wearing-off

The first sign of poor treatment-related control of PD symptoms is wearing-off.³⁰ In simple terms, wearing-off is a gradual decrease in the duration of benefit seen with each dose of medication. Because PD is always progressive, wearing-off will eventually impact every patient.³¹ A widely accepted theory as to why wearing-off occurs relates to the incessant deterioration of dopaminergic neurons in the nigrostriatal region of the brain. This results in lowered presynaptic handling and storage of dopamine, which eventually leads to an intermittent dearth of activity that occurs before the next administration of an exogenous source of dopamine (levodopa).³² In addition, the repeated stimulation of D₁ receptors may lead to eventual desensitization and tolerance to the effects of levodopa, possibly due to internalization.³³

Wearing-off tends to occur earlier in patients who are younger at disease onset. Longer disease duration is an additional risk factor that corroborates the storage theory.³⁰ Patients with delayed medication absorption due to gastrointestinal-related manifestations of PD (e.g., non-peristaltic swallowing, belching, segmental spasm, esophageal dilatation, reflux, delayed gastric emptying) may also experience symptoms of wearing-off.³⁴ A major risk factor for wearing-off is non-adherence. For example, ingestion of dietary protein at the same time as or close to medication administration may result in less levodopa reaching the CNS, thereby decreasing the peak concentration achieved. In turn, this may lead to an early end to the efficacy of the dose.

The non-motor symptoms of PD are also important when considering motor fluctuations. Despite knowledge about such symptoms, they are often overlooked in the context of wearing-off.³⁵ It has been demonstrated that neuropsychiatric symptoms may be more prominent when medication effects wane. Depression scores as measured by the Beck Depression Inventory are noted to be higher when a patient is experiencing an episode of wearing-off.³⁶ Symptoms found to be significantly different compared to when PD is well controlled include success perception, capacity to feel pleasure, work capacity, and health concerns. Anxiety is also found to be more pronounced when patients experience off-time (i.e., the time when the medication is not having an effect).³⁶ Additional non-motor fluctuations may include fatigue, difficulty thinking, restlessness, sweating, and increased salivation.^37,38 It is easy for clinicians to miss such symptoms of wearing-off, as they are not closely related to alterations in motor control or performance.³⁹ However, patients should be asked about such intermittent symptoms throughout the day, and confirmation of their existence should be taken as potential evidence of undertreated PD. It is important to understand that undertreated patients may not be able to easily recognize the transition from on-time to off-time.⁴⁰

Dyskinesia

Dyskinesia in PD is characterized by chorea, dystonia, or athetosis. Movements may be focal, segmental, or generalized in nature.⁴¹ Dyskinesias are rare early in the PD process. Rather, they tend to emerge in patients once the nigrostriatal pathway is significantly compromised.³¹ Treatment-naïve patients who are in the later stages of the disease tend to progress to dyskinesia more quickly, which is reflective of the severity of dopaminergic cell loss. A study comparing patients in Italy who began levodopa therapy earlier than their counterparts in Ghana demonstrated that it was not length of exposure that was associated with dyskinesia development, but rather disease duration and total daily dose, as onset of dyskinesia occurred a mean of 6 to 7 years after diagnosis in both groups with an average of 6.5 to 7 mg/kg of levodopa daily.⁴² Evidence points to dyskinesia being a postsynaptic phenomenon while wearing-off is primarily a presynaptic occurrence.³¹

When patients are chronically exposed to levodopa, overstimulation of both D₁ and D₂ receptors can occur. The consequence of this is the potential for overactivity in the direct pathway and underactivity in the indirect pathway. Glutamatergic thalamocortical output is subsequently ramped up, causing excess motor movement in the form of levodopa-induced dyskinesia (LID).²⁵ Glutamatergic N-methyl-D-aspartate (NMDA) receptors are also believed to be involved in the development of dyskinesia. Due to the increase in glutamatergic thalamocortical output, NMDA receptors become upregulated over time. Excitatory signaling is further enhanced in both the direct and indirect pathways.⁴³ Levodopa administration biases signaling toward the direct pathway, causing further enhancement of excessive motor movement.

TREAMENT OF OFF-TIME AND DYSKINESIA

After asking LG to keep a symptom diary for 1 week, it becomes apparent that her tremor emerges 45 to 60 minutes before her next dose of medication is due. She admits that she often misses her midday dose because “she gets busy.” What strategies can be employed to regain control of LG’s motor symptoms? What are the risks and benefits of each option?

Until recently, options for treating motor fluctuations in patients with PD have been limited. For dyskinesia, decreasing exposure to levodopa is the obvious option. However, this often means making a choice between decreasing dyskinesia and controlling the motor symptoms of PD. Striking a balance in this context can be extremely challenging.

