Pharmacology of Parkinson's Disease Grand Rounds
Pharmacologic treatment of Parkinson's disease
Daniel Tarsy, MD
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INTRODUCTION The array of pharmacologic and surgical treatments available for the treatment of idiopathic (or Lewy body) Parkinson's disease (PD) is broader than for any other degenerative disease of the central nervous system. Management of individual patients requires careful consideration of a number of factors including the patient's symptoms and signs, age, stage of disease, degree of functional disability, and level of physical activity and productivity. Treatment can be divided into nonpharmacologic, pharmacologic, and surgical therapy. A useful algorithm for the management of PD has been published by the American Academy of Neurology (AAN) [1].
The routine medical management of PD is reviewed here. The nonpharmacologic management of PD, including education, support, exercise, and nutrition, is discussed separately. (See "Nonpharmacologic management of Parkinson's disease").
Treatment of advanced PD, particularly the complications associated with long-term levodopa therapy, and management of the comorbid problems including daytime sleepiness, hallucinations, and psychosis are discussed separately. (See "Motor fluctuations and dyskinesia in Parkinson's disease" and see "Surgical treatment of Parkinson's disease" and see "Comorbid problems associated with Parkinson's disease").
DIAGNOSIS OF PD Correct diagnosis is fundamental to the appropriate therapy of Parkinson's disease (PD), although the same menu of antiparkinson drugs is used to treat all of the various parkinsonian syndromes. The four cardinal signs of parkinsonism are rest tremor, rigidity, akinesia, and gait disturbance. Usual criteria for a clinical diagnosis of PD require the presence of at least two of these four features; diagnostic certainty increases in proportion to the predominance of rest tremor as a finding, especially if it is unilateral.
Postmortem and magnetic resonance imaging (MRI) studies indicate a substantial diagnostic error rate based upon the use of these criteria. In some studies, up to 25 percent of patients with a diagnosis of PD during life were found to have other causes of parkinsonian symptoms at autopsy, such as cerebrovascular disease involving the basal ganglia or other neurodegenerative disorders, such as multiple system atrophy and progressive supranuclear palsy [2,3]. On the other hand, the clinical diagnostic accuracy of PD and the other parkinsonian syndromes, confirmed by neuropathology, increases substantially if patients are evaluated and observed throughout the long course of their illness by specialists at movement disorders centers [4,5].
The clinical features most suggestive of idiopathic PD include asymmetric or unilateral onset, the presence of rest tremor, and a clear cut response to treatment with levodopa. Clues to the diagnosis of the other parkinsonian syndromes include a history of exposure to dopamine receptor blocking drugs such as antipsychotic agents or metoclopramide, hyperactive tendon reflexes, Babinski signs, cerebellar signs, prominent abnormalities of ocular motility, the early development of dementia, significant postural instability, and major autonomic manifestations (orthostatic hypotension, atonic bladder, sexual impotence, and gastrointestinal dysmotility).
A practice parameter from the American Academy of Neurology (AAN) concluded that features probably useful for distinguishing other parkinsonian syndromes from PD include early falls, poor response to levodopa, symmetry of motor manifestations, lack of tremor, and early autonomic dysfunction [6].
NEUROPROTECTIVE THERAPY The pharmacologic treatment of Parkinson's disease (PD) can be divided into neuroprotective and symptomatic therapy. In practice, however, nearly all of the available treatments are symptomatic in nature and do not appear to slow or reverse the natural course of the disease.
Several potential neuroprotective agents for PD have shown some promise in animals and/or humans and are undergoing further investigation. Neuroprotective therapy for PD is discussed in greater detail separately. (See "Neuroprotective therapy for Parkinson's disease").
SYMPTOMATIC THERAPY The decision to initiate symptomatic medical therapy in patients with Parkinson's disease (PD) is determined by the degree to which the patient is functionally impaired. The timing of this decision varies greatly among patients but is influenced by a number of factors, including [1]:
The effect of disease on the dominant hand
The degree to which the disease interferes with work, activities of daily living, or social and leisure function
The presence of significant bradykinesia or gait disturbance
Personal philosophy regarding the use of drugs
The major drugs available for symptomatic therapy include (show table 1):
Levodopa
MAO B inhibitors
Dopamine agonists
COMT inhibitors
Anticholinergic agents
Amantadine
In addition to these agents, low-dose estrogen may be helpful as adjunctive therapy in postmenopausal women [7,8].
Levodopa Levodopa (L-dopa) is well established as the most effective drug for the symptomatic treatment of idiopathic or Lewy body PD. It is particularly effective for the management of akinetic symptoms and should be introduced when these become disabling and are uncontrolled by other antiparkinsonian drugs. Tremor and rigidity can also respond to levodopa therapy, but postural instability is less likely to do so.
Levodopa is combined with a peripheral decarboxylase inhibitor to block its conversion to dopamine in the systemic circulation and liver (before it crosses the blood-brain barrier) in order to prevent nausea, vomiting, and orthostatic hypotension. In the United States, the decarboxylase inhibitor is carbidopa. The combination drug carbidopa/levodopa (immediate-release Sinemet) is available in tablets of 10/100, 25/100, and 25/250 mg, with the numerator referring to carbidopa and the denominator referring to the levodopa dose. An immediate-release formulation of carbidopa/levodopa (Parcopa) is available that dissolves on the tongue and can be taken without water [9], but there are no published studies of this formulation, and its onset of action is no different from Sinemet.
