Optimizing Use of a Dopamine Agonist in Parkinson's Disease

• Describe the features of dopamine agonists (DAs) as a class and their role in Parkinson's disease (PD) therapy.
• Discuss the importance of individualized treatment regimens in PD and explain the intrinsic patient differences that may affect treatment decisions.
• Assess potential strategies to optimize treatment, including minimizing motor complications, and maximizing safety and tolerability when using DAs in the treatment of PD.
• Evaluate available data on switching among the DAs and discuss dose conversions for these agents.
• Describe the impact of patient adherence on treatment outcomes and counsel patients on factors that may positively influence adherence.
• Counsel PD patients on pharmaceutical care issues related to DAs.

Idiopathic Parkinson's disease (PD) is a progressive, neurodegenerative illness with no known cure. Hallmark motor features of the disease include resting tremor, rigidity, bradykinesia, and gait disturbance.1 Nonmotor symptoms such as depression and dementia are common, particularly in later stages of the disease, and can be as debilitating as the motor symptoms.^{2 The average PD patient is 64.2 years old at symptom onset and 65.5 years old when diagnosed. Initiation of pharmacologic treatment is often delayed until symptoms are profoundly impacting the patient's quality of life and/or producing significant disability.}3Currently available treatments for PD are those that provide symptomatic benefit, and none have been proven to alter the underlying progression of the disease or provide neuroprotective benefits.4 The available treatments include levodopa (with carbidopa), catechol-O-methyltransferase inhibitors (which improve levodopa bioavailability), dopamine agonists (DAs), monoamine oxidase-B inhibitors, amantadine, and anticholinergics.5Levodopa has been recognized for more than 40 years as the most effective pharmacologic treatment for PD.4 The benefits of levodopa on motor symptoms, activities of daily living, and quality of life are so pronounced in PD patients that a lack of effect is strongly suggestive of other disorders that mimic PD (eg, atypical parkinsonisms, essential tremor, normal pressure hydrocephalus). A major limitation of chronic levodopa use in PD, however, is the development of motor complications such as dyskinesia and fluctuations.^{1 The risk of developing dyskinesia following long-term levodopa use is profound: an estimated 50% of PD patients will become dyskinetic after 5 years of levodopa therapy.}6 Similarly prevalent is the "wearing-off" phenomenon, the most common type of motor fluctuation, in which the duration of effect with each levodopa dose progressively shortens over time.DAs have long been used as adjunctive therapy to levodopa to improve treatment-associated motor complications in patients already experiencing them. It is becoming increasingly common to initiate treatment of PD patients with DA monotherapy (particularly in younger patients) to delay the need for levodopa treatment until later stages, thereby reducing the risk of or delaying development of motor complications.3,7,8 The issue of whether a DA or levodopa should be considered the first-line treatment in PD remains debatable and is beyond the scope of this article.This review is therefore limited to treatment of the PD patient already identified as a good candidate for DA therapy, with a focus on strategies to optimize the benefit achieved from DA use. The basic properties of DAs as a class will be reviewed, followed by a discussion of 3 main opportunities to optimize DA benefit: individualizing treatment choices, successfully performing treatment switches, and improving patient adherence.DAs as a Drug Class

DAs have been available in the United States for the treatment of PD since the FDA approved bromocriptine in 1978. Most DAs contain an ethanolamine moiety, but there are 2 different pharmacophore derivations (ergot and nonergot) as well as varying receptor specificities.

The ergot DAs include bromocriptine, cabergoline, dihydroergocriptine, lisuride, and pergolide; nonergot DAs are pramipexole, ropinirole, rotigotine, piribedil, and apomorphine (Table 1^{9-11). The ergot-derived DAs have fallen out of favor for clinical use in PD patients due in part to their potential for severe side effects, specifically fibrotic reactions affecting cardiac valve, pulmonary, and retroperitoneal soft tissues.}12-17 These fibrotic reactions are thought to be due to the lack of specificity of ergolinic DAs for dopamine receptors and/or 5-hydroxytryptamine 2B (5HT2B) serotonergic receptor activation.18,19 Recently, the manufacturers of pergolide (Permax) and its generic forms agreed to voluntarily withdraw the drug from the US market.

