Pharmacologic Management of Parkinson’s Disease



While many aspects of the neurodegenerative process underlying Parkinson’s disease (PD) are now understood, treatments with proven disease-modifying effects have not yet reached the stage of clinical applicability. However, since the introduction of the first dopamine (DA)-replacing drug, levodopa (L-dopa), considerable progress has been made with respect to the symptomatic treatment of the parkinsonian motor features, and a wide range of dopaminergic treatments are now available (1,2) and are in development (3). As the disease advances, motor as well as nonmotor symptoms become more prominent, and the latter can even dominate the clinical picture. It is increasingly recognized that several nondopaminergic neurotransmitter systems are involved in PD, which may give rise to significant clinical problems. These often have more impact on patients and carers’ quality of life than the primary parkinsonian motor signs do and include dementia, depression, behavioral and sleep disturbances, autonomic dysregulation, impaired balance, and falls. In advanced stages, problems increasingly appear related to drug treatment, which may be difficult to distinguish from symptoms related directly to PD.


The clinical features in the early stages of PD are largely related to the cardinal motor symptoms of the disorder. Nonmotor symptoms can also be present but generally cause little disability. In advanced PD, problems closely linked to the long-term side effects of drugs used for treatment are prominent. An increased risk of motor complications is encountered with the use of L-dopa, while other clinically relevant problems, such as neuropsychiatric complications, are more likely to occur with drugs such as DA agonists, amantadine, or anticholinergics (Table 10.1). With this close interaction of disease-related and treatment-related factors in mind, the structure for this chapter was chosen in such a way that the clinical problems encountered in PD are described first, and subsequently the various drugs available for their management are presented. The chapter is centered mostly on the management of symptoms related to the dopaminergic system. In the last part of this chapter, management recommendations are given for typical situations in early, stable, and advanced PD. Other chapters in this book extensively review the management of nonmotor symptoms.


PROBLEMS IN PD ASSOCIATED WITH DOPAMINERGIC TREATMENTS


In the early stages, motor symptoms that relate to the cardinal manifestation of the disease—mostly tremor and bradykinesia—are those that alarm the patients and their families and bring the patient to medical attention. They reflect progressive degeneration of dopaminergic nigral cells and respond to dopaminergic replacement therapy. Nonmotor symptoms may also occur early, such as anosmia or rapid eye movement (REM) sleep behavior disorder (RBD), but these are less disabling and worrisome to the patients who rarely complain about them. Apathy or pain may be early manifestations, but usually, the disability inflicted by motor symptoms is what determines the timing and type of medication with which we initiate treatment.












TABLE 10.1


 


Common Clinical Problems Encountered in Advanced Parkinson’s Disease




Complications Related to Dopaminergic Therapy


  Motor and nonmotor fluctuations


  Dyskinesia


  Neuropsychiatric problems: hallucinosis and behavioral disorders (e.g., dopaminergic dysregulation, punding, hypersexuality)


  Excessive daytime sleepiness


  Leg edema


Disease-Related Motor Complications


  Gait difficulties (freezing)


  Postural imbalance (falls)


  Dysarthria


Disease-Related Nonmotor Symptoms


  Depression


  Dementia


  Sleep disorders (REM behavior disorders, insomnia)


  Autonomic dysfunction


  Sensory symptoms













TABLE 10.2


 


Fluctuations in Motor Disability in Parkinson’s Disease




Unrelated to Drugs


Kinesia paradoxica


Freezing of gait


Sleep benefit (improvement of symptoms after sleep)


Stress-related tremor


Related to l-dopa Treatment


Nocturnal and early morning akinesia


Wearing-off (end-of-dose deterioration)*


Delayed onset effect (delayed on)


Dose failure (no on)


Super off


Unpredictable (random) on–off fluctuations


*Can also occur with dopamine agonists



The initiation of treatment in early PD is followed by a phase of good to excellent symptomatic response in nearly all patients (“honeymoon phase”). A stable response may be sustained in some patients throughout the course of their illness, but the majority will develop motor complications. Motor complications include response fluctuations, which are characterized by a shortening of the response to individual L-dopa doses, and dyskinesias or involuntary movements. Dyskinesias are a side effect of L-dopa and other dopaminergic drugs. These drugs also frequently cause behavioral changes that require medical attention.


RESPONSE FLUCTUATIONS


In early PD, the clinical effect following an individual L-dopa dose wanes slowly and may still be detectable after days and up to weeks (long-duration L-dopa response). As the disease progresses, the duration of effect gradually becomes shorter and patients become aware of a missed or delayed dose as their parkinsonian symptoms and signs reemerge. The time when this wearing-off at the end-of-a-dose effect first becomes noticeable depends on the dosing intervals in each patient’s drug regimen. Eventually, the clinical response closely reflects peripheral L-dopa pharmacokinetics, characterized by a plasma half-life of 1 to 1.5 hours. At later stages, some patients experience unpredictable fluctuations, which occur independently of the timing of medication and which may, therefore, cause considerable distress. Delayed on refers to a prolonged latency to the onset of a noticeable drug effect following intake. Dose failure, a complete lack of effect of individual doses, causes distress and carries the additional risk of worsened dyskinesias if patients attempt to compensate for the missed effect by taking additional medication. The various types of fluctuations in motor disability occurring in PD, both disease- and drug-related, are listed in Table 10.2.


In patients with motor fluctuations, nonmotor problems associated with the off periods may cause significant distress (4,5). In one study, all patients who had motor fluctuations also experienced at least one nonmotor problem during off phases (4). The nonmotor symptoms most frequently reported during off periods include anxiety, drenching sweats, slowness of thinking, fatigue, akathisia, irritability, pain, and hallucinations. In another study, patients reported tiredness as the most frequent nonmotor symptom (5). Dopaminergic mechanisms are important in nonmotor fluctuations, and they can improve with optimization of dopaminergic therapies.


DYSKINESIAS


Dyskinesias are involuntary, hyperkinetic movements and may occur at any stage during the motor cycle in fluctuating patients (Table 10.3). Dyskinesias tend first to become apparent during the peaks in plasma concentration and clinical effect following each dose of dopaminergic medication, and later on, they often are present during the entire duration of drug effect (peak-dose dyskinesia). At earlier stages, they may go unnoticed by patients, while carers and observers are aware of their presence and may be socially embarrassed. While patients themselves may prefer mild or moderate forms of dyskinesias to the immobility and the nonmotor symptoms of off periods, severe chorea and more complicated patterns such as ballistic, stereotypic, and dystonic dyskinesias pose a considerable burden on patients and may be a major cause of disability in advanced PD. Dyskinesias may be prominent at the onset- and end-of-a-dose effect (diphasic dyskinesia). These often involve one or both legs and often have stereotypical or ballistic features. Off-period dyskinesias are usually dystonic, often affect the lower limbs, and may be painful. Such cramping of feet and toes typically occurs in the early morning hours or upon awaking, when plasma concentrations of drugs are lowest (6). All dyskinesias tend to be more marked on the side of the body or in the limb most affected by parkinsonism.












TABLE 10.3


 


Types of Drug-Induced Dyskinesias




On or interdose dyskinesia


Limbs and trunk: mostly choreic movements


Craniocervical: mostly dystonic movements


Diphasic Dyskinesia (Beginning-of-Dose, End-of-Dose Dyskinesia)


Occur at the beginning- or end-of-dose effect


Stereotyped, ballistic, and dystonic movement


Sometimes accompanied by profuse sweating, tachycardia, and anxiety


Tremor may worsen with beginning-of-dose dyskinesia


Off-Period Dystonia


Mostly distal in one leg


Frequently painful


Sometimes isolated occurrence early in the morning (early morning dystonia)


Worse when walking



Incidence figures for motor complications vary in the literature. In a meta-analysis of published prospective studies, the risk of dyskinesias as well as fluctuations after 5 years was found to be around 40% (7), while a study showed that response fluctuations may be a fairly early phenomenon when subtle and nonmotor signs are also considered (5). Some information on long-term risk is available from prospective treatment trials, which showed a further increase at 10 (8) and 15 years (9), although motor complications were considered disabling in less than half of the affected patients. Age at onset has an important impact: in young-onset PD, dyskinesias have been reported in up to 94% of patients (10). A population-based study showed a 5-year dyskinesia incidence of 16% in patients with disease onset after 70 years of age compared with 50% when onset was between 40 and 59 years of age (11).