In Europe and Canada, benserazide is the peripheral decarboxylase inhibitor. The combination drug benserazide/levodopa (Madopar or Prolopa) is available in 25/100 and 50/200 mg tablets.
Controlled-release formulations of carbidopa/levodopa and benserazide/levodopa are available as Sinemet CR and Madopar HBS, respectively.
Dosing Treatment should be initiated with small doses such as one-half tablet of carbidopa/levodopa (Sinemet) 25/100 mg three times daily with meals, titrated upward over several weeks to 25/100 mg three times daily as tolerated and according to the response (show table 1). Elderly patients or those with dementia should begin with smaller doses and titrate more slowly because of their increased susceptibility to psychiatric side effects. The usual practice is to use the lowest dose that produces a useful clinical response. This varies from patient to patient, but at the start typically is in the vicinity of 300 to 600 mg of levodopa daily.
The vast majority of patients with idiopathic PD will enjoy a significant therapeutic response to moderate doses of levodopa (400 to 600 mg daily); complete absence of response to a dose of 1000 to 1500 mg/day strongly suggests that the original diagnosis of PD was incorrect and that the diagnosis should be revised to one of the other parkinsonian syndromes, such as multiple system atrophy or progressive supranuclear palsy.
Controlled release levodopa preparations are less completely absorbed and require a dose up to 30 percent higher to achieve an equivalent clinical effect. The clinical effect of each tablet is typically less dramatic than for immediate release preparations, since controlled release formulations reach the brain more slowly. This presents a disadvantage in assessing the response of patients just beginning therapy. As a result, it is recommended that therapy be initiated with an immediate release preparation with a subsequent switch to controlled release if desired. Both the immediate and the controlled release formulations appear to maintain a similar level of symptom control after several years of use [10].
Patients taking levodopa for the first time should take each dose with a meal or snack to avoid nausea, a common early side effect. Patients with more advanced disease, especially those with motor fluctuations, often notice that a dose of levodopa is more effective if taken on an empty stomach one hour before or after meals due to reduced competition with other amino acids for gastrointestinal absorption.
Small starting doses of levodopa combined with a decarboxylase inhibitor (eg, Sinemet, Madopar, or Prolopa) are more likely to cause nausea because of inadequate amounts of carbidopa; this can be managed by administering supplemental doses of carbidopa (Lodosyn) or by use of antiemetics such as trimethobenzamide (Tigan) or domperidone (not available in the United States) taken prior to Sinemet. Phenothiazine antiemetics and metoclopramide should be avoided because they are dopamine receptor blockers that can aggravate the symptoms.
Adverse effects Nausea, somnolence, dizziness, and headache are among the more common side effects that may accompany treatment with levodopa, but they are not likely to be serious in most patients. More serious adverse reactions to levodopa (mainly in older patients) may include confusion, hallucinations, delusions, agitation, and psychosis.
Levodopa may also induce a mild to moderate elevation in serum homocysteine levels [11-14], which in turn may be associated with an increased risk of hip fractures in elderly patients. (See "Epidemiology and causes of osteoporosis", section on Homocysteine).
Compulsive dopaminergic drug use has been reported in patients taking dopamine agonists, typically in conjunction with levodopa therapy. However, it is unclear if these behavioral issues arise with levodopa monotherapy. (See "Dopaminergic dysregulation syndrome" below).
Motor fluctuations A substantial number of patients develop levodopa-induced motor fluctuations within several years of starting levodopa. These include involuntary movements known as dyskinesia, abnormal postures of the extremities and trunk known as dystonia, and a variety of complex fluctuations in motor function [15]. (See "Motor fluctuations and dyskinesia in Parkinson's disease"). Such complications occur in at least 50 percent of patients after 5 to 10 years of treatment [1]. In the large group of patients with early PD studied in the DATATOP study, motor complications occurred in 30 percent after only two years of treatment with levodopa [16]. However, in a study of early PD, the prevalence of motor complications was only 20 percent after five years of treatment with levodopa [17].
A sudden exacerbation of Parkinson's disease (PD) characterized by an akinetic state that lasts for several days and does not respond to treatment with antiparkinson medication is called acute akinesia. This phenomenon is very different from the more common wearing "off" effects and is discussed separately. (See "Motor fluctuations and dyskinesia in Parkinson's disease", section on Acute akinesia).
The increase in motor fluctuations over time is most likely due to the progressive degeneration of nigrostriatal dopamine terminals, which increasingly limits the normal physiologic uptake and release of dopamine, thereby leading to reduced buffering of the natural fluctuations in plasma levodopa levels that occur due to levodopa's 90-minute pharmacologic half-life [1]. Controlled release preparations are useful for management of these fluctuations, although, in one report, the use of Sinemet CR from the start of therapy, in an effort to provide more continuous stimulation of dopamine receptors, was not associated with fewer motor complications than immediate release Sinemet [17].
There has been longstanding concern among some clinicians that levodopa causes motor fluctuations and dyskinesia by its potential to promote oxidative stress and accelerated neurodegeneration, rather than by the change in levodopa pharmacodynamics that occurs with natural progression of the underlying disease [18,19]. Therefore, it is commonly proposed that the initiation of levodopa be delayed until symptoms significantly interfere with function. Others contend, however, that there is no strong evidence that levodopa is responsible for late motor complications, and that delay of treatment unnecessarily deprives patients of therapeutic benefit early in the disease, when the potential for sustained improvement is greatest [20].