When faced with a patient in whom current levodopa dosing is no longer adequate due to a breakthrough of symptoms prior to the next dose, there are several basic strategies that can be employed.²⁷ The first is to increase the current dose at the same dosing interval. This should lead to an increase in peak concentration with each dose and a longer time to decrease below the threshold where motor symptoms re-emerge. However, with a higher peak concentration, the appearance of dyskinesia or other potentially troublesome side effects is possible.⁴⁴

Another common strategy, and one that is arguably preferable over the former when wearing-off first begins to occur, is to add additional doses during the day and shorten the interval between them. A drawback to this strategy is the additional risk that adherence to treatment is going to be affected with a growing number of daily doses. IR levodopa is typically initiated as a 3-times-daily medication. Adding additional doses, especially in patients with comorbidities necessitating the consumption of other drugs, may complicate the regimen to the point that it becomes exceedingly difficulty for a patient to successfully manage his or her therapies.⁴⁴

Adding an additional drug class is another frequently employed strategy to combat wearing-off. Depending on the mechanism of the drug, this may also result in the emergence of dyskinesia, although sometimes the dose of levodopa can be adjusted downward to offset this side effect. Decreased adherence may or may not be an issue with this type of intervention since dosing times vary.⁴⁴

The final strategy is the employment of levodopa via novel a dosage form (Table 1).^45-49 When considering the efficacy of such medications, note that the minimum change in off-time that is generally accepted as clinically significant is 1 hour per day.⁴⁴

Traditional strategies to decrease motor symptoms may be employed for LG, including adding a fifth daily dose of medication, increasing her dose but maintaining the same dosing interval, or adding a new medication. LG’s pattern of non-adherence suggests that additional medications or daily doses may not be effective. A dose increase at the same interval may work if her midday non-adherence is addressed, but side effects and dyskinesias may emerge. What other options exist for LG?

NOVEL DELIVERY SYSTEMS

While changes to doses and dosing intervals of traditional oral medications may improve adherence and outcomes, these are not always the best options for patients experiencing motor fluctuations. New delivery systems may offer benefit over simply adjusting oral medications.

Extended-release carbidopa/levodopa

The original controlled-release formulation of carbidopa/levodopa was approved in the early 1990’s. Despite a fair degree of excitement among practitioners who hoped that the new formulation might help treat or avoid episodes of wearing-off, studies demonstrated little evidence that the medication was more effective in improving motor fluctuations than the original IR formulation.^50-52 The medication was shown to undergo less absorption than its IR counterpart and it had a delayed time to effect.^53,54 In January 2015, a new incarnation of extended-release (ER) carbidopa/levodopa was approved by the United States Food and Drug Administration (FDA). 

An ER formulation of carbidopa/levodopa (Rytary) is available as a capsule that contains a 1:4 ratio of the 2 therapeutic ingredients as both IR and ER components.⁴⁸ Compared with the IR formulation, systemic levodopa exposure has been shown to be 30% to 40% higher with the ER formulation, but the IR and ER forms achieve similar peak concentrations.⁵⁵ A randomized trial of 381 patients was conducted to determine the change in Unified Parkinson’s Disease Rating Scale (UPDRS) parts II (ADLs) and III (motor examination) compared to placebo through week 30.⁵⁶ Three doses of levodopa were utilized in the study (145 mg, 245 mg, and 390 mg) and they achieved roughly the same area under the plasma drug concentration-time curve (AUC) as 300 mg, 500 mg, and 800 mg doses of IR levodopa, respectively. All patients receiving the active medication demonstrated significant improvements compared to those receiving placebo (p=0.0001 for all). The associated side effects were similar to those experienced by patients who utilized the commercial IR formulation to treat their symptoms. The most common side effects were nausea, dizziness, headache, and insomnia. No serious adverse event was attributed to the ER formulation.

A double-blind, placebo-controlled, head-to-head phase III trial of the ER and IR formulations was conducted specifically to compare the effects on motor fluctuations.⁵⁷ A total of 393 individuals were enrolled. Patients in the ER group were taking a mean of 3.6 doses of medication daily and patients in the IR group were taking 5 daily doses. Daily off-time was reduced in the ER cohort by 1.17 hours (p<0.001). Increases in on-time with non-troublesome dyskinesia (0.22 h) and on-time with troublesome dyskinesia (0.07 h) were observed, but the changes were not statistically significant. On-time without dyskinesia increased by 0.72 hours, and on-time without troublesome dyskinesia increased by 0.93 hours (p=0.0269 and p=0.0002, respectively). As in the previous study, no unexpected adverse events emerged. Doses of ER carbidopa/levodopa are unique to the formulation and switching from the IR form requires careful conversion.