PATHOPHYSIOLOGY OF RESPONSE FLUCTUATIONS AND DYSKINESIAS


The exact mechanisms underlying motor fluctuations and dyskinesias are not yet completely understood. While the peripheral pharmacokinetics of L-dopa remain unchanged throughout the course of the illness (12,13), presynaptic nigrostriatal nerve terminals gradually lose their ability to store DA as the neurodegeneration progresses. Therefore, fluctuations in plasma DA levels can no longer be buffered by reuptake into presynaptic terminals. This storage hypothesis is useful for explaining some of the changes that occur in later-stage PD, but ample evidence now exists for a far more complex basis of the development of motor complications.


Although the overall risk of developing dyskinesias has been shown to increase with the duration (14) and dose (10,15) of L-dopa treatment, the timing of L-dopa initiation as such does not appear to be the primary factor. Rather, current evidence suggests that the degree of nigrostriatal degeneration and the mode of drug administration are of central importance (16). The role of the degree of neuronal loss is supported by the short latency to the occurrence of motor complications in the presence of severe nigrostriatal degeneration: Motor complications develop within days following L-dopa initiation in 1-methyl-4-phenyl-1,2,3,6-tetra-hydropyridine (MPTP)-treated primates, where there is a 90% to 95% cell loss (17), and within weeks or months in PD patients in whom treatment was started at an advanced stage (18) or in MPTP-induced parkinsonism (19). Because disease severity determines the timing and doses of symptomatic treatment to a large degree, these factors and their respective roles in the development of motor complications are difficult to disentangle in PD patients.


Age at disease onset is another factor intrinsic to the disease process that is related to the risk of motor complications. As already outlined, younger age of onset is associated with a higher rate of fluctuations and dyskinesias.


As yet, neither the rate of neuronal loss nor the age of onset is amenable to modification. However, treatment-related factors also contribute to the risk of motor complications. As neurodegeneration progresses, the activation of DA receptors becomes increasingly dependent on the peripheral availability of exogenous dopaminergic agents. In addition to postsynaptic mechanisms, there is growing evidence that presynaptic DA depletion predicts L-dopa–induced dyskinesia (20). Because of reduced striatal buffer capacity, fluctuating plasma L-dopa concentrations linked to the short half-life of L-dopa (21) may be translated into peaks and troughs in striatal DA concentration. The result is intermittent receptor activation (22), which can result in plastic changes in gene expression and in neuropeptide formation within the striatal pathways (23,24). These changes lead to alterations in the firing patterns of basal ganglia output neurons, which convey signals to cortical motor regions (25,26). The hypothesis has been put forward that L-dopa–associated motor complications, and dyskinesias in particular, may be caused by such intermittent or pulsatile stimulation of striatal DA receptors linked to intermittent L-dopa delivery to the brain. Studies in patients with advanced disease have shown that continuous delivery of dopaminergic drugs such as subcutaneous (SC) apomorphine (27,28), or parenteral or enteral L-dopa (2932) can improve dyskinesia and indirectly support the concept that the manner of administration of dopaminergic drugs is of central importance, and argues against a specific detrimental effect of L-dopa. Still, results from a large trial (STRIDE-PD) addressing the clinically important question of whether the early combination of L-dopa with a COMT inhibitor may be a useful strategy to avoid motor complications in patients with early-stage untreated patients has shown that addition of entacapone to L-dopa/carbidopa (L/C) therapy does not reduce the development of dyskinesias (33).


BEHAVIORAL DISTURBANCES


In the course of treatment, a substantial number of patients develop psychiatric complications of antiparkinsonian treatment. These complications include the psychiatric symptoms of the nonmotor fluctuations, described above, psychosis (hallucinations, delusions, hypomania), impulse-control disorders (ICDs), and the so-called DA dysregulation syndrome. Recognition of the various ICDs and the less-common and underrecognized DA dysregulation syndrome and associated behavioral abnormalities is essential for appropriate treatment.


The most common treatment-related psychiatric complications in patients with PD are hallucinations. In population-based, cross-sectional studies, their prevalence rate is approximately 15% to 20% (34,35), with preserved insight in the majority of cases.


Hallucinations in PD occur generally on medication, although they may persist for days or weeks after discontinuation or reduction of the offending drug. However, the dose and duration of treatment have not been shown to be of great influence in the development of hallucinations, suggesting that other factors are more important (36,37). The most consistent risk factor for hallucinations has been found to be cognitive impairment (38,39).


ICDs have been conceptualized as “behavioral addictions” (40) and are often performed without the patient experiencing subjective distress (41). They are characterized by an irresistible and uncontrollable drive or temptation to perform an action, although the activity may be potentially detrimental to oneself or others. Common ICDs observed in PD include pathologic gambling, hypersexuality, compulsive eating, and compulsive buying.


ICDs as a group are not uncommon in PD. A large cross-sectional study of 3,090 patients with PD being treated at 46 centers across the United States and Canada identified an ICD in 13.6% of patients. Problem gambling was diagnosed in 5%, aberrant sexual behavior in 3.5%, excessive spending in 5.7%, and binge eating in 4.3%. More than one-fourth of patients had two or more ICDs, and many patients also had concurrent compulsive behaviors (42). Other series have observed similar (43) or even higher (44,45) ICDs rates in PD patients receiving dopaminergic therapies. Although ICD are especially prevalent in parkinsonian patients receiving a DA agonist as part of their treatment regimen, they have also been reported when DA agonists are used for other indications such as restless legs syndrome (46) or fibromyalgia (47). The association of ICDs with DA agonist treatment seems to occur as a class effect unrelated to a specific DA agonist or specific doses. However, recently in a multicenter transversal study, ICD was significantly associated with the use of the nonergolinic oral DA (pramipexole and ropinirole) when compared with transdermal nonergolinic DA (45). Possible factors raised by the authors to explain the different risk between drugs were the more constant plasmatic levels on rotigotine or the route of administration (transdermal versus oral route).


Other demographic and clinical risk factors that have been associated with ICD in PD are an early disease onset, male gender, depression, novelty-seeking personality traits, and a positive (family) history of substance abuse (42,48,49).


The cause of ICD’s development in PD is not known, but increased evidence suggests a role of impaired orbitofrontal functioning and a relatively increased ventral striatal dopaminergic signaling due to treatment with DA, which influences reward-based learning in susceptible PD patients (50,51). A sensitization process with increasing incentive salience of behaviors has also been implicated. The release of DA following a reward may shift to cues of the reward, triggering a reward response (52).


Patients with DA dysregulation syndrome develop a pattern of compulsive dopaminergic drug use, which includes taking increasing quantities of medication beyond those required to treat motor disabilities and continuing to request more dopaminergic drugs. This occurs despite the emergence of drug-induced motor complications, in particular dyskinesias (53,54). Predisposing factors include young age at disease onset, high dopaminergic drug intake, past drug use, depression, novelty-seeking personality traits, and alcohol intake (55).


A behavioral abnormality that may be associated with high doses of dopaminergic replacement therapy and often with DA dysregulation is “punding” (5557). This phenomenon was first described in amphetamine addicts and is a complex stereotyped behavior characterized by an intense fascination with repetitive activities, such as manipulations of technical equipment; the continual handling, examining, and sorting of objects; grooming; hoarding; or using a computer. These activities are carried out during on phases, and they are often associated with dyskinesias. Initially, the activities are mainly present at night, and if abnormal behavior is suspected, it is important to inquire how patients cope with insomnia, particularly because patients rarely report punding behavior spontaneously. Punding is sometimes acknowledged as disruptive and unproductive by the patients, but attempts to interrupt the behavior typically lead to irritability and dysphoria. It is important to note that punding is distinct from both obsessive–compulsive and manic disorders.


It is believed that punding in vulnerable persons results from a process of psychomotor stimulation, mediated by ventral striatal structures, and an increasing inability to control automatic response mechanisms resulting from impaired frontal lobe function. It is closely linked to reward responses, and a sensitization process induced by dopaminergic therapy is believed to have a central role. This is supported by the finding of an association with frequent use of short-acting rescue medication, such as soluble L-dopa and apomorphine injections (57).