Neurotoxic versus neuroprotective effects The concern that prolonged use of levodopa may directly hasten the degeneration of dopamine neurons in the substantia nigra by promoting the generation of free radicals and oxidative stress is the basis for delaying the use of levodopa in the treatment of PD [1,21]. However, the evidence is not strong enough to justify a definitive conclusion regarding levodopa toxicity to dopamine neurons.
In vitro, levodopa is toxic to cultured dopamine neurons [22], although it does not damage dopamine neurons in normal humans (who do not have PD) or intact animals [23]. Nevertheless, it remains possible that levodopa is toxic in patients with PD. In one study in rodents, for example, levodopa increased neuronal damage in animals with partial injury to dopaminergic neurons [24]. However, this was not confirmed in subsequent reports [25,26].
A consensus conference convened to discuss the issue of levodopa toxicity reached the following conclusions [27]:
There is no evidence that levodopa causes neuronal death in animal models of parkinsonism
The relevance of in vitro studies of levodopa toxicity to clinical use of levodopa is highly uncertain
There is no evidence that chronic administration of levodopa exacerbates the degenerative process in PD
Late motor complications arise due to the combination of progressive degeneration of dopamine neurons and the reversible effects of levodopa administration
Accumulating clinical trial data suggest that levodopa, rather than being neurotoxic, either slows the progression of PD or has a prolonged benefit even after the drug has been stopped. To address the continuing uncertainty surrounding the long term effect of levodopa, the Earlier versus Later Levodopa Therapy in Parkinson Disease (ELLDOPA) study examined 361 patients with newly diagnosed PD and randomly assigned them to one of three carbidopa/levodopa doses (37.5 mg/150 mg; 75 mg/300 mg; 150 mg /600 mg) three times daily or placebo for 40 weeks, followed by withdrawal of treatment for two weeks [28].
At 42 weeks, when the underlying native disease would be theoretically revealed as a result of the two week washout, all groups assigned to levodopa showed significantly less worsening in the symptoms of parkinsonism (as measured by the UPDRS) than did the placebo group (show figure 1) [28]. Patients receiving the highest levodopa dose schedule (600 mg/day) had the lowest (better) UPDRS score but also had significantly more dyskinesia. Hypertonia, infection, headache, and nausea were also more common than in the placebo group. Therefore, the clinical data suggested, surprisingly, that the use of levodopa for 40 weeks was neuroprotective.
On the other hand, imaging data from a substudy of 116 patients supported the observations from two previous studies that levodopa treatment is associated with a greater decline in basal ganglia uptake of dopamine [28]. The substudy used single photon emission computed tomography (SPECT) to assess striatal dopamine by measuring [123I]beta-CIT uptake, and showed greater reduction in nigrostriatal dopamine transport in patients taking levodopa compared with those on placebo. Once again, the question of levodopa toxicity versus levodopa-related down regulation of the dopamine transporter receptors could not be resolved. Therefore, the question of potential neuroprotective versus neurotoxic effects of levodopa can not yet be answered.
Further clinical trials are underway to study the effects of levodopa on the progression of PD [29]. In the meantime, levodopa remains the most effective therapy for PD, and should be introduced if there is sufficient compromise of quality of life or functional ability to warrant treatment.
MAO B inhibitors Selegiline (Eldepryl), a selective monoamine oxidase (MAO) type B inhibitor (show table 1) [30], is modestly effective as symptomatic treatment for PD [31] and may have neuroprotective properties. (See "Neuroprotective therapy for Parkinson's disease", section on Selegiline).
In many individuals, however, selegiline monotherapy does not produce a functionally significant benefit, thereby leaving patients disappointed. However, the use of selegiline in early PD is a reasonable option as long as the patient understands its limitations.
The selective MAO B inhibitor rasagiline has neuroprotective properties in animal models and appears modestly effective as symptomatic treatment for PD in human clinical trials [32,33]. (See "Neuroprotective therapy for Parkinson's disease", section on Rasagiline).
Rasagiline is approved by the European Commission as initial monotherapy in patients with early PD and as adjunct treatment in moderate to advanced PD. It received similar approval by the United States Food and Drug Administration in May 2006 [34].
Effectiveness Evidence supporting the symptomatic effect of MAO B inhibitors for PD has been bolstered by the findings of a meta-analysis that examined data from 17 randomized trials involving
3525 patients [35]. These individual trials compared MAO B inhibitors (predominately selegiline) with either levodopa or placebo (predominately placebo) in the treatment of early PD. Many of these trials were limited by short-term follow-up, poor reporting of results, and absence of quality of life data. With these limitations in mind, the following observations were made [35]:
Data for clinical rating scales were available from six trials of selegiline; treatment with MAO B inhibitors was associated with significantly better total scores, motor scores, and activities of daily living scores on the Unified Parkinson's Disease Rating Scale (UPDRS) at three months compared with controls.
Data on the need for levodopa were available from eight studies with a median follow-up of 13 months; treatment with MAO B inhibitors was associated with a reduction in the need for additional levodopa compared with controls.
Data on motor complications were available from five trials; treatment with MAO B inhibitors was associated with a modest reduction in the development of motor fluctuations compared with controls. However, MAO B treatment was not associated with a significant difference in the incidence of dyskinesia.