Levodopa enteral suspension

Recently, a formulation of carbidopa/levodopa that is administered via the lower gastrointestinal tract (Duopa) became available.⁴⁹ It is approved for the treatment of motor fluctuations in patients with advanced PD. Due to the invasive nature of the mechanism for administration, it is not a first-line medication for the treatment of motor fluctuations, but it may be appropriate for a certain subset of patients. 

A phase III, 12-month, open-label study of the carbidopa/levodopa enteral suspension confirmed its efficacy in the PD population.⁵⁴ The 354 patients enrolled in the study were required to abstain from all adjunctive therapy for PD during the initial phase of the study. (Supplemental medications were allowed to be used after the first 28 days.) Initially, patients were hospitalized for placement of a nasogastric tube (a step not currently necessary for initiation of the medication) to begin to titrate the medication to an effective dose. Those who continued the study underwent placement of a percutaneous endoscopic gastrostomy (PEG) tube for continued medication administration via a wearable pump. Administration of this drug formulation consisted of a morning bolus for rapid achievement of adequate plasma concentrations followed by a continuous infusion over 16 hours. During that time, if symptoms re-emerged, patients were able to administer a pre-determined bolus dose of medication to regain control. While oral levodopa supplementation was allowed during the time the pump was off overnight, only 4.4% of patients used supplemental doses. Efficacy data were collected via patient diary. Off-time was significantly reduced from baseline to the final study visit (4.4 ± 2.9 hours [p<0.001]), while on-time with and without troublesome dyskinesia decreased by 6.4 ± 2.8 hours and 4.8 ± 3.4 hours (p=0.023 and p<0.001, respectively). These changes were noted to be consistent at each visit throughout the study (p<0.05). The mean daily dose as determined at the final visit was 1572.4 mg. This dose was relatively consistent throughout the 54 weeks of the trial, suggesting that tolerance to the medication does not occur. Nearly all (92%) of the patients experienced an adverse event after PEG tube placement: the majority were related to device insertion, including procedural pain and abdominal pain. Most of these events were considered mild to moderate in nature and proved transient. Of note, the improvement in motor symptoms associated with this medication far exceeded the 1-hour threshold. However, the invasive and semi-permanent nature of the administration device must be carefully considered for each patient.

LG may benefit from a transition to the ER formulation of carbidopa/levodopa, since using this medication may allow her to take fewer doses on a daily basis (thus aiding her ability to adhere to treatment) while preventing wearing-off. With disease progression, she may eventually be a candidate for enteral carbidopa/levodopa, but other strategies should be attempted before that course of action is chosen.

ER amantadine

Over the next several years, LG’s doses of carbidopa/levodopa are further increased to keep up with disease progression, and a long-acting dopamine agonist is added to her therapy. Her off-time is minimal, but the trade-off is the development of dyskinesia. What can be done to combat this side effect of levodopa?

IR amantadine was first developed as an agent to be used in the treatment and prophylaxis of infection with the influenza virus. Its utility as an agent for the treatment of the motor symptoms of PD was discovered by chance, but it was eventually approved for this indication.⁴⁵ While not approved for the treatment of LID, it has been employed on an off-label basis for this purpose. At one point, the American Academy of Neurology evidence-based guidelines recommended (with level-C evidence) that amantadine might be considered for the treatment of LID.⁵⁹ Of note, this guideline was retired in February 2018 and no new version has been published to date.

Amantadine is a low-affinity, uncompetitive NMDA receptor antagonist that reduces dyskinesia in a dose-dependent manner.⁶⁰ The drug may work to improve dyskinesias by reducing cortical input to glutamatergic striatal neurons that are overactive secondary to the loss of dopamine, or possibly by exhibiting maladaptive neuroplasticity from the long-term administration of levodopa.^61-63 The half-life of IR amantadine is fairly long at 17 hours, though due to the frequency with which patients receiving high doses of the drug experience CNS side effects and edema, it is typically divided to either 2- or 3-times-daily dosing.⁶⁴ Data suggest that the majority of patients given IR amantadine for dyskinesias receive the equivalent of 100 mg twice daily.⁶⁵

Studies in both animal species and humans have demonstrated that the half-maximal concentration (EC₅₀) expected to produce a reduction in dyskinesias, and thus the target plasma concentration for amantadine administration, is roughly 1400 ng/mL.⁶⁶ This concentration is unlikely to be achieved with twice-daily amantadine dosing and may or may not be achieved with 3-times-daily dosing. Additionally, because the IR formulation would not reach this threshold until the evening hours, limited effects would be expected with regard to improvement in daily functioning through dyskinesia reduction. Subsequently, new dosing modalities for the treatment of LID with amantadine were pursued. Of note, doses of the IR formulation of amantadine are expressed as the hydrochloride salt, and the newer formulations express dosing as pure amantadine. As such, a 1:1 dose conversion is not possible. Additionally, dose adjustments for impaired renal function must be made for all formulations.