CLASSES OF DRUGS FOR THE SYMPTOMATIC TREATMENT OF MOTOR FUNCTION IN PD


The drugs discussed in this section are used for the management of those motor aspects of PD that are related to the dopaminergic deficit in PD, in particular the cardinal motor signs, tremor, bradykinesia, and rigidity. As outlined, severe motor impairment may occur, particularly in later stages of the disease, independently of dopaminergic function, for example, freezing during on phases and loss of balance. Possible management approaches will be discussed in a later section of this chapter, but for these problems, the dopaminergic drugs discussed here typically have a very limited role.


L-DOPA


L-dopa, the precursor of DA, is an aromatic amino acid that occurs naturally in a number of leguminous plants. The highest concentration is found in the bean plant Mucuna pruriens, which has been used in Ayurvedic medicine since 1500 BC, including for conditions resembling parkinsonism (58,59). Synthetic L-dopa was introduced into Western medicine in the early 1960s (60,61) and has since remained the gold standard among antiparkinsonian drugs due to the degree of symptom relief it is capable of providing. L-dopa continues to be the most powerful orally active antiparkinsonian drug (62).


L-dopa has a marked symptomatic effect on all components of the cardinal parkinsonian motor signs—bradykinesia, rigidity, and tremor—and in many patients L-dopa therapy initially leads to complete or nearly complete reversal of symptoms. L-dopa increases the duration of time patients remain independent and employable, and there is evidence to suggest a beneficial effect on life expectancy, although this has not been confirmed in all studies (6365). While a wide range of other symptomatic treatment options is available, which are often used now to delay the use of L-dopa, virtually all patients will at some stage require the more powerful symptomatic effects of L-dopa (Table 10.4).












TABLE 10.4


 


Treatment of Parkinson’s Disease with L-dopa




Advantages of l-dopa Therapy


  The vast majority of patients who start treatment with l-dopa experience good to excellent functional benefit.


  Tolerability is usually good.


  The antiparkinsonian effect is maintained throughout the course of the illness.


  l-dopa is not toxic to humans.


  There is evidence to show that l-dopa extends life expectancy.


  l-dopa improves quality of life.


  l-dopa is the drug of choice for treatment of elderly patients, and in the presence of neuropsychiatric problems.


  l-dopa today remains the gold standard and the most effective drug for the symptomatic treatment of Parkinson’s disease.


Limitations of l-dopa Therapy


  Development of motor and nonmotor fluctuations


  Dyskinesias


  Limited or no response of some symptoms (e.g., freezing of gait, dysautonomia, dysarthria)


  Occurrence of nonmotor dopaminergic adverse effects (less frequently than with other drugs): nausea, neuropsychiatric problems, including hallucinosis, sleepiness, autonomic problems



Basic Pharmacology and Metabolism


L-dopa is absorbed in the gastrointestinal (GI) tract at the level of the small intestines, where it uses the large neutral amino acid transport system, competing with protein from food. The same transport system is utilized to cross the blood–brain barrier. The plasma half-life of L-dopa is 1 to 1.5 hours. In the periphery, it is metabolized to DA by aromatic amino acid decarboxylase (AADC) and to 3-O-methyl dopa by catechol-O-methyltransferase (COMT). Due to the high peripheral degradation rate of L-dopa, high doses were required in the early days of L-dopa therapy, which were associated with dopaminergic side effects such as nausea, vomiting, and orthostatic reactions. The introduction of decarboxylase inhibitors (DDCIs) greatly facilitated L-dopa treatment, and either carbidopa or benserazide are now routinely coadministered with each L-dopa dose. They block peripheral degradation of L-dopa to DA, thus increasing plasma concentrations and allowing more L-dopa to cross the blood–brain barrier. This enables a reduction of exogenous L-dopa by 60% to 80%, while dopaminergic side effects—mainly nausea and vomiting—occur much less frequently (66,67). The GI mucosa is also a site for decarboxylation of oral L-dopa (68), and DDCIs enhance duodenal L-dopa absorption (69).


The latency to a clinical effect after L-dopa ingestion depends on a number of variables. At all stages of PD, gastric emptying time may have an impact, which is delayed by food and is also slowed by PD itself (70,71), as well as by anticholinergic drugs. Intestinal absorption is influenced by the competition of dietary proteins for the transmucosal transport system. In individual patients, particularly when dyskinesias or acute tolerability are a concern, slowing L-dopa absorption may be helpful, and these patients may prefer to take L-dopa with food. In the majority of cases, however, a reliable and rapid effect is desired, and patients should be informed that taking L-dopa with meals may limit its absorption and may delay the clinical response. Although peripheral L-dopa pharmacokinetics remain unchanged throughout the course of the illness, disease severity has been shown to have an impact on the time from ingestion to effect, with a mean delay of 53 minutes in patients at Hoehn and Yahr stages I and II to 28 minutes at stage IV (72).


Limitations of L-dopa Therapy and the Issue of L-dopa Toxicity


While L-dopa continues to be highly effective for many years with respect to the cardinal parkinsonian motor signs, its use is limited by several factors (see Table 10.4). Response fluctuations and dyskinesias develop in the majority of patients; L-dopa has no or little effect on clinically important nondopaminergic problems such as dementia, depression, on-period freezing, autonomic dysfunction, or sleep disturbances; and it does not modify the underlying neurodegenerative process.


Ever since treatment-related motor complications became apparent following the introduction of L-dopa, a potential negative or toxic effect on a cellular level has been discussed. In vitro, either toxic or protective effects on dopaminergic neurons have been demonstrated, depending on the experimental conditions such as L-dopa concentration and the presence or absence of glia cells and ascorbic acid (7376). In vivo, L-dopa induces neither dopaminergic cell death in normal animals (77,78) nor additional cell death in lesioned animals (79,80), and trophic effects were found in some models (80). Similarly, there is no neuropathologic evidence of L-dopa–induced neural degeneration in humans without PD who received chronic high-dose L-dopa (82).


In patients with early PD, functional neuroimaging studies using positron emission tomography (PET) and single-photon emission computed tomography (SPECT) tracer uptake as a surrogate marker of nigrostriatal function have reported a slower decline in tracer uptake on DA agonists compared with L-dopa (83,84). As these studies lacked a placebo arm, it is not clear whether this observation was due to a drug-related pharmacologic response, an agonist-related protective effect, or a direct effect of L-dopa. A placebo-controlled, double-blind trial (the ELLDOPA study) in untreated PD patients demonstrated that compared with placebo, the three L-dopa arms showed a slower rate of decline in United Parkinson’s Disease Rating Scale (UPDRS) motor scores after washout, and, importantly, this was observed in a dose-dependent manner. Conversely, the rate of changes on b-CIT-SPECT was increased (85). The significance of these imaging findings remains to be determined. It has been suggested that sufficient proof is as yet lacking that PET and SPECT tracers can be used reliably as surrogate markers of the degree of neurodegeneration (86,87). The clinical results of all these studies argue against any meaningful deleterious effect of L-dopa.


In the light of the cumulative available data, the current consensus is that there is no evidence to indicate that L-dopa is toxic to dopaminergic neurons in PD patients. Ample evidence now exists to suggest that the short half-life of L-dopa and the manner of its administration are much more likely to be related to the development of motor complication than some property of the molecule itself (81,8890).


Practical Use of L-dopa


Based on theoretical concerns and on interpretations of recent comparative trials, where a smaller risk of motor complications was found in the agonist arms, the use of L-dopa in clinical practice has changed over the past few years, at least in those parts of the world where alternative drugs (which are usually more expensive) are available. Many clinicians have advocated initiating therapy with a DA agonist in virtually all patients, and L-dopa doses now are often kept at the lower end of the range in an attempt to minimize the risk of later-stage complications. While this approach is indeed useful in the majority of younger patients, it is important to keep in mind that the trials comparing early L-dopa and agonist treatment consistently showed significantly better and longer-lasting motor improvement in the L-dopa arms. The consequences of undertreatment may ultimately hamper employability and may lead to social withdrawal or, at later stages, to complications associated with bradykinesia, such as falls.


For each patient, the best initial dose should be determined individually. In early PD or when first adding L-dopa, daily doses are usually between a minimum of 150 mg and up to 400 mg, or more in some cases. The risk of developing dyskinesia and wearing-off has been shown to increase in a dose-dependent manner (15,33). Factors shown to be predictive of dyskinesia include young age at onset, higher L-dopa dose, low body weight, female gender, and more severe motor disability. The patient’s current needs in terms of symptom control, including employment status and subjective impairment, should be weighed against the factors that have an impact on the individual risk of motor complications. As the disease progresses, adaptations should be made as required and as tolerated. At each stage, physicians should use the lowest dose of L-dopa that provides satisfactory clinical control to minimize the risk of both dyskinesia and wearing-off. Additional L-dopa also may be required to cover for the discontinuation of other dopaminergic drugs in the course of the illness due to reduced tolerability, for example, in the presence of dementia or psychosis. Eventually, the total daily L-dopa dose may be in the order of 1,000 to 2,000 mg/day or higher.