Data on mortality were available from 10 trials, nine of which involved selegiline. MAO B inhibitor treatment was not associated with increased mortality compared with controls, in contrast to one observational study from the United Kingdom that showed increased mortality in patients using selegiline [36]. The results of the UK study have not been confirmed by subsequent reports, including an earlier meta-analysis [37-39].
Additional evidence supporting the long-term symptomatic benefit of selegiline for PD comes from the continuation phase of a randomized controlled trial involving 157 patients with PD, in which patients who were initially assigned to selegiline in the earlier phase of the study were treated with combined selegiline and levodopa, while those initially assigned to placebo were treated with combined placebo and levodopa [40]. At seven years, treatment with the combination of selegiline and levodopa was associated with significantly better symptom control than treatment with placebo and levodopa.
Uncertainty remains about the relative risks and benefits of MAO B inhibitors, as few trials compared them with other antiparkinson medications [35]. Comparative data are particularly lacking for the dopamine agonists [35,41].
Dosing The dose of selegiline used in DATATOP was 5 mg twice daily, with the second dose given at noon to avoid insomnia. However, lower doses are sufficient to induce MAO B inhibition, and 5 mg once a day in the morning is currently recommended. Doses higher than 10 mg daily are of no additional benefit and may result in nonselective MAO inhibition, thereby placing the patient at risk of hypertensive crisis in the absence of dietary restrictions.
Adverse effects Nausea and headache are associated with the use of MAO B inhibitors, and the amphetamine metabolites of selegiline can cause insomnia [31].
Selegiline often causes confusion in the elderly, thereby limiting its use in patients with late-onset of disease. As previously mentioned, selegiline enhances the effect of levodopa by slowing its oxidative metabolism. Thus, it may increase levodopa-induced side effects such as dyskinesia and psychiatric toxicity (see "Levodopa" above). However, the need for continued selegiline is debatable once patients have reached the point of requiring levodopa.
Serious adverse reactions have rarely occurred following the concomitant use of selegiline with tricyclic antidepressants or selective serotonin reuptake inhibitors (SSRIs). In practice, the vast majority of patients on these combinations are able to tolerate them for years without problems. However, the Physicians' Desk Reference (PDR) warns not to use selegiline with either tricyclics or SSRIs. The possible interaction of SSRI and MAO B inhibitor treatment in patients with PD is discussed in greater detail separately. (See "Comorbid problems associated with Parkinson's disease", section on Concerns with SSRI use).
Unlike nonselective MAO inhibitors, selegiline does not precipitate a hypertensive crisis in patients who concomitantly ingest tyramine-containing foods. (See "Clinical presentation and diagnosis of pheochromocytoma").
Dopamine agonists The dopamine agonists are a group of synthetic agents that directly stimulate dopamine receptors. The drugs currently approved by the United States Food and Drug Administration (FDA) include bromocriptine (Parlodel), pergolide (Permax), pramipexole (Mirapex), ropinirole (Requip), and injectable apomorphine (show table 1).
Apomorphine and lisuride are additional dopamine agonists that can be administered parenterally for "rescue therapy" in patients experiencing sudden akinetic episodes. Lisuride is not currently approved in the United States, but it is available in Europe. Injectable apomorphine has been approved by the United States FDA for treatment of motor fluctuations in PD [42]. (See "Motor fluctuations and dyskinesia in Parkinson's disease", section on Dopamine agonists).
Unlike carbidopa/levodopa (Sinemet), these drugs are direct agonists that do not require metabolic conversion, do not compete with amino acids for transport across the gut or into the brain, and do not depend upon neuronal uptake and release. An additional advantage over immediate-release forms of levodopa is the longer duration of action of most of these agents.
Monotherapy Dopamine agonists were initially introduced as adjunctive treatment for advanced PD complicated by reduced levodopa response, motor fluctuations, dyskinesia, and other adverse effects of levodopa. However, the hypothetical concern that free radicals generated by the oxidative metabolism of dopamine contribute further to the degeneration of dopaminergic neurons has prompted some investigators, despite lack of conclusive evidence, to advocate the early use of dopamine agonists as an levodopa sparing strategy [43,44].
With this approach, treatment with levodopa can be postponed and saved for a later time in the course of the disease, when disability worsens and the less effective agonists no longer provide adequate benefit. This strategy is based upon the unproven concept that the long-term duration of a given patient's responsiveness to levodopa is finite and that the drug, like money in a savings or retirement account, should be rationed. However, whether reduced responsiveness to levodopa over time is due to a decline in drug response or progression of underlying PD is currently uncertain.
Controlled trials have shown that bromocriptine, pergolide, pramipexole, and ropinirole are all effective in patients with advanced PD complicated by motor fluctuations and dyskinesia [1]. However, these drugs are ineffective in patients who have shown no therapeutic response to levodopa.
Several studies have examined the use of dopamine agonists in patients with early PD; pramipexole, ropinirole, and pergolide were effective as monotherapy in patients with early disease [45-50]. In relatively long-term studies, patients with early PD treated with dopamine agonist monotherapy have a lower incidence of dyskinesia and motor fluctuations compared with those treated with levodopa [51-53]. As an example, one study found that the cumulative incidence of dyskinesia over five years was 20 percent in patients treated with ropinirole (plus or minus supplementation with levodopa) and 45 percent in patients treated with levodopa [53].