The most commonly prescribed DAs in the United States are pramipexole and ropinirole, although a once-daily transdermal patch formulation of the nonergolinic DA rotigotine has just recently been approved in the United States (rotigotine is also approved in the European Union for the treatment of both early and advanced PD), and lisuride, an ergot-derived DA, is an investigational agent. An extended-release formulation of ropinirole may also be available in the near future.

Each DA has a unique dopamine receptor affinity profile (Table 19-11). At least 5 dopamine receptor types are known, divided among 2 receptor classes. The first is the D_{1-like class, which includes D}1 and D_{5 receptors. The second is the D}2-like class, which includes D_{2, D}3, and D_{4 receptors. The D}1 class receptors are adenylyl cyclase-coupled, and their activation increases cyclic adenosine 3',5'-monophosphate levels.20 The D2 class receptors frequently interact with the inhibitory G protein leading to inhibitory effects on adenylyl cyclase and other second messenger systems.21-23 Among the D2 class receptors, the D_{2 receptor couples efficiently to inhibit adenylyl cyclase, while the D}4 receptor couples less efficiently and the D_{3 receptor least efficiently or not at all. The neuroanatomical distribution of these receptor types also varies widely, with D}1 and D_{2 receptors having far greater expression than D}3, D_{4, and D}5. Some data suggest that stimulation of both D_{1-like and D}2-like receptors may lead to synergistic benefits in PD patients, based on the functional interactions between those 2 receptor subtypes.24 All of the DAs have activity at the D_{2-like receptor subtype, and apomorphine, pergolide, and rotigotine also act on D}1-like receptors (Table 1).23-25 Because DAs act directly at dopamine receptors, metabolic conversion to an active moiety, as is the case with levodopa, is not required.