Tolerability


The use of L-dopa is associated with an increased risk of motor complications, as outlined. In contrast, with respect to short-term tolerability, it offers a favorable side-effect profile compared with the other classes of antiparkinsonian agents.


L-dopa, like any dopaminergic drug, can induce typical dopaminergic adverse effects such as orthostatic hypotension, nausea, vomiting, drowsiness, and, rarely, peripheral edema. The addition of DDCIs in routine clinical practice has greatly limited these side effects. Although direct comparative data to support this are lacking, in rare cases of persistent lack of L-dopa tolerability, it may be useful to switch to a preparation containing a different DDCI. However, compared with other drugs used in the treatment of parkinsonism, including DA agonists, L-dopa tends to be better tolerated with respect to these dopaminergic effects (8,9194).


Unplanned episodes of sleep during daytime, including while driving a vehicle, were originally described in nonergot DA agonists but now also have been shown to be associated with other agonists, and they may occur in L-dopa monotherapy (95).


L-dopa can be associated with psychosis and confusion, but these problems tend to be less pronounced than with other antiparkinsonian agents, and L-dopa is typically the drug of choice in patients with dementia or hallucinosis (81,96).


Recently, a mixed axonal neuropathy has been described in patients under long-term treatment with an intrajejunal infusion of L-dopa. The potential causes of this complication, object of a recently published review (97), remain poorly understood, but it is thought to originate from cobalamine deficiency.


Motor Fluctuations: Strategies to Modify L-dopa Administration


There are various manners in which L-dopa can be administered. Once motor complications have occurred, the timing and dosage may be adjusted, for example, by using frequent smaller doses in order to minimize peak-dose complications. In patients without disabling peak-dose dyskinesias, larger L-dopa doses may be helpful to extend the duration of on periods. Other strategies include individually adjusting the times of L-dopa intakes to strictly avoid meal times, reduction in concomitant dietary protein in order to avoid competition with other amino acids for absorption, and the use of preparations with different release properties.


Controlled-release L-dopa This formulation leads to a longer delay to peak plasma concentrations with prolonged half-life and a slower decline in plasma levels and clinical effect. Controlled-release L-dopa is available with either DDCI, although different mechanisms are used to achieve delayed absorption: L/C is embedded in a slowly dissolving matrix (98,99), while L-dopa/benserazide floats on the surface of gastric content (100).


In patients with motor complications, conflicting results have been reported in the literature: Some (101104) but not all (105) studies showed prolonged daily on time or shorter off duration, while in some cases, study design or reported data were insufficient for definite conclusions (106).


While some patients with wearing-off benefit from the longer effect duration of controlled-release L-dopa, the clinical use of these preparations is often hampered by their lower bioavailability. Intestinal absorption is reduced, and it is also less reliable, which may cause delayed on or dose failures and can make it difficult to achieve a constant dose effect. Due to low bioavailability, required dosages are higher than with standard L-dopa, usually by around 30%. To overcome the disadvantage of a longer delay to on, slow-release and standard L-dopa can be administered in combination. Controlled-release L-dopa may be used at bedtime to improve mobility during the night, although a definite benefit of this common approach has not been proven (107).


In view of its ability to induce fewer peaks and troughs in plasma concentration compared with standard L-dopa, there were hopes that using a controlled-release preparation as initial treatment in early PD might delay motor complications. Two double-blind, controlled 5-year trials failed to demonstrate such a reduction in the risk of motor complications compared with regular L-dopa (108110). In one of these studies, dosing was only twice daily, thus making it unlikely that plasma concentrations and receptor stimulation were more continuous than with standard L-dopa (109,110). The design of this particular study therefore precludes firm conclusions.


Dual-release L-dopa This formulation, which is currently available in only a few countries, combines immediate and slow-release properties in one tablet. A single-dose study in fluctuating patients showed a significantly shorter delay to peak L-dopa concentrations with dual-release compared with slow-release L-dopa, while plasma half-life was similar. The delay to a clinical effect was 43 minutes with dual-release and 81 minutes with slow-release L-dopa. On-time duration was significantly longer, and no increase in dyskinesias occurred on dual-release L-dopa (111).


Soluble L-dopa formulations Soluble L-dopa formulations dissolve and are absorbed quickly, and a clinical effect usually sets in very reliably around 20 to 30 minutes after ingestion, compared to 30 to 60 minutes with standard l-dopa. Soluble L-dopa can be useful for delayed morning start-up time or as a rescue medication to provide quick relief from bothersome or disabling off symptoms. However, due to its short half-life, the duration of effect is also shorter and, therefore, chronic or very frequent use should be avoided in view of the pulsatility of its action in the striatum. Although as yet there are no data to prove that soluble L-dopa use is directly associated with increased motor complications, evidence from other short-acting drugs suggests that these should be used sparingly. Moreover, there is evidence of the association of dopaminergic rescue medication (of any kind) with behavioral and motor abnormalities, including punding, which may be related to receptor sensitization, including in neural systems mediating psychomotor functions (57).


L-dopa infusion Continuous L-dopa administration via an intravenous route is difficult due to its low solubility in water and its lack of stability at room temperature (32). The development of a stable water-based gel suspension of L/C in methylcellulose has enabled direct duodenojejunal infusion avoiding gastric emptying as a factor of delayed or erratic L-dopa absorption. This results in a nearly stable plasma profile (32,112,113).


Continuous L/C intestinal gel (LCIG) infusion therapy via a percutaneous endoscopic gastrostomy (PEG) and portable infusion pump was first established in Scandinavian countries and then extended to other European countries and the United States. Although this treatment approach is expensive and invasive and requires special expertise, short- and long-term data are available to show that in patients with refractory fluctuations and dyskinesias, marked and sustained improvements can be achieved. Uncontrolled clinical studies in PD patients treated for periods ranging from 6 weeks to 36 months have demonstrated that L-dopa infusion leads to a significant reduction in off time, varying from 46% to 78%, compared to baseline (31,114119). It has also been associated with a significantly greater improvement in on time without troublesome dyskinesia and in on time without dyskinesia.


Interim results of the largest open-label trial carried out internationally have recently been reported (120) In 192 advanced PD patients who were prospectively studied, daily “off” time was reduced by a mean of 3.9 hour (±3.2) and “on” time without troublesome dyskinesia was increased by 4.6 hour (±3.5). Mean duration of therapy was 256.7 days (±126).


In a recently published 12-week, randomized, double-blind, double-dummy trial comparing intrajejunal LCIG infusion vs. intermittent doses of oral immediate-release (IR) L/C, benefits obtained with intestinal delivery were of greater magnitude than those obtained with oral medication (121). Thirty five patients in the LCIG group and 31 patients in the IR oral L/C group completed the trial. Treatment with LCIG provided a greater reduction in off time than did IR oral L/C (–4·04 [0·65] versus 2·14 [0·66] hour/day) without an increase in on time with troublesome dyskinesia, and this improvement was reflected in significantly improved quality of life.


A prospective observational study focused on nonmotor symptoms showed a significant improvement of sleep disorders, fatigue, cognition, cardiovascular, GI, and urinary symptoms in 22 advanced PD patients over a period of 6 months (122). The therapeutic effect of LCIG also provides a clinically meaningful impact upon quality of life (QoL) assessed by the short and large version of the PD questionnaire (PDQ-8 and PDQ-39) as has been observed in all the studies where this was investigated (117124). The burden and stress felt by caregivers assessed by the Zarit burden interview improved in some (125) but not others (121).


In advanced patients with cognitive and psychiatric comorbidities that do not allow surgery with deep brain stimulation (DBS) or SC apomorphine pump, LCIG can be tried. In a multicenter retrospective study, the characteristics of 91 patients receiving duodenal L-dopa infusion in France from 2003 to 2008 were evaluated (126). Before initiation, 42% of patients had severe, persistent visual hallucinations. None of these patients reported worsening or hallucinations during the study, although antipsychotics (mainly clozapine) were used (126). Patients who develop significant cognitive deficits during enteral L-dopa infusion can continue to benefit from its positive effect on motor complications without a need to discontinue treatment, although neuroleptic treatment should be considered (119).