A second four-year trial found a similar 20 percent absolute reduction in the development of dyskinesia and a 15 percent reduction in wearing "off" with pramipexole compared with levodopa (show figure 2) [51]. On the other hand, initial treatment with levodopa resulted in lower incidences of freezing, somnolence, and leg edema (the latter two attributable to side effects of pramipexole) and provided for better symptomatic control. Both treatments resulted in similar quality of life.
In practice, while symptoms can be controlled initially with dopamine agonists, few patients with progressive disease can be satisfactorily maintained on dopamine agonist monotherapy for more than a few years before levodopa is needed. Studies comparing the long-term effects of levodopa monotherapy versus early bromocriptine or ropinirole followed by the delayed addition of levodopa have produced mixed results, showing either fewer motor complications with combined therapy [53-55] or no significant difference [56].
Thus, the hypothesis that early dopamine agonist monotherapy reduces the future incidence of motor complications is supported by several clinical trials, but this benefit occurs at the expense of reduced efficacy when compared with levodopa. Furthermore, one comparative study found that while early treatment with bromocriptine was associated with a slightly lower incidence of motor complications compared with levodopa therapy, overall disability scores were worse in the bromocriptine group throughout the first years of therapy [57].
Effectiveness The few studies that have compared the efficacy of various dopamine agonists with each other have found either no significant difference [58,59] or only mild superiority of one agent over another [60,61].
The two classes of dopamine agonists, ergot (bromocriptine and pergolide) and nonergot (pramipexole and ropinirole), stimulate dopamine D2 receptors preferentially. Some stimulate D1 receptors. D1 and D2 are the most important of the five known dopamine receptors that relate to levodopa therapy. Differences in receptor selectivity are as follows:
Pramipexole and ropinirole are nonergot compounds that also selectively stimulate D3 dopamine receptors in the ventral striatum, a non motor region of the basal ganglia. Since D3 receptors are not present in the dorsal or motor striatum, their role in drug responsiveness in PD is unclear. Ropinirole and pramipexole also differ from bromocriptine and pergolide in their ability to nonselectively stimulate serotonin or adrenergic receptors.
Bromocriptine is a mixed D1 agonist and antagonist, and a D3 agonist.
Pergolide stimulates D1 receptors.
Apomorphine is a short-acting D1 and D2 receptor agonist.
Whether these differences will translate into greater efficacy and less toxicity of the newer dopamine agonists (pramipexole and ropinirole) over the older ergot compounds (bromocriptine and pergolide) remains to be seen. At the present time, however, there is probably no indication to switch from one agonist to another in a patient experiencing a satisfactory therapeutic benefit from one agent.
Dosing The dopamine agonists generally require administration at least three times a day at maintenance doses:
Bromocriptine (Parlodel) is usually started at 1.25 mg twice a day; the dose is increased at two to four week intervals by 2.5 mg a day. Most patients can be managed on 20 to 40 mg daily in three to four divided doses, although total daily doses as high as 90 mg can be used.
Pramipexole (Mirapex) is usually started at 0.125 mg three times a day. The dose should be increased gradually by 0.125 mg per dose every five to seven days. Most patients can be managed on total daily doses of 1.5 to 4.5 mg.
Ropinirole (Requip) is usually started at 0.25 mg three times a day. The dose should be increased gradually by 0.25 mg per dose each week for four weeks to a total daily dose of 3 mg. Most patients can be managed on this dose. After week four, the ropinirole dose may be increased weekly by 1.5 mg a day up to a maximum total daily dose of 24 mg. Benefit most commonly occurs in the dosage range of 12 to 16 mg per day.
Pergolide (Permax) is best avoided because of the potential for cardiac valve problems (see "Adverse effects of DAs" below). If used, it is usually started at 0.05 mg a day for two days, then increased by 0.1 or 0.15 mg a day every three days for 12 days. After that, the dose may be increased by 0.25 mg a day every three days until the optimal therapeutic response is achieved. The usual total daily dose range is 1.5 to 3 mg in three divided doses. The maximum total daily dose is 5 mg.
Apomorphine (Apokyn) may be administered either as intermittent rescue injections or as continuous infusions to treat "off" episodes or levodopa-induced motor fluctuations. A challenge test dose must precede routine use. This is usually done with a 2 mg subcutaneous injection under medical supervision and monitoring of standing and supine blood pressure before the injection, and repeated at 20, 40, and 60 minutes after.
Antiemetic therapy (eg, with trimethobenzamide) is initiated three days prior to starting apomorphine and is usually continued for two months before reassessing need. However, the use of apomorphine is contraindicated with ondansetron and other serotonin receptor agonists commonly used to treat nausea and vomiting, as the combination may cause severe hypotension and loss of consciousness [62]. In addition, dopamine antagonists used to treat nausea and vomiting such as prochlorperazine and metoclopramide should be avoided, as they may reduce the effectiveness of apomorphine.
The usual starting dose for intermittent apomorphine use is 2 mg, if the patient tolerates and responds to the test dose. The dose may be increased by 1 mg per dose every two to four days to a maximum of 6 mg per dose. The average dosing frequency is three times daily and should not exceed five times a day dosing or a total daily dose of 20 mg.