In addition to their direct action, DAs possess other pharmacokinetic and pharmacodynamic features that may be considered advantages over levodopa as a treatment for PD. Unlike levodopa, DAs do not require carrier-mediated transport for gastrointestinal absorption or entry into the brain and thus are not influenced by the presence of food containing high amounts of large neutral amino acids that compete for the same carrier-mediated transporters. DAs also have longer half-lives, which should not only circumvent the motor complications seen with prolonged levodopa treatment, but also decrease the frequency of doses required to maintain adequate levels of drug.25 Finally, DAs do not undergo oxidation and thus avoid the generation of free radicals that may contribute to neuronal degeneration.Because of their free-radical scavenging properties26 and lack of free-radical generation, a potential role in neuroprotection has been proposed for DAs. Positive results with in vitro assays and tests in animal models of PD suggest that DAs have the potential to act as neuroprotective drugs.^{27,28 Pramipexole and ropinirole have been investigated in clinical trials using imaging techniques to assess changes in striatonigral neuron populations.}29,30 Pramipexole and ropinirole are associated with slower decline in imaging biomarkers of dopaminergic function, compared with levodopa monotherapy, suggesting neuroprotection. These results are inconclusive due to several issues, however, including study methodology and the possibility of a pharmacologic interference by the DAs on imaging biomarker activity level. The theory that DAs are truly neuroprotective cannot be conclusively confirmed or negated without further investigation.Individualizing DA Choice in PD PatientsWhether prescribing a DA as a monotherapy in early PD or as an adjunctive therapy to levodopa in advanced PD, comparative data (or a lack thereof) do not indicate a superior first-line choice among the newer nonergolinic DAs. Rather, prescribing decisions are usually made based on clinician preference or experience with a particular agent.31 It is not clear if attempts to differentiate DAs based on half-lives, receptor affinities, and modes of delivery will lead to improved clinical outcomes or more favorable safety profiles, but striking differences among the DAs in these categories do exist, making advantages or disadvantages a possibility.Although an extensive literature search is beyond the scope of this article, the remainder of this section will briefly review the distinguishing DA characteristics that may potentially impact clinical outcomes or guide decisions. With the understanding that comparative statements are limited by the paucity of head-to-head clinical trial data, it is worthwhile to explore any potential treatment advantages that can guide clinical decisions in individual patients.Optimizing Treatment by Patient ProfileIndividual clinical profiles in PD patients are distinct, varying due to the complex phenotype of PD and differences in patient age, disease stage, and comorbidities. These differences in clinical characteristics may guide optimal treatment decisions in certain PD patients. For example, many patients with PD experience a reemergence of motor symptoms, specifically slowness and rigidity, at night and in the early morning. As a result, sleep quality and function on awakening can be poor.^{32 Treatment of motor symptoms during sleep may be optimized with continuous administration of drug, which would be ideally achieved by a transdermally delivered agent such as the lisuride (investigational) or rotigotine patch. Another example is the patient who presents with tremor as the dominant symptom throughout the course of disease. Pramipexole may have advantageous antitremor effects when compared with other DAs}33 and may therefore be the drug of choice for treating this type of patient.Patients experiencing specific nonmotor manifestations of PD may be candidates for treatment optimization with particular DAs. Depression, for example, is a common comorbidity in PD patients.^{32,34 Pramipexole has demonstrated antidepressant qualities in clinical studies and may therefore offer additional benefit to a PD patient experiencing depression.}35-38 Other DAs may also be associated with antidepressant activity, but a clinical effect on depression has not been rigorously studied. Some nonmotor aspects of PD may specifically warrant a medication that is given via a route other than oral. PD patients have delayed colonic transit times, compared with matched controls,^{32 and the resulting constipation can affect the absorption of oral medications; thus, nonoral formulations can be used to circumvent this issue. In addition, dysphagia occurs in an estimated 30% of PD patients.}39 Because this may affect adherence to an oral medication regimen, a transdermal DA agent may be favored in these patients.Minimizing Motor ComplicationsPulsatile stimulation of striatal dopamine receptors has long been thought to be one of the critical underlying causes of motor complications associated with intermittent levodopa therapy.40 A number of lines of evidence support this theory, such as the observation that continuous infusion of levodopa administered either duodenally or intravenously is associated with a lower risk of motor complications than orally administered levodopa.^{41-43 The occurrence of subthreshold levels of dopaminergic stimulation may also play a role in the development of motor complications.}42,44DAs are associated with a decreased risk of developing motor complications. Therefore, it is logical to predict that DAs, which have longer half-lives than levodopa, may provide more continuous stimulation of striatal dopamine receptors and thus cause fewer motor complications. Indeed, numerous studies in monkey models of PD have shown that long-acting DAs are associated with a decreased frequency and severity of motor complications when compared with levodopa.^{45 These findings also have been confirmed in several large-scale, long-term trials that examined the frequency of motor complications in patients randomized to therapy with either a long-acting DA or levodopa.}46-50 In all studies, DA-treated patients had significantly fewer motor complications than did patients treated with levodopa alone.Transdermal delivery is an effective method for achieving prolonged, stable drug plasma levels and possible continuous dopamine receptor stimulation with minimal disturbance to the patient.