The pharmacologic side-effect profile of LCIG is similar to the well-known side effects of other L-dopa preparations. The most frequent adverse events are related to mechanical problems with the intestinal tubing (occlusion, kinking, dislocation from the pump,) and complications of the gastrostomy (infection, secretion from the stoma, localized pain) (127). If the tubing becomes obstructed or the distal end of the tube is displaced to the stomach, there may be acute worsening of parkinsonism. Although rare, there have been reports of more serious complications associated with the device, in particular peritonitis. Cases of phytobezoars presenting with duodenal obstruction (128), fistulation and jejunal wall perforation (129), or recurrent pancreatitis (130) have been observed.


Mostly, axonal neuropathy has been described in patients on intrajejunal L-dopa infusion. The causes of this complication remain poorly understood (97), but cobalamine deficiency is thought be involved. Vitamin B12 levels and baseline nerve conduction studies should be performed in all patients and vitamin B12 supplementation should be considered.


Although there is no doubt about the effectiveness of LCIG in patients carefully selected, this technique is not free from risks and requires a continuous cooperation between neurologist, gastroenterologists, and a nurse specialist. A supportive and motivated carer to assist setting up and adjusting the pump/line is very important to the successes of this therapeutic modality.


COMT INHIBITORS


L-dopa is metabolized via two main pathways: decarboxylation and O-methylation. Blocking peripheral decarboxylation by adding a decarboxylase (AADC) inhibitor has long been the standard in L-dopa treatment. When AADC is inhibited, methylation of L-dopa to 3-O-methyldopa becomes more prominent. This process is catalyzed by COMT. By inhibiting COMT, slower degradation of L-dopa and thus prolonged maintenance of plasma levels can be achieved.


Two COMT-inhibiting substances are in clinical use: entacapone and tolcapone. While entacapone acts only on peripheral L-dopa, tolcapone also crosses the blood–brain barrier and inhibits central L-dopa degradation. Moreover, tolcapone has a longer half-life than entacapone. When administered in combination with L-dopa, both drugs lead to prolonged availability of L-dopa in the GI tract and to increased plasma half-life, thereby prolonging the clinical effect of L-dopa. Peak L-dopa plasma concentrations are not significantly increased, and, importantly, COMT inhibitors do not prolong the delay to peak concentrations (131). This is in contrast to slow-release L-dopa formulations for which the delay to a noticeable clinical effect is longer than with standard preparations. COMT inhibitors can be used in conjunction with slow-release L-dopa, where similar pharmacologic effects have been demonstrated as with standard L-dopa (132).


From a clinical perspective, dual inhibition of both COMT and dopa decarboxylase (DDC) pathways results in a significant increase in daily on time and a corresponding decrease in off time (133136). Increasing the bioavailability of L-dopa by coadministration of COMT inhibitors may be associated with an initial increase in dyskinesia that can generally be controlled with adjustments in the doses of L-dopa.


Although another COMT inhibitor, tolcapone, has been shown to be more effective than entacapone (94), its association with an increased risk of potentially fatal hepatotoxicity (137) has limited its clinical use to patients who do not respond to entacapone (138). Its use now is on condition of close safety monitoring and has generally been replaced by entacapone.


Entacapone is rapidly absorbed and has a half-life similar to that of L-dopa (1–1.2 hours). The dose of entacapone that has been shown to offer the best ratio of efficacy and tolerability is 200 mg. Therefore, the standard manner of administration is 200 mg of entacapone together with each L-dopa dose.


Four 6-month, randomized, controlled studies have evaluated the efficacy and tolerability of L-dopa/DDCI and entacapone versus L-dopa/DDCI and placebo treatment in patients with prominent motor fluctuations (133,135,139,140). In the entacapone group, mean daily on time was increased by around 1 hour compared with the group receiving placebo, and UPDRS motor and activities of daily living scores were significantly decreased. An increased incidence of dyskinesias with L-dopa/DDCI and entacapone was observed, but in general could be managed by a reduction in the L-dopa dosage (133,135,139,140). The most frequent adverse events associated with L-dopa/DDCI and entacapone therapy are chromaturia (harmless urine discoloration) and diarrhea, reported to occur in 8% to 10% of patients but rarely the cause of stopping treatment, constipation, and dizziness (97,133,139,140).


Entecapone has also been shown to be effective in improving early mild wearing-off (141,142). In addition, a small randomized, controlled 6-month study in 41 patients with stable disease found activities of daily living significantly improved and an L-dopa reduction of 40 mg/day (143). A larger 24-week study in 750 stable patients permitted no changes in L-dopa doses (81). Several quality-of-life scales and clinical global assessments improved significantly, but UPDRS motor scores did not change significantly.


The triple combination preparation of L-dopa/carbidopa/entacapone (LCE) is available as a single tablet in multiple L-dopa–dose strengths, which facilitates a low-dose, gradual titration of L-dopa. At the pharmacokinetic level, manipulation of the dosing strategy of LCE, by using, for example, higher doses in the morning and lower ones at later points during the day, avoids the accumulation of L-dopa toward the end of the day without significantly lowering the trough value of plasma L-dopa (143). The simplicity of the dosing regimen may also influence treatment adherence (144).


A recent pharmacokinetic study evaluated the potential of LCE for control of nighttime symptoms (145). The results of the phase I trial demonstrated that LCE 200 mg provides a superior pharmacokinetic profile to that of controlled-release (CR)-L/C 200/50 mg, when administered either as a single evening dose or as a three-times-daily dosing regimen (99).


COMT Inhibitors and Prevention of Motor Complications


As outlined, the current concept of the formation of motor complications in PD is essentially thought to be based on two main factors: degree of neurodegeneration and pulsatility of drug treatment. Evidence supporting pulsatility as an important causative factor of dyskinesias includes reduction of dyskinesias with continuous SC apomorphine or enteral L-dopa and a correlation between the half-life of drugs and the emergence of motor complications in animal models and humans. This has given rise to expectations that prolonging L-dopa half-life by adding a COMT inhibitor early in the disease, before motor complications have developed, might lead to sufficiently continuous dopaminergic stimulation (CDS) to reduce this risk. A study investigating repeated small L-dopa doses combined with entacapone versus L-dopa alone in untreated MPTP-lesioned primates found, in line with previous rodent data, reduced dyskinesia induction (146). A large prospective double-blind clinical trial (STRIDE-PD) has evaluated the value of adding entacapone to L/C therapy in 747 early-stage untreated patients. STRIDE-PD failed to demonstrate that initiation of LCE in early PD patients was associated with a reduced frequency of dyskinesia in comparison to standard L/C, suggesting that the CDS hypothesis may not be correct but perhaps the dose frequency employed in the trial (4 daily administration at 3.5-hour intervals) was not adequate to provide CDS (33). STRIDE-PD does not support the early administration of L-dopa in combination with entacapone to reduce the risk of motor complications.


DA AGONISTS


In an attempt to alleviate symptoms of parkinsonism, compounds have been sought that can stimulate DA receptors. These drugs are generally regarded as “DA agonists,” but most of them do not duplicate the pharmacologic properties of DA. Besides stimulating DA receptors these compounds, for example, have activity in other neurochemical systems, and some ergot compounds are known to have mixed agonist–antagonist profiles at the DA receptors.


Schwab et al. (147) observed transient improvement of rigidity and tremor in parkinsonian patients after injection of the emetic drug apomorphine. At that time, the dopaminergic properties of this drug were not known. Cotzias et al. (148) later carried out extensive studies with apomorphine and also tested a congener N-n propyl-norapomorphine. This drug proved effective but was not well tolerated and was toxic to some patients. In the 1970s, an ergot DA agonist bromocriptine (149) was tested in PD in an attempt to overcome the limitation of high-dose L-dopa therapy and was shown to be efficacious. Since then, bromocriptine and a number of DA agonists have been introduced into the market. Proposed advantages of this class of drugs over L-dopa in the management of PD include longer striatal half-life, direct stimulation of receptors bypassing degenerating nigrostriatal neurons, lack of competition for transport in the gut or at the blood–brain barrier, option of alternate routes of administration, and association with reduced incidence of motor complications, their antioxidant effects, and the possibility that they may provide neuroprotection (150).