An ER formulation of amantadine (Gocovri) is delivered in a capsule containing beads with a coating that allows pores to be formed after ingestion such that gradual release of amantadine can take place over time.⁴⁶ It is currently the only medication that has received FDA approval for the treatment of LID. Because the drug is formulated to allow a lag time of approximately 3 hours before absorption begins, which is then followed by a slow increase to peak concentration over several hours, the drug is recommended to be administered at 10:00 PM. This allows for patients to wake at a time when serum concentrations are high enough (approximately 1500 ng/mL) to be useful to combat dyskinesia as they begin the day. If necessary, the capsule may be opened and its contents may be sprinkled on a small amount of soft food for immediate consumption. Steady state concentrations are achieved in approximately 4 days.⁴⁶

Several studies have demonstrated the efficacy of ER amantadine in decreasing dyskinesia. A randomized, double-blind, placebo-controlled, parallel-group study of 83 individuals measured the change in the Unified Dyskinesia Rating Scale (UDysRS) at bedtime from baseline to the end of the 8-week study.⁶⁷ Data were gathered via patient diary. Doses given were 260 mg, 340 mg, and 420 mg. Increases in on-time without troublesome dyskinesia reached statistical significance for all doses of the active therapy compared to placebo (260 mg, p=0.004; 340 mg, p=0.008; and 420 mg, p=0.018). Adverse events were reported in 82%, 80%, 95%, and 90% of the placebo, 260-mg, 340-mg, and 420-mg groups, respectively. The most common patient-reported adverse events were constipation, hallucinations, dry mouth, and dizziness. In the placebo group, 9% of the subjects withdrew. All withdrawals in the active treatment groups were due to adverse events, most of which were CNS related (hallucinations), which is not an unexpected finding with amantadine. The withdrawal rates of the 260-mg and 340-mg groups were similar (15% and 14%, respectively); the withdrawal rate of the 420-mg group was comparatively higher at 40%. Overall, the 340-mg group demonstrated the best balance between efficacy and side effects.⁶⁷

Two additional studies with identical designs (2-arm, placebo-controlled trials) were completed to measure the primary end point of UDysRS change from baseline over 12 weeks.^68,69 Secondary endpoints, including change in on-time without troublesome dyskinesia and change in off-time, were also recorded. The first study enrolled 121 patients, and the second enrolled 75. Initially, patients received 137 mg of ER amantadine or placebo for 1 week. The dose was doubled at the beginning of week 2. Changes in UDysRS scores demonstrated that duration, severity, and impact of dyskinesia was reduced significantly in both trials. In the first study, the total score decreases were 15.9 points in the amantadine group and 8 points in the placebo group (p<0.001). This study was continued for an additional 12 weeks, during which the treatment effect was maintained.⁶⁸ The second study demonstrated a more robust change in UDysRS with amantadine than with placebo (20.7 points vs. 6.3 points; p<0.001).⁶⁹ Off-time decreased by 0.6 hours with active treatment in the first study, and the placebo group experienced an increase in off-time of 0.3 hours (p=0.02).⁶⁸ Again, the second study corroborated the findings: the active treatment group achieved a decrease in off-time of 0.5 hours and the placebo groups experienced an increase in off-time of 0.6 hours (p=0.02).⁶⁹ Finally, on-time without troublesome dyskinesia favored the active treatment arm in both studies at 12 weeks (3.6 vs. 0.8 hours [p<0.0001]⁶⁸ and 4 vs. 2.1 hours [p=0.02]⁶⁹). Improvement in both studies was demonstrated as early as 2 weeks from the beginning of the study, and differences compared to placebo were independent of the severity of dyskinesia recorded at baseline.⁷⁰

Interim results from an open-label safety study of ER amantadine capsules enrolling 223 individuals who were treated for up to 64 weeks demonstrated that long-term tolerability was similar to that seen in the clinical trials.⁷¹ The most common adverse events included falls (the majority of which were deemed unrelated to drug therapy, and instead, more likely a manifestation of advanced disease in the study population), hallucinations, and anticholinergic side effects that are well known to occur with amantadine preparations (e.g., dry mouth, constipation). Most adverse events did not lead to changes in therapy. Serious side effects included 2 patients with suicidal ideation (also not uncommon in the advanced PD population). No changes in the UPDRS score from parts I (mentation, behavior, and mood), II, or III were noted, indicating the drug had no observed negative effects on motor control.⁷¹

More recently, another ER amantadine preparation was approved, this one in tablet form (Osmolex ER). While not approved specifically for LID, the drug does have an indication for the treatment of PD and for drug-induced extrapyramidal reactions in adults.⁷² The tablets contain a combination if IR and ER amantadine. Data specific to this medication are limited, as it was approved via the 505(b)(2) regulatory pathway for new drug approvals. Drugs approved via this mechanism are not strictly generics but are, also, not necessarily novel molecular entities. Instead, they may be new dosage forms of existing medications. Manufacturers may receive approval utilizing efficacy data and study results pertaining to another drug and collected by other manufacturers or researchers as long as submitted bioavailability data are sound.^73,74 In the case of the ER tablets, the drug was compared to IR amantadine syrup in a group of healthy volunteers.⁶⁹ Unlike the other ER capsule formulation of amantadine, the tablet is meant to be given in the morning, normally beginning with a dose of 129 mg and increasing at weekly intervals to a maximum daily dose of 322 mg.⁴⁷ The tablet should be taken intact.

Two phase III clinical trials (ALLAY-LID I and ALLAY-LID II) were initiated in 2014 to measure the effects of amantadine ER tablets on LID as measured by the UDysRS over a span of 12 to 22 weeks. Both trials were terminated in May 2016. As of the writing of this program, no outcomes data generated by either trial has been published.^75,76 

ER amantadine may be an option to help control LG’s dyskinesias. Amantadine use may also result in a decrease in the off-time she still experiences.

ROLE OF THE PHARMACIST IN IMPROVING OUTCOMES

There are many ways that a pharmacist can improve clinical and QOL outcomes for patients with PD. As discussed, increasing regimen complexity often negatively affects rates of adherence. By working with prescribers and patients, pharmacists may be able to identify long-acting alternatives to many medications that would substantially decrease daily pill burden. In addition, pharmacists can offer advice on how to alter dose timing according to the patient’s needs (e.g., protein intake during meals) without compromising effectiveness and safety. Teaching those responsible for medication administration about which dosage forms should and should not be altered to aid in swallowing may help prevent an adverse event due to inappropriate manipulation of a medication to aid in administration. Pharmacists can also offer options for segmented pill containers and electronic reminders to assist patients.

It is important for pharmacists to communicate with patients and caregivers about the problems that may be encountered as PD progresses. Symptoms can be highly variable from one moment to another, and the assumption that what a pharmacist observes during an encounter is representative of a patient’s function over the course of a day may be a mistake. Questions about motor control, motor fluctuations, and non-motor symptoms should all be included in any inquiry about symptom control. Suggestions to use over-the-counter products (such as polyethylene glycol for constipation) should be offered when appropriate. For suspected issues needing additional follow-up (e.g., undiagnosed depression or emerging or advancing cognitive impairment), pharmacists can facilitate consultations and conversations between the patient and prescriber for further evaluation to determine if medicinal intervention is warranted.

It is important for patients and caregivers to have realistic expectations about the course of PD and the limitations that exist with current therapy choices. To date, there are no medications that have been proven to slow disease progression and there is no cure, so informing the patient that changes in symptom control may be due to disease progression rather than medication failure may lead to increased adherence and help-seeking behaviors. Patients may need to be counseled on the difference between on-time and off-time, especially as it pertains to non-motor symptoms. Encouraging the patient to keep a diary of issues encountered throughout the day can help the pharmacist and prescriber identify areas where intervention might be warranted to smooth fluctuations in symptoms. It is also essential to make sure that any new medication is given with sufficient information about potential adverse effects and strategies to mitigate or manage them. Well-informed patients armed with techniques for overcoming medication-related issues are much more likely to be adherent to their therapy in the long term.

CONCLUSION

While no new chemical entities for the treatment of the motor symptoms of PD have come to market in recent years, there have been a number of novel dosage forms created in an effort to improve existing treatment modalities. Targeted symptoms that have benefitted from new formulations include wearing-off (ER and enteral forms of carbidopa/levodopa) and LID (ER amantadine). Newer agents combined with pharmacist-provided patient and caregiver education to improve adherence and disease state competence can serve to enhance the lives of patients with PD while patients and providers alike await therapies that have the ability to alter the disease course.

REFERENCES

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