^{51 Rotigotine is currently the only transdermal DA available in the United States. In randomized, double-blind, placebo-controlled trials of advanced PD patients treated with rotigotine, ropinirole, or pramipexole and also taking levodopa, rotigotine use was associated with a lower rate of dyskinesia (12%-17%), as compared with ropinirole (12%-35%) or pramipexole (15%-61%).}47,52-60 Such comparisons are, however, limited by a number of confounding factors including differences in study design, patient population, and levodopa dose/duration of use. The concept that continuous dopamine receptor stimulation via transdermal drug delivery may result in a reduced risk of developing motor complications is attractive, and clinical studies are warranted to test this hypothesis.Maximizing Safety and TolerabilityAs a class, the DAs are associated with specific side effects, many of which are dose-related, including confusion, constipation, dizziness, hallucinations, insomnia, nausea, orthostatic hypotension, pedal edema, and somnolence.31,61 As would be expected with a transdermal patch, application site reactions (mostly mild-to-moderate severity) are to be expected with rotigotine. A rare but potentially serious side effect that has been associated with all DAs and levodopa is the sudden onset of sleep, also termed excessive daytime sleepiness or "sleep attacks."^{62,63 Whether this is a side effect of pharmacologic treatment,}62 disease etiology,^{64 or a combination of these and other factors}63 remains to be determined. Another DA-associated side effect that has received much attention is the occurrence of impulse-control disorders (eg, excessive gambling). Debate regarding the prevalence and cause of these disorders is lively, and experts disagree as to whether certain DAs are associated with higher risk,^{65-67 although it does appear that pramipexole is linked to increased risk of developing pathologic gambling.}65,68 Recent evidence suggests that younger-onset PD patients with higher novelty-seeking behavior or family history of alcohol abuse may be more susceptible to impulse-control disorders when on dopaminergic treatments.^{69 Because this side effect is common, all DA-treated PD patients should be monitored for development of compulsive behaviors.}70As mentioned, fibrotic valvular heart disease (VHD) has been reported in association with ergot DAs such as pergolide, and data from a recent case-control study indicated significantly increased frequency of VHD in patients taking ergot DAs (22%), compared with patients taking nonergot DAs (3%) and controls (0%).71 Two other recent studies have also reported increased risk for VHD in PD patients taking DAs. Pergolide and cabergoline were associated with an increased risk of newly diagnosed cardiacvalve regurgitation,^{14 and the frequency of clinically important valve regurgitation was significantly increased in patients taking pergolide or cabergoline, but not in patients taking nonergot-derived DAs.}16 (Note: In the United States, cabergoline is indicated for the treatment of hyperprolactinemia but is not approved for the treatment of PD.)The Role of the PharmacistRegardless of the initial choice of DA, pharmacists are in a unique position to counsel patients (and caregivers) and provide a guidepost for treatment experiences. Patients should be informed that changes in medication dosage are common as well as necessary to optimize benefits and reduce treatment-related side effects, and optimal results from the DAs may not be fully realized for weeks to months. They should also be encouraged to communicate any changes in symptoms (even nonmotor symptoms) and the occurrence of side effects to their prescribing physicians. In addition, face-to-face patient interaction presents an important opportunity to review the side-effect profile of any medication and to provide recommendations for minimizing or managing adverse events. For example, application-site reactions will be unique to transdermal agonists, so patients can be reminded that rotation of application sites is recommended, and, if needed, OTC or prescription topical corticosteroids may alleviate skin irritations.Switching Between DAsSwitching from one DA to another DA can be performed if there is (1) a lack of response or waning efficacy with the currently prescribed DA, (2) concern about or emergence of specific drug-related side effects, or (3) a perceived advantage (clinical and/or practical) of one DA over another.^{72 Response (or lack of response) to one DA is not necessarily predictive of response (or lack of response) to another.}73-75 Individual and varying response to DAs are well-appreciated in the field, due not only to intrinsic patient differences, but also to the unique profiles of the DAs in terms of dopamine receptor affinity, activity at nondopaminergic receptors, and drug half-life.Preliminary data from an open-label rotigotine switch study indicate that a majority of ropinirole- and pramipexole-treated patients (76/94, 81%) who were switched to the rotigotine patch76 preferred the use of a patch over an oral medication. This suggests that patients with PD have significant preferences for types of drug-delivery systems (eg, tablet vs patch) and dosing frequency.Implementing the SwitchCurrent clinical evidence suggests that an overnight switch to an appropriate dose may be superior to the once-common clinical practice of switching via a slow taper of one DA followed by titration of the other.^{72,73,75,77 In a small prospective clinical study that specifically compared rapid titration schedules to slow titration schedules in advanced PD patients, a rapid titration was found to be safer, with a similar rate of dopaminergic adverse events and without compromising efficacy.}77 Overnight switching may also improve adherence due to its simple and less time-consuming schedule.Assuming that an overnight switch is preferable for most patients, the clinician is still left with the task of identifying the proper starting dose for the new DA. To examine evidence in the scientific literature, a MEDLINE search was conducted using the terms "switch" or "switching" and "dopamine agonist." Using these search criteria, a total of 8 clinical studies evaluating a DA switch were identified.^{13,73,77-82 A search for abstract publications from presentations at scientific meetings, where available, revealed 3 additional switch studies.}83-85