Eight different orally administered DA agonists are presently approved and marketed for the treatment of PD: bromocriptine, cabergoline, dihydroergocryptine, lisuride, pergolide, piribedil, pramipexole, and ropinirole. Among these agonists, five are ergot derivatives (bromocriptine, cabergoline, dihydroergocryptine, lisuride, and pergolide), while the three others are not (piribedil, pramipexole, and ropinirole). Apomorphine is a nonergot DA agonist administered parenterally, and rotigotine is a nonergot agonist delivered transdermally.


Mechanism of Action


The various DA agonists in use have different receptor stimulation profiles and different effects upon non-DA receptors. They also differ in their pharmacokinetic properties (151). The clinical consequences of such differences remain mostly theoretical and cannot be used to influence a practice based on strong clinical evidence. Among the eight orally active DA agonists, cabergoline has the longest plasma elimination half-life (60 hours) (152).


Among the DA agonists, intrinsic potency at the D2 receptors can differ by one or more orders of magnitude, but trials have not revealed any major differences in their overall clinical efficacy. Most studies of dopaminergic agonists have concluded that stimulation of D2 receptors accounts for most or all of the benefits exerted against parkinsonian features (153,154). This D2 effect also explains why all DA agonists can induce similar peripheral (GI: nausea and vomiting; cardiovascular: orthostatic hypotension; central neuropsychiatric: somnolence, psychosis, hallucinations) side effects.


Apart from binding to DA and nondopamine receptors, DA agonists have in vitro and in vivo properties (free radical scavenging, reduction in DA turnover, anti-apoptotic effect) that explain why they have been tested as putative “neuroprotective” agents to reduce the progression of PD (155159).


Efficacy and tolerability in individual patients may vary greatly with different agonists, and switches are therefore advisable if the clinical effect is unsatisfactory or if adverse effects occur on a given agonist.


DA Agonists in Early Stages of PD: Symptomatic Effect and Prevention of Motor Complications


The benefit of the agonists as monotherapy in mild PD has been shown in large, prospective, randomized, double-blind, placebo-controlled trials. In these trials, ropinirole, pramipexole, cabergoline, dihydroergocryptine (160), or pergolide (161) used as monotherapy provided antiparkinsonian benefits to early PD superior to placebo. These benefits are particularly powerful in patients with Hoehn and Yahr stages I and II (162168). For safety reasons, however (see Safety), pergolide is not used anymore as first-line antiparkinsonian medication.


Direct comparison studies of the DA agonists as monotherapy are lacking. The clinical relevance of the reported differences—bromocriptine versus ropinirole (169,170) and bromocriptine versus pergolide (171)—if any, remains questionable, especially since the exact dose equivalence between the different agonists remains unknown.


There are no published direct head-to-head comparisons between any agonist given as monotherapy and any other antiparkinsonian medication frequently used in early PD such as the MAO-B inhibitors, amantadine, or the anticholinergics. Changes reported in the UPDRS with most agonists are usually greater than those reported with MAO-B inhibitors, suggesting a possibly greater symptomatic effect of the agonists.


Trials comparing DA agonists as monotherapy against L-dopa—ropinirole (92), pramipexole (172), cabergoline, bromocriptine (173,8), and pergolide (174)—have been performed. Patients randomized to the agonist arm had less improvement in motor impairments and disability. In terms of tolerability, hallucinations were significantly worse with ropinirole than in the L-dopa arm, and somnolence was worse with pramipexole. Withdrawals because of adverse events were greater with the agonists than with L-dopa. The proportion of patients capable of remaining on an agonist monotherapy falls progressively over years to less than 20% after 5 years of treatment (91,172,173,175). For this reason, after some years of treatment, most patients who start on an agonist will receive L-dopa as a replacement or an adjunct treatment to keep control of the parkinsonian motor signs.


Several prospective randomized, controlled trials have compared the probability of developing motor complications in patients receiving an agonist versus L-dopa–treated controls. These trials have consistently demonstrated the ability of the early use of an agonist to reduce the incidence of motor complications, while at the same time motor improvement was significantly better in the respective L-dopa arms. One study included quality-of-life measures that corroborated better symptomatic improvement on L-dopa (172). Such studies, of 2 to 5 years duration, are available for cabergoline, pramipexole (172), ropinirole (92,84), and pergolide (174). Ten-year results of a study comparing bromocriptine and L-dopa similarly showed less risk of motor complications at the expense of less motor improvement in the agonist arm (8). Conflicting results have been reported with lisuride (176), and published controlled data are lacking for other orally active agonists (dihydroergocryptine, piribedil). In two recent clinical trials, chronic treatment with ropinirole or pramipexol (83,84) was associated with a slower decline of imaged striatal signal, compared to L-dopa monotherapy. The results of these neuroimaging studies, however, could well reflect a pharmacologic effect on proteins that interact with the imaging radioligands, and the role of neuroimaging as a surrogate marker has been questioned (177). In both these studies, patients experienced greater clinical improvement with L-dopa than with a DA agonist.


Trials indicating that starting treatment with an agonist reduces the risk of motor complications support a treatment strategy for early PD in which DA agonists are used as initial therapy and supplemental L-dopa is added when symptoms cannot be satisfactorily controlled with a DA agonist as monotherapy. The clinical importance of the ability of a DA agonist to reduce or delay “time to motor complications,” however, is tempered by the fact that there is no direct demonstration that this translates into disability and quality-of-life benefit on longer follow-up. Once L-dopa supplementation is required, the rate of development of dyskinesia is the same as in patients whose treatment was initiated with L-dopa (178), suggesting that early DA agonist treatment delays, but not prevent dyskinesias.


Conversely, in patients who started treatment with L-dopa and require a higher dopaminergic dose, adding a DA agonist instead of increasing L-dopa may still delay the onset of dyskinesia (179).


DA Agonists as Adjuncts to L-dopa in Advanced PD


Several trials have shown that DA agonists such as pergolide, (180182) pramipexole (183187), or ropinirole (188,189) effectively reduce off time in patients with L-dopa–related motor fluctuations. Less-convincing evidence exists for bromocriptine (183,190,191) and cabergoline (192). There are only open-label or anecdotal data to suggest that other agonists like lisuride or piribedil could improve motor fluctuations.


Reported evidence (bromocriptine vs. cabergoline, lisuride vs. pergolide) suggests that efficacy is similar among the various agonists. The same was true when comparing bromocriptine (193) and pergolide (194) to the COMT inhibitor tolcapone. No other comparisons have been published.


When used as monotherapy or as adjunct to L-dopa therapy, adequate dosing of the agonists is important, depending on individual responsiveness and tolerability. However, the dose ranges vary among these drugs. Licensing details vary among countries, but usual maximum doses are between 4 and 6 mg/day for pramipexole, cabergoline, pergolide, and lisuride, whereas bromocriptine (20 mg/day) and ropinirole (24 mg/day) have higher dosing ranges. Underdosing is frequently encountered when patients are referred as “refractory” to treatment. As with all dopaminergic drugs, adaptations and increases are required in most patients during the course of their illness.


DA Agonist Long-Acting Formulations


In the past decade, novel oral long-acting formulations of DA agonist, including extended-release (ER) pramipexole and ropinirole prolonged release (PR) have been developed. Compared with the IR formulation, potential advantages of long-acting DA are more stable plasma concentrations over 24 hours and possibly a more CDS (195,196). In addition, some studies clearly established that once-daily intake significantly improve patient’s adherence to treatment, particularly timing adherence (197).


Different randomized-controlled trials have been carried out to evaluate the efficacy and safety of these novel long-acting DA versus their standard counterpart.


Efficacy and safety of pramipexole ER administered once daily as monotherapy in early PD were studied in two randomized, double-blind, placebo-, and active comparator–controlled trials (198,199). Pramipexole ER was noninferior to pramipexole IR and significantly more effective than placebo. Tolerability and safety did not differ between the formulations.


Patients taking pramipexole IR in a dose regime of three times daily can be switched overnight to ER with posterior adjustments if needed. In a double-blind, double-dummy, randomized, parallel-group study in early PD patients, pramipexole ER was not equivalent to IR, but the difference was marginal: at 9 weeks, 84.5% of the ER group had been successfully switched, versus 94.2% for IR group (200).