Adverse effects of DAs Adverse effects caused by dopamine agonists (DAs) are similar to those of levodopa, including nausea, vomiting, sleepiness, orthostatic hypotension, confusion, and hallucinations. Peripheral edema is common with the chronic use of DAs but is rare in patients using levodopa alone.
These adverse effects can usually be avoided by initiating treatment with very small doses and titrating to therapeutic levels slowly over several weeks. Patients intolerant of one agonist may tolerate another. As with all of the antiparkinsonian drugs, elderly and demented patients are much more susceptible to psychiatric side effects.
Accumulating evidence suggests that pathologic gambling and other impulse control disorders may be associated with the use of dopamine agonists as a class. (See "Pathologic gambling and impulse control disorders" below).
Adverse events with apomorphine are usually mild and consist, predominantly of cutaneous reactions and neuropsychiatric problems [42]. The incidence of these problems is higher in patients receiving continuous infusion than in those receiving intermittent subcutaneous injections. Chest pain, angina, and orthostatic hypotension are more serious problems; orthostasis peaks 20 minutes after dosing and lasts at least 90 minutes. A test dose of apomorphine to establish tolerance and responsiveness is essential prior to routine administration.
Ergot-related side effects such as Raynaud phenomenon, erythromelalgia, and retroperitoneal or pulmonary fibrosis are uncommon with bromocriptine and pergolide, and they do not occur at all with the nonergot agonists ropinirole and pramipexole.
Valvular heart disease, with lesions similar to those associated with carcinoid, ergot, and fenfluramine-induced valve disease, has been reported in patients taking pergolide [63-67]. As an example, a retrospective study of patients with PD compared 78 patients treated with pergolide and 18 controls never treated with an ergot-derived dopamine agonist; important restrictive valvular heart disease was significantly more frequent in patients treated with pergolide compared with controls (19 versus 0 percent) [66]. Another report found that pergolide treatment was associated with a two to three-fold increased risk of abnormal valves and an estimated 14-fold increased risk of tricuspid regurgitation compared with historical controls [67].
Thus, restrictive valvular heart disease may not be rare in patients treated with pergolide, especially at high doses (5 to 7 mg daily). Patients doing well on pergolide should, at the very least, have periodic echocardiograms to assess the health of the heart. Alternatively, switching to a non-ergot dopamine agonist such as ropinirole or pramipexole may be considered.
Dopamine receptor agonists decrease prolactin concentration [68]. Thus, there is a potential for decreased milk production in postpartum women taking these agents, which are contraindicated in women who are breast feeding.
The manufacturer of pramipexole has issued a warning regarding somnolence that can occur abruptly and without premonition, particularly at a dose above 1.5 mg/day. Patients with PD who drive are at particular risk of developing these "sleep attacks" [69]. (See "Comorbid problems associated with Parkinson's disease", section on Daytime sleepiness). They advise that patients be warned of this potential side effect and asked about factors that may increase the risk of drowsiness, such as concomitant sedating medications, sleep disorders, and medications that increase pramipexole levels (eg, cimetidine).
Dopaminergic dysregulation syndrome Compulsive use of dopaminergic drugs develops in a small number of patients with PD and has been termed the dopaminergic dysregulation syndrome (DDS) [70].
DDS typically involves male patients with early onset PD who take increasing quantities of dopaminergic drugs despite increasingly severe drug-induced dyskinesia [70,71]. DDS can be associated with a cyclical mood disorder characterized by hypomania or manic psychosis. Tolerance (or frank dysphoria) to the mood elevating effects of dopaminergic therapy develops, and a withdrawal state occurs with dose reduction or withdrawal. Impulse control disorders including hypersexuality and pathologic gambling may accompany DDS [70]. (See "Pathologic gambling and impulse control disorders" below).
A form of complex, prolonged, purposeless, and stereotyped behaviour called punding may be also be associated with DDS [72].
DDS appears to be uncommon but not rare. In a series of 202 patients with PD, criteria for DDS were fulfilled in seven (3.4 percent) [73]. DDS may occur more frequently with dopaminergic agonists than with levodopa [73], but data are scarce. A small case-control study found that susceptibility factors for DDS included younger age at disease onset, higher novelty seeking personality traits, depressive symptoms, and alcohol intake [74].
Management of DDS is not well studied. Practitioners should limit dopaminergic dose increases when possible, particularly in patients who may have increased susceptibility to DDS. Continuous subcutaneous apomorphine infusions may be useful to suppress off-period dysphoria, and low doses of clozapine or quetiapine may be useful for some patients [74]. Treatment of psychosis in patients with PD is discussed in detail elsewhere. (See "Comorbid problems associated with Parkinson's disease", section on Psychosis and hallucinations).
Pathologic gambling and impulse control disorders Dopamine agonist therapy may be associated with an increased risk of impulse control disorders including pathologic gambling [75], compulsive sexual behavior, or compulsive buying, as illustrated by the following reports:
A prospective Canadian case series of 297 patients with PD found that the lifetime prevalence of pathologic gambling for all patients and for those receiving any dopamine agonist was 3.4 and 7.2 percent, respectively, compared with a lifetime prevalence of 1.0 percent in the Ontario population [76]. There was a statistically significant association of pathologic gambling with earlier PD onset and dopamine agonist therapy, but not with dopamine agonist subtype or dose. In line with earlier retrospective studies [75,77], pathologic gambling did not develop in patients receiving levodopa monotherapy [76]. (See "Pathologic gambling").
Another series of 272 patients with PD found that criteria for impulse control disorders, either anytime during the course of PD or currently active, were met by 6.6 and 4.0 percent of patients, respectively [78]. The frequency of pathologic gambling, compulsive sexual behavior, and compulsive buying anytime during PD were 2.6, 2.6, and 1.5 percent, respectively. On multivariate analysis, significant predictors of an active impulse control disorder were use of a dopamine agonist and a history of impulse control disorder symptoms before the onset of PD.
In a retrospective case series of 11 patients with PD who developed pathologic gambling linked to dopamine agonist therapy, the pathologic gambling resolved with tapering or discontinuation of dopamine agonist therapy in all patients available for follow-up (8 of 11). Only one of 11 patients in the series met criteria for the dopaminergic dysregulation syndrome described above, although six patients simultaneously developed other inappropriate behaviors such as hypersexuality [77]. (See "Dopaminergic dysregulation syndrome" above).
COMT inhibitors The catechol-O-methyl transferase (COMT) inhibitors tolcapone (Tasmar) and entacapone (Comtan) are useful as levodopa extenders [79]. They are ineffective when given alone, but they may prolong and potentiate the levodopa effect when given with a dose of levodopa. These medications are mainly used to treat patients with motor fluctuations who are experiencing end-of-dose wearing "off" periods. When given to patients without motor fluctuations, entacapone did not improve UPDRS motor scores but was associated with several improved quality of life measures [80]. (See "Motor fluctuations and dyskinesia in Parkinson's disease", section on Unpredictable "off" periods).
Inhibition of catechol-O-methyl transferase reduces the peripheral (entacapone) and central (tolcapone) methylation of levodopa and dopamine, which in turn increases the plasma half-life of levodopa, produces more stable plasma levodopa concentrations, and prolongs the therapeutic effect of each dose. Use of COMT inhibitors may allow a reduction in the total daily levodopa dose by as much as 30 percent. The net result is an increased levodopa effect [79,81].
Dosing The starting dose of tolcapone is 100 mg three times daily; the clinical effect is evident immediately. The dose of entacapone is one 200 mg tablet with each dose of levodopa, up to a maximum of eight doses per day.
Adverse effects The most common side effects of tolcapone are due to increased dopaminergic stimulation and include dyskinesia, hallucinations, confusion, nausea, and orthostatic hypotension. The adverse effects are managed by lowering the dose of levodopa either before or after the addition of tolcapone. Diarrhea poorly responsive to antidiarrheal medications appears in approximately 5 percent of patients. An orange discoloration of the urine is a common but benign adverse event. Elevations in liver enzymes may rarely occur.
Three reported deaths from hepatotoxicity in patients using tolcapone prompted its removal from the market in Canada and Europe, although it is still available in the United States with the recommendation that it be used for treatment of motor fluctuations only after other methods have been exhausted and with regular monitoring of ALT and AST levels.
Side effects of entacapone are similar to tolcapone, although entacapone has thus far not been associated with hepatotoxicity.
Anticholinergics Dopamine and acetylcholine are normally in a state of electrochemical balance in the basal ganglia. In PD, dopamine depletion produces a state of cholinergic sensitivity so that cholinergic drugs exacerbate and anticholinergic drugs improve parkinsonian symptoms [82,83].
Centrally acting anticholinergic drugs such as trihexyphenidyl (Artane) and benztropine (Cogentin) have been used for many years in PD and continue to have a useful role (show table 1) [84]. Other anticholinergic agents such as biperiden (Akineton), orphenadrine (Disipal), and procyclidine (Kemadrin) produce similar effects and are more commonly used in Europe than the United States. Benztropine also may increase the effect of dopamine by inhibiting its presynaptic reuptake, but it is not known whether this contributes to its mechanism of action.
Anticholinergic drugs are most useful as monotherapy in patients under age 70 with disturbing tremor who do not have significant akinesia or gait disturbance. They also may be useful in patients with more advanced disease who have persistent tremor despite treatment with levodopa or dopamine agonists.
Dosing Trihexyphenidyl is the most widely prescribed anticholinergic agent, although there is little evidence to suggest that one drug in this class is superior to another. The starting dose of trihexyphenidyl is 0.5 to 1.0 mg twice daily, with a gradual increase to 2 mg three times daily. Benztropine traditionally is more commonly used by psychiatrists for the management of antipsychotic drug-induced parkinsonism; the usual dose is 0.5 to 2.0 mg twice daily.
Adverse effects Adverse effects of anticholinergic drugs are common and often limit their use. Elderly and cognitively impaired patients are particularly susceptible to memory impairment, confusion, and hallucinations and should not receive these drugs. When an anticholinergic drug is used to treat sialorrhea or urinary frequency, peripherally acting agents such as propantheline (probanthine) should be used, although confusion and hallucinations are not infrequent adverse effects with these drugs as well. Younger patients usually tolerate these agents better than the elderly, although some experience dysphoric symptoms, sedation, or memory impairment.
Peripheral antimuscarinic side effects include dry mouth, blurred vision, constipation, nausea, urinary retention, impaired sweating, and tachycardia. Caution is advised in patients with known prostatic hypertrophy or closed-angle glaucoma. Discontinuation of anticholinergic drugs should be performed gradually to avoid withdrawal symptoms that may manifest as an acute exacerbation of parkinsonism, even in those in whom the clinical response has not seemed significant.
Amantadine Amantadine is an antiviral agent that has mild antiparkinsonian activity [85]. Its mechanism of action is uncertain; it is known to increase dopamine release, inhibit dopamine reuptake, stimulate dopamine receptors, and it may possibly exert central anticholinergic effects (show table 1) [86]. Amantadine has N-methyl-D-aspartate (NMDA) receptor antagonist properties that may account for its therapeutic effect by interfering with excessive glutamate neurotransmission in the basal ganglia.
In early uncontrolled clinical trials, two-thirds of patients receiving amantadine monotherapy showed an improvement in akinesia, rigidity, and tremor [85]. Subsequent controlled studies demonstrated that it was more effective than anticholinergic drugs for akinesia and rigidity [87]. The benefit induced by amantadine appears to be transient in some patients; it is best used as short-term monotherapy in those with mild disease. Amantadine is of little benefit when added to levodopa, although the addition of levodopa to amantadine causes significant additive improvement [88].
Amantadine in divided doses of 200 to 400 mg a day may reduce the intensity of levodopa-induced dyskinesia and motor fluctuations in patients with PD. Although the published randomized trials on amantadine in advanced PD are limited by serious methodological flaws and small numbers of patients [89], experience has shown that individual patients with advanced PD who have motor fluctuations and dyskinesia can benefit dramatically, at least for a while, from the addition of amantadine to a regimen of levodopa.
Dosing The dose of amantadine in early PD is 200 to 300 mg daily; there is no evidence that larger doses are of additional benefit. The main advantage of this agent is a low incidence of side effects. It is excreted unchanged in the urine and should be used with caution in the presence of renal failure.
Adverse effects Peripheral side effects include livedo reticularis and ankle edema, which are rarely severe enough to limit treatment. Confusion, hallucinations, and nightmares occur infrequently, but unpredictably, even after long periods of use without side effects. These effects are more likely when amantadine is used together with other antiparkinsonian drugs in older patients.
Estrogen Low-dose estrogen may be helpful as adjunctive therapy in postmenopausal women with motor fluctuations on antiparkinsonian medication. In one study, administration of premarin 0.625 mg daily for eight weeks significantly improved "on" time and motor control in such women, although it did not result in global improvement on an activities of daily living rating scale [7]. There is no evidence that estrogen has a specific effect on dopamine receptors; the benefit attributable to estrogen use may be related to an overall sense of well being.
It is not clear if these results would be similar in women taking combined estrogen/progestin therapy (necessary in women with an intact uterus). Furthermore, concerns about adverse effects associated with long-term estrogen/progestin therapy may limit its use in PD. (See "Postmenopausal hormone therapy: Benefits and risks").
SUMMARY AND RECOMMENDATIONS Either levodopa or a dopamine agonist can be used initially for patients who require symptomatic therapy [90-92].
Levodopa (combined with a peripheral decarboxylase inhibitor, ie, Sinemet, Madopar, or Prolopa) is the most effective symptomatic therapy for Parkinson's disease (PD) and should be introduced when the patient and physician jointly decide that quality of life, particularly related to job performance or self care, is substantially compromised. However, levodopa is associated with a higher risk of dyskinesia than the dopamine agonists. There does not appear to be a benefit of initiating treatment with controlled release levodopa compared with the immediate release preparation, and the former may limit the ability to follow the initial response to therapy. As a result, it is recommended that therapy be initiated with an immediate release preparation with a subsequent switch to controlled release if indicated.
The dopamine agonists are a useful group of drugs that may be used either as monotherapy in early PD or in combination with other antiparkinsonian drugs for treatment of more advanced disease. They are ineffective in patients who show no response to levodopa. They possibly delay initiation of levodopa therapy and the subsequent appearance of levodopa dyskinesia and motor fluctuations, but at the risk of slightly less efficacy and increased adverse effects [51,53].
It is reasonable to initiate therapy with a dopamine agonist in younger patients (age <65) with PD, and with levodopa in elderly patients (age >65). However, there are exceptions to these general rules, and all treatments should be individualized. Levodopa is the drug of choice if symptoms seriously threaten the patient's lifestyle.
Selegiline has mild symptomatic benefit, and it may be used in patients with early PD [1,92]. Its use should be limited to patients with early disease since the symptomatic benefits are unlikely to be significant in those with more advanced PD. Nevertheless, patients should understand that there may not be much symptomatic improvement if selegiline is the initial treatment for early PD, and early follow-up and consideration of additional symptomatic therapy should be arranged. The value of selegiline for neuroprotection is unclear [92].
Rasagiline is a newer MAO B inhibitor that produces significant benefit as monotherapy in PD, as demonstrated in randomized clinical trials [32]. It therefore has a better defined role than selegiline in the symptomatic treatment of patients with early PD. Rasagiline is approved by the European Commission and the United States Food and Drug Administration (FDA). (See "MAO B inhibitors" above).
Anticholinergic drugs should be reserved for younger patients in whom tremor is the predominant problem. Their use in older or demented individuals and those without tremor is strongly discouraged. Amantadine is a relatively weak antiparkinsonian drug with low toxicity that is most useful in treating patients with early or mild PD and perhaps later when dyskinesia becomes problematic.
Sincerely,
GC Hospital Chief of Medicine
Dr. AKA_Monet
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