Methodological shortcomings, such as restricted dose ranges, the use of open-label design, and protocol differences, among the 11 studies identified limit the ability to confidently propose standardized switching guidelines that are applicable in real-life clinical settings. In fact, based on the data as a whole, it becomes clear that standardized switching guidelines may not be a realistic goal; rather, physicians should make dosing decisions based on individual patient factors in addition to published conversion ratios. For example, a notable difference among studies was the widely varying patient populations?4 studies evaluated a switch protocol in advanced-PD patients, 4 in early-PD patients, and 3 in a mixed-patient population. Although as a whole this may indicate that a DA switch need not be restricted to any particular disease stage, it is not appropriate to assign a single conversion ratio between agents and expect it to be applicable to all stages of the disease. Advanced-PD patients, in particular, are often treated with more than one dopaminergic agent, which is likely to impact the proper starting dose for the switch.

Another significant difference among the studies is the protocol-defined reason for the switch. The majority of the studies included patients who were eligible for a switch based on a lack of adequate symptom control using their current medication. In fact, only 2 studies identified report allowing patients to switch for non?efficacy-based reasons. Of these, one allowed patients to switch once they had been informed of the pulmonary and cardiac risks associated with ergolinic DAs,^{13 and the other allowed patient preference as a reason for the switch.}76 In a real-life clinical setting, the motivating factors for a DA switch are expected to vary, and switching due to reasons other than waning efficacy may become a more common practice, especially with the introduction of drugs or formulations that allow for once-daily dosing or ease of use (eg, rotigotine transdermal patch, investigational ropinirole sustained-release tablet). Patients who switch for varied reasons (eg, those who are adequately controlled but elect to switch based on preference, as compared with those who require a switch due to waning efficacy) may require tailored switching doses based on the nature of their switch.Furthermore, the majority of these studies included bromocriptine, cabergoline, and/or pergolide as the original agent, which are either rarely used (bromocriptine and pergolide) or not approved in the United States for PD (cabergoline). Only 2 studies specifically addressed a switch between the 2 most commonly used DAs (ropinirole and pramipexole),82,85 and striking differences exist between these protocols (4:1 vs 3:1 ratios of ropinirole: pramipexole, overnight switch vs gradual switch, and advanced-PD vs early-PD patients). An additional challenge in attempting to identify the most accurate starting dose following a treatment switch is a lack of head-to-head trials between drugs that could be used to confirm dose relationships in an internally controlled setting.Despite the challenges in the synthesis of the available switching data, Thobois (2006) performed an extensive literature review, including not only switch studies, but also crossover and direct-comparator studies (which allowed post hoc calculations of dose equivalence) to provide a "first attempt to define conversion factors that might facilitate rapidly switching."75 However, the set of proposed arithmetically precise conversion factors were not designed for direct clinical use. Grosset et al^{13 have proposed dose-based recommendations for DA switching that account for commercially available tablet strengths and, therefore, are more practical in a clinical setting (Table 2}13,86). Conversion ratios to/from rotigotine were not included in this analysis, as they were not yet available.

It is important to note that conversion ratios may result in doses that are not available or are cumbersome to administer.17 For example, patients maintained at the target pramipexole dose of 1.5 mg (1 tablet) 3 times daily would be converted to a ropinirole dose of 6 mg 3 times daily, which would require the administration of ropinirole with 2 tablets (eg, two 3-mg tablets) at each of the 3 daily administrations. Therefore, adjustments to account for practicality and available dosage strengths must be considered.

Currently, the universal clinical utility of any "conversion" table will be limited by the arguments outlined earlier (ie, differences in individual patient factors, reasons for the switch, etc), and clinicians should appreciate that it is preferable to consider "switch" tables as an important benchmark to identify an estimated starting switch dose that can be implemented safely, with the understanding that additional adjustments should be expected for the circumstances of each patient. The risk associated with significant undertreatment (or an underdosed switch) is an increase in symptoms, whereas significant overtreatment could result in increased side effects. Either of these is manageable with dose adjustments, and, therefore, careful patient monitoring following a switch is recommended.

Because rotigotine was not included in the DA conversions proposed by either Thobois or Grosset et al, preliminary suggestions for switching guidelines that include rotigotine doses are provided in Table 2 (adapted from Grosset et al^{13) and are based on available rotigotine clinical data.}76,87-89 As rotigotine is not yet approved for advanced PD, these recommendations should be considered most applicable to the early-PD patient and are based on an open-label switch study (SP824), key early-PD trials with rotigotine (SP506, SP512, and SP513), and results from a post hoc analysis of the SP513 trial.In a phase 3b, open-label switch study (SP824), 116 patients with PD were switched overnight from an oral dopamine agonist (n = 22 cabergoline, n = 47 pramipexole, n = 47 ropinirole) to rotigotine (2-8 mg/24 h).76,90 Outcome measurements included safety and tolerability as well as the effect on PD symptoms and patient preference. In addition to an oral dopamine agonist, patients were allowed to be on other antiparkinson drugs at baseline. Patients were included if their baseline pramipexole dose (<2 mg/day), cabergoline dose (<3 mg/day), or ropinirole dose (<9 mg/day) was not providing satisfactory control. Per the protocol, patient dissatisfaction with treatment could be due to inadequate symptom control, adverse events, the inconvenience of multiple oral dosing and/or any other patient-specified reason. After switching to rotigotine, 80% of patients did not require further dose adjustment, and 9.5% required a single adjustment, (the majority involving a dose increase). Forty-seven percent of patients were switched to the highest allowable rotigotine dose per the trial (8 mg/24 h). The overnight switch was generally well-tolerated and was not associated with significant worsening of PD symptoms. It should be noted that pre-switch doses of the oral DAs allowed in this study did not represent the full dose range of those agents, underscoring the need to carefully monitor patients following a switch and to consider a switch regimen with a slower titration, particularly when switching from the highest dose ranges of an oral DA.Although rotigotine is approved in the United States for the treatment of early PD up to a dose of 6 mg/24 h, a consideration of the 8-mg dose is included here based on the results from the open-label switch study outlined above and from other key clinical trials with rotigotine in early PD (SP506, SP512, and SP513). These 3 double-blind, randomized, placebo-controlled studies served as the basis for approval in the United States (<6 mg/24 h) and the EU (<8 mg/24 h) in early PD. In the published report of the SP506 trial, treatment with both 6 and 8 mg/24 h resulted in significant improvement relative to placebo (P = .001 and P < .001, respectively) as assessed by the Unified Parkinson's Disease Rating Scale (UPDRS) (II & I II).87 In SP512, rotigotine-treated subjects were optimally dosed up to a maximum of 6 mg/24 h (64% of rotigotine-treated patients received the maximum dose of 6 mg/24 h for the duration of the maintenance period [27 weeks]). Statistically significant improvements as assessed by the UPDRS (II & III) were observed for rotigotine-treated patients relative to placebo (P < .001), and a significantly greater proportion of rotigotine-treated patients experienced at least a 20% improvement in UPDRS scores (48% vs 19% placebo, P < .001).88 In SP513, a placebo- and comparator (ropinirole)-controlled trial, rotigotine-treated patients were optimally dosed up to a maximum of 8 mg/24 h. In this trial, rotigotine treatment was associated with a statistically significant improvement in PD symptoms relative to placebo (P < .001) as assessed by the UPDRS (II & III).86,89 A post hoc analysis of the SP513 data compared patient outcomes with doses of rotigotine (<8 mg/24 h) to ropinirole (< 15 mg/day), doses that can be particularly relevant in the treatment of early PD.^{89 In this analysis, both patient groups showed similar efficacy,}89 providing valuable data on which initial dosing for early PD patient switches can be based. Ongoing studies with rotigotine will provide data to extend switching recommendations into the advanced stages of the disease. It is evident from this review of switch studies that proposed conversion factors among the DAs have varied widely, underscoring the difficulty in determining a standardized conversion ratio and serving as a reminder that, on initiation of the new agent, a need for follow-up dose adjustments to account for variations in individual patient response is to be expected. Clearly, prospective, double-blind, randomized clinical trials assessing switch protocols among the commonly used DAs are warranted. In the absence of those trials, pharmacists can play an important role in implementing a successful switch. In particular, the new dosing regimen as well as any particular side-effect concerns about the new agent can be reviewed and discussed with the patient.Strategies to Improve Medication Adherence as a Means to Optimizing BenefitAdherence issues can be divided into 2 categories: primary nonadherence, when a patient never fills a prescription, and secondary nonadherence, when a patient fails to take a drug as prescribed.91 The most common reasons for primary nonadherence are (1) prohibitive cost of prescription, (2) disagreement between patient and physician on diagnosis, (3) lack of symptoms and therefore feeling that the prescription is unnecessary, and (4) cognitive impairment such as dementia. The most common causes of secondary nonadherence are side effects and lack of perceived efficacy of the medication. Fortunately, secondary nonadherence can be significantly impacted by pharmacists.^{92 Side effects are a very common and legitimate reason for patients to stop taking a medication. If patients have prior knowledge of the side effects often associated with their medications, however, they are more likely to continue with the therapy, report the side effects, or request a switch to another medication when such side effects occur.}93 A perceived lack of efficacy is also an understandable reason for a patient to discontinue use of a medication, and pharmacists are adept at counseling patients about the need to titrate a DA for optimal efficacy and minimal side effects and to establish appropriate expectations regarding therapeutic response.Improving Medication Adherence in PD PatientsStudies specifically investigating PD patients found that 15.3% to 20% of patients have significant nonadherence.^{94,95 The number of patients who acknowledge missing any doses via self-report (24.3%) versus those who missed at least 1 dose per week as measured by a computerized medication event monitoring system (51.3%) is statistically significant.}94 Furthermore, 90% of patients had some problem with adherence if mistimed doses were included.^{91 Grosset et al found that, even among the patients who had good overall adherence, medications were taken during the correct time interval only 25% of the time. Patients in the less adherent group had only 11% time-interval adherence.}95 The authors of these studies stipulate that even these estimates likely underrepresented the actual rate of nonadherence among PD patients.Thus, the 3 main reasons for lack of adherence in the PD patient population are (1) difficulty with the number and complicated schedule of drugs they are taking, (2) depression, and (3) unrealistic (or improperly explained) expectations from their drug treatment. All of these can be significantly impacted by intervention and education by a pharmacist.Sticking to the RegimenA study reports that PD patients are taking on average 5.2 ? 0.4 concomitant medications, with a mean number of doses per day of 3.9 ? 0.2.^{94 Adherence has been shown to be inversely proportional to the number of daily doses}96 for 1 drug, and it is likely that patients taking multiple drugs with multiple doses will have greater difficulty adhering to demanding dosing schedules.In addition to increasing adherence, a review of 5 PD studies using sustained-release levodopa formulations (requiring at least twice-daily dosing) for PD therapy found that the less frequent dosing schedule was associated with greater patient preference and quality-of-life scores.97 This suggests that new and emerging DA products requiring once-daily dosing (eg, the recently approved once-daily rotigotine patch or the investigational once-daily ropinirole tablet) may have a positive impact on patient health-related outcomes as well as adherence. Pharmacists should be aware of new and less complicated DA treatment options to help patients simplify and understand medication dosing schedules for optimal outcomes.Recognizing and Coping with DepressionDepression has long been known to decrease adherence. A meta-analysis of depressed patients found that they are 3 times more likely to be nonadherent, as compared with patients who are not depressed.98 This has particular relevance for PD patients, as depression is a common concomitant psychiatric condition, more so than other mood or cognitive disorders,^{34,35,99 and other studies have reported depression at rates of 40% to 50% in PD patients.}100,101Compounding the problems associated with depression in PD is the disparity in the likelihood that PD patients will even be screened for or diagnosed with depression. Swarztrauber et al found in a recent study that only 16.6% of PD patients (within a regional Veterans Affairs [VA] Healthcare System) received the recommended yearly screening for depression (a quality indicator within the VA system) when seen by a nonspecialist.^{102 This did not differ significantly even when patients were seen by a VA specialist in geriatrics, neurology, or movement disorders. In another study (conducted within a different VA system), approximately 50% of patients with PD received the recommended annual screening for depression, and this increased to 75% if a movement disorder specialist was involved.}103 Because non-VA providers (eg, private practice physicians) may not implement quality indicators for depression screening in PD patients, the disparity in this provider sector may be even greater.Pharmacists can help to ensure that patients are not missing basic testing and medication monitoring that can be overlooked by physicians in their community. Asking patients (and their caregivers) about mood and whether patients receive annual screening for depression is another step toward the optimal management of this condition.Managing ExpectationsBecause DAs need to be titrated to a therapeutic dose over the course of weeks, if not months (Table 3^{59,60,104-106), it is imperative that patients understand that it may take time to realize the full benefit of the medication on PD symptoms. Disappointment in lack of immediate response can often lead to decreased adherence. In such situations, a DA with a more rapid titration schedule may be preferable to increase patient adherence.}107,108

Once the initial titration phase of the prescribed DA is completed, it is important that the patient continue to take the medication as prescribed. Patients improperly taking their medication may assume that a drug has lower or diminished efficacy when in fact it would be more effective if they were taking it correctly. A perceived lack of efficacy will prompt patients to either abandon the drug or request a switch to another agent (perhaps in another drug class).

It may be difficult for patients to determine the effect of a treatment because of the inherent problems in properly recognizing or describing some symptoms. For example, patients (and caregivers) may use the term "shaking" to describe either a PD-related tremor or drug-related dyskinesia. In the former, an increase in dosage may be indicated; in the latter, a reduction in dosage would be indicated. In this example, failure to clarify terminology can result in inappropriate medication adjustments or recommendations. Thus, knowledge of PD symptoms and the efficacy and safety of available pharmacologic therapies, including DAs and new treatments, will further enable pharmacists to provide education and drug information on issues such as drug dosing, administration, switching, and methods to optimize medication adherence.Conclusion

DA treatment in PD can be optimized by knowledge of the disease and available treatments, individual patient factors, and methods to improve medication adherence. Pharmacists are afforded a unique opportunity to communicate important treatment issues in PD and to directly impact the level of benefit achievable with DA therapy.

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