Similar studies in PD patients with advanced PD and motor fluctuations have been done. In a randomized, controlled, parallel-group trial comparing ER with placebo and with IR as adjunctive treatment, using ER for 18 weeks, and in some patients as long as 33 weeks, pramipexole ER showed superiority to placebo and the efficacy, safety, and tolerability resembled those of IR (201). In patients who completed this double-blind trial and with the aim to evaluate feasibility of an overnight switch from IR to ER at an unchanged daily dosage, an extended trial using a double-dummy design was carried out (202). By off-time and UPDRS criteria, most patients (86.2% of 123 IR to ER and 83.8% of 105 ER to ER) were successfully switched from pramipexole IR to ER, indicating that such a switch can be safely performed in patients with advanced PD. Similar results have been observed in Japanese PD population with L-dopa–induced motor complications or treated with a suboptimal L-dopa doses in a 16-week trial (203).


Efficacy and safety of ropinirole PR has also been studied in both early and advanced PD. The EASE-PD Monotherapy study was a 36-week randomized, double-blind crossover study comparing ropinirole IR with ropinirole PR in 161 early PD patients (204). The primary end point of noninferiority of ropinirole PR versus ropinirole IR was reached. Mean total UPDRS improvements were similar between the agents and so was the frequency of adverse events (AEs). The overall medication compliance was significantly better in those taking ropinirole PR compared to ropinirole IR. An overnight switch with an approximate1:1 conversion ratio was well tolerated.


Two studies with ropinirole PR have been done in advanced patients presenting motor fluctuations. The EASE-PD Adjunct study was a multicenter, randomized, double-blinded, placebo-controlled trial that examined the use of once-daily ropinirole PR or placebo for 24 weeks in 393 patients with idiopathic PD inadequately controlled by L-dopa (205). The mean final dose of ropinirole PR was 18.8 mg/day. A significant decrease in “off” time and in UPDRS motor scores was obtained with PR when compared to IR. Significant improvements in UPDRS-AD, Beck Depression Inventory II scale, and some domains of the PD Quality of Life Questionnaire-39 (PDQ-39), such as mobility, activities of daily living, emotional well-being, stigma, and communication, were also noted. The most common adverse effect of PR versus placebo was worsening and development of dyskinesia (13% versus 3%). In patients suffering troublesome nocturnal disturbance, ropinirole PR was effective in improving nocturnal symptoms (206).


In the PREPARED trial, ropirinole PR and IR were compared in patients with motor fluctuations (207). The trial met its predetermined primary endpoint of percentage of patients with a ≥20% maintained reduction in awake time spent “off” from baseline to last observation, finding a significant difference in favor of the ropinirole PR group (66%) compared with the ropinirole IR group (51%). The observation of higher doses of ropinirole PR at the end of the study has questioned its possible superiority over the IR formulation.


If once-daily dosing of long-acting DA agonists results are unsatisfactory, multiple dosing of these formulations might be a therapeutic option. In an open-label crossover study designed to evaluate the patient’s preference of one versus two doses of ropinirole PR, half of the 80 enrolled patients preferred two doses, one-quarter one dose and one-quarter had not preferences. Mean UPDRS-III, H&Y, Epworth scale, sleep quality, compliance, and adverse events were not statistically different in both regimens. Patients’ global impression of wearing-off was better in twice-daily dosing regimen (208).


Safety


Currently available DA agonists share a wide range of side effects with L-dopa that are due to peripheral and central dopaminergic stimulation. Both types of adverse effects occur more frequently on agonists than on L-dopa monotherapy. Nausea and vomiting, postural hypotension, dizziness, bradycardia, and other signs of autonomic peripheral stimulation are common peripheral dopaminergic side effects of all DA agonists. Erythromelalgia-like reactions have been described with the ergot agonists, and leg edema is also commonly observed with most agonists. The mechanism of such an adverse drug reaction is poorly understood.


Central side effects include confusion, hallucinations and psychosis, and excessive daytime sleepiness (150,209). Insomnia also can occur. Some reports have suggested that nonergot agonists such as pramipexole and ropinirole may induce sleep attacks without warning (210), raising the question of safety of these medications for those who drive. Subsequent reports have described similar problems with other nonergot agonists and even with L-dopa monotherapy (211,212).


Postmarketing surveillance has shown that the rare but severe risk of pleuropulmonary/retroperitoneal fibrosis is greater with ergot than with nonergot agonists. Restrictive valvular heart disorders have been recognized as a relevant adverse event associated with DA agonists. Although this appears to be more common in ergot agonists, some evidence suggests that the problem may be related to an affinity to serotonin receptor subtypes rather than ergot properties. To date, pergolide has been the most frequently reported drug to cause valvular changes (213). Pergolide is nowadays rarely used and only as a second-line alternative option, when other agonists fail to provide adequate control of symptoms. However, severe restrictive heart valve changes requiring surgery have been described with cabergoline as well (214). Recently, the use of DA agonists, mainly pramipexole and cabergoline, has been associated with an increased risk of heart failure (215,216).


When added to L-dopa, a DA agonist can trigger first-time dyskinesias or more commonly exacerbate existing L-dopa–induced dyskinesias (217). Both peak-dose and diphasic dyskinesias can be aggravated by orally administered agonists. Such an occurrence requires reduction of L-dopa dose for optimal control of the patient’s symptoms. The effect of an agonist on L-dopa–induced dyskinesia might be related to the doses of the agonist used, occurring rarely with low doses. In general, worsening of dyskinesias is not a serious consequence of the addition of a DA agonist as long as L-dopa dosages are reduced appropriately.


DA Agonist Withdrawal Syndrome


DA agonists dose reduction or discontinuation can be complicated by what has been called the DA agonist withdrawal syndrome (DAWS). Rabinak and Nirenberg (218) were the first to define and characterize this syndrome in 5 patients (19% of total) that had had to taper DA agonists for different reasons, mainly for presenting ICDs. DAWS was defined as a severe, stereotyped cluster of physical and psychological symptoms that correlate with DA agonist withdrawal in a dose-dependent manner, cause clinically significant distress or social/occupational dysfunction, are refractory to L-dopa and other dopaminergic medications, and cannot be accounted for by other clinical factors. Symptoms include irritability, anxiety, agoraphobia, dysphoria, depression, drug cravings, fatigue, pain, and autonomic manifestations (218,219).


Risk factors for DAWS are the presence of ICDs (218220), a higher DA use and cumulative exposure of a DA, lower scores on the UPDRS motor score (218,220), higher L-dopa dose at withdrawal, and a previous smoking habit (219).


The fact that this syndrome has been also described in one patient with RLS (221) and one other with a prolactinoma (222) suggests a drug-specific withdrawal syndrome instead of a disease-specific one.


In general, the prognosis is good with full recovery in weeks to months in more than 60% of patients. Some patients may be unable to achieve complete discontinuation of DA in spite of a very slow tapering (219).


Parenteral Apomorphine


Apomorphine is the oldest and the most potent DA agonist in clinical practice, acting on both D1 and D2 receptor subtype families. When given as a single dose, the magnitude of its effect is equivalent to that of oral L-dopa, but it has a considerably faster onset (5–15 minutes) and shorter duration (mean 40 minutes) of effect. Due to its low bioavailability, it cannot be administered orally, but SC injections can be very effective in rapidly resolving off states in patients with motor fluctuations. Intermittent SC injection therapy, using an average of 3 to 4 mg per injection, can be a useful option for quick relief from off periods in selected patients (223226). Prospective, randomized, placebo-controlled clinical trials either in apomorphine-naïve patients (227) or patients already receiving intermittent apomorphine therapy (228) showed that SC apomorphine injections are an effective rescue treatment for “off” episodes. Injection therapy significantly improved UPDRS motor scores and significantly decreased “off” hours per day. Adverse events, including nausea and vomiting, dyskinesia, dizziness, somnolence, hallucination, yawning, and injection site bruising, are mild to moderate, but can lead to treatment discontinuation in a considerable number of patients (229).


Patients suitable for this treatment must have “offs” despite optimization of their oral drug regimen. They must be able to distinguish their off symptoms from other conditions such as dyskinesias. Patients who suffer from sudden, unexpected offs often benefit from this rescue medication. Pretreatment assessments include an apomorphine challenge test to determine responsiveness and to establish effective doses, and to observe for side effects, such as nausea, postural hypotension, confusion, or somnolence. Patient selection and counseling must be based on the fact that the optimum response that can be expected is equal to the patient’s best L-dopa response, and that patients whose on periods are associated with dyskinesias also will likely experience dyskinesias following apomorphine injections. Patients should take their usual oral medication at the time of apomorphine administration so the onset of effect of the oral medication coincides with the waning apomorphine effect. To counteract dopaminergic side effects such as nausea, domperidone at a dose of 10 mg three times daily or trimethobenzamide 250 mg three times daily should be initiated at least 2 days before starting treatment. Due to a concern about possible effects of domperidone on QT duration, the European Medicines Agency has recently stated that the maximum treatment duration should not usually exceed 1 week and has limited the dose to 30 mg daily.


In patients who use high numbers of daily injection or in whom motor complications have become refractory to oral drug adaptations, apomorphine can be applied in a continuous manner, via the SC route. While the usual daily duration of pump treatment is around 14 to 16 hours, some patients with severe nocturnal off symptoms benefit from 24-hour administration.


Uncontrolled studies have shown that apomorphine given via continuous SC infusion during waking hours leads to important reductions in daily off time (27,28,230233). In a prospective, consecutive cohort analysis using blinded rating of video assessments, a 20% increase in “on” time with a 38% decrease in “off” time from baseline were reported (28), with functionality maintained for 79% of the waking day at 6 month. A retrospective analysis of 82 patient records of patients receiving apomorphine infusion for a mean of 20 months reported “off” time reduction from 55% of the waking day at baseline to11% at the end of the study (233). Recently, in a retrospective analysis and in patients treated with lower doses of apomorphine (average doses 3.15 ±1.71 mg/hour) and concomitant oral L-dopa, no efficacy in motor fluctuations was detected (234).


Several, but not all, studies have shown marked and sustained antidyskinetic effects in patients on continuous SC apomorphine therapy (44%–83% reduction in dyskinesia severity compared to baseline). Dyskinesia reduction is significantly more marked in those patients who gradually manage to substantially reduce their oral dopaminergic therapy, or who achieve “apomorphine monotherapy” (i.e., apomorphine pump treatment only during the waking day with complete discontinuation of oral drugs) (28,29,231,232). This is in keeping with the current concept of dyskinesia formation and believed to be due to the replacement of pulsatile with continuous DA receptor stimulation. The maximum dyskinesia improvement has been observed around 12 months following the initiation of pump treatment, on mean daily doses of around 100 mg (231). A small study in patients on a waiting list for DBS reported off-time reduction with both treatments but no significant dyskinesia reduction with apomorphine infusion (235).


A comparative, but not randomized, study of 17 patients on apomorphine infusion versus 17 who did not receive reimbursement for this treatment showed significant improvements in a variety of nonmotor symptoms and in quality of life, assessed by PDQ-8 (236).


Randomized-controlled studies are lacking that would provide comparative data on the effect of DBS of the subthalamic nucleus (STN), intrajejunal L-dopa infusion, and continuous SC infusion of apomorphine, so conclusions remain limited. A randomized, placebo-controlled trial of apomorphine infusion is underway.


Potential side effects of continuous apomorphine treatment include nausea, orthostatic hypotension, somnolence, ICDs, punding, or other behavioral disturbances. Skin changes are common and usually involve SC nodule formation but may rarely include necroses or abscesses. Hemolytic anemia is rare, but regular checks for full blood count and Coomb’s test are recommended. Confusion or hallucinations may occur, although there is evidence to suggest that these neuropsychiatric problems are not more common than with oral DA agonists (231,237,238). A positive effect on mood has also been observed (239).


Transdermal Delivery of DA Agonists


In an attempt to minimize L-dopa–related motor complications, dopaminergic agents with long half-lifes have been developed. Routes of delivery alternative to the oral route can produce relatively continuous drug delivery and include intraintestinal infusions of L-dopa and subcutanous infusions of apomorphine. Moreover, continuous noninvasive drug delivery can be achieved via transdermal drug delivery systems (240). One such drug, rotigotine, is now in clinical use in patients with PD.


Rotigotine is a lipid-soluble, nonergoline, highly selective D3>D2>D1 and 5HT1A agonist and a2b antagonist with a structure similar to DA and apomorphine. (241) It has potent antiparkinsonian activity in MPTP monkeys (242). Rotigotine cannot be given orally because of extensive GI metabolism, but its high lipid solubility makes it ideal as a transdermal preparation. In the transdermal product, rotigotine is dissolved in a silicone adhesive and then spreads across a silicone backing that permits uniform release of the drug at a constant rate, with drug delivery directly proportional to the size of the patch. The system produces a stable drug release and steady-state plasma concentrations over a period of 24 hours when administered once every 24 hours.


Clinical trials have demonstrated both the efficacy and the tolerability of rotigotine administered by the transdermal route. Three randomized placebo-controlled trials have shown rotigotine administered transdermally to be an effective once-daily drug for the treatment of early PD. In one trial (243) enrolling 242 patients, improvement occurred in combined motor and activities of daily living scores of the UPDRS, and a dose response relationship was evident from 4.5 to 13.5 mg. In a second trial (244) with a total of 227 patients with early PD, placebo rotigotine significantly reduced UPDRS parts 2 and 3 scores compared with placebo. Furthermore, there was a significantly higher proportion of responders at the end of treatment when compared with placebo (48% versus 19%). There was no evidence of tachyphylaxis related to CDS, and benefits persisted for up to 27 weeks. In a third trial (245) versus ropinirole and placebo, patients in both the rotigotine and ropinirole groups had improvements in combined UPDRS II and III scores that were significantly better than placebo (p < 0.001).


Transdermal rotigotine has been tested in patients with motor complications on L-dopa treatment. In addition to its benefits in patients with early PD, the PREFER study (246), involving 131 patients, found rotigotine transdermal patch to be effective in patients with advanced PD. In an active comparator study vs. placebo and pramipexole in patients with motor fluctuations (CLEOPATRA-PD), the responder rates were 67% (134 of 200 patients) for pramipexole, 60% (120 of 201 patients) for rotigotine, and 35% (35 of 100 patients) for placebo, and the study showed that rotigotine is noninferior to pramipexole (247). In a double-blind, placebo-controlled trial (RECOVER) involving 287 patients with PD and “unsatisfactory early-morning motor symptom control,” the mean PD Sleep Scale total score decreased more than threefold with rotigotine compared with placebo, indicating significant improvements in early-morning motor dysfunction and nocturnal sleep disturbances with once-daily, morning administration of rotigotine patch (248).


Rotigotine at therapeutic doses displays a good safety profile and is generally well tolerated. Its use was associated with the characteristic adverse reactions to DA agonists such as nausea, leg edema, excessive daytime sleepiness, and dizziness. Application-site reactions are common but usually mild or moderate in nature. These required discontinuation of treatment in 5% of patients. Rotigotine had no clinically relevant effects on laboratory parameters or physical examination.


MAO-B INHIBITORS


MAO-B plays an important role in the biotransformation of DA in the human brain. It constitutes about 80% of the total MAO activity in the human brain and is the predominant form of the enzyme in the striatum. Inhibitors of this enzyme block the oxidative deamination of DA and increase its half-life in the brain. There are currently two MAO-B inhibitors commercialized for the treatment of PD: selegiline (deprenyl) and rasagiline. Both are irreversible MAO-B inhibitors, which means that the duration of their effect, rather than either drug’s plasma half-life, reflects the ability of the body to resynthesize the enzyme.


Mechanism of Action


Selegiline, at the doses commonly used of 10 mg/day, produces a selective and irreversible MAO-B inhibition with only minimal effects upon MAO-A, an enzyme that is involved in the deamination of serotonin and noradrenaline (249). Selegiline is extensively metabolized in humans mainly in the liver to form desmethylselegiline and methamphetamine, which are further metabolized to amphetamine. These metabolites may contribute to the dopaminergic effect of the drug and can explain some of the stimulating effects of the drug. Blockade of presynaptic DA receptors and inhibition of DA reuptake from the synapse by selegiline has also been suggested to contribute to the dopaminergic effect of the drug (250,251). Selegiline also has been shown to protect nigral neurons against damage by oxygen-free radicals generated during MAO-B activity, to protect against MPP + toxicity in the MPTP model of parkinsonism, and to have an antiapoptotic effect in vitro and in vivo in experimental animals (252255).


Rasagiline is a second-generation propargylamine that irreversibly and selectively inhibits monoamine oxidase type B (256,257). Unlike the prototype propargylamine selegiline, which is metabolized to amphetamine derivatives, rasagiline is biotransformed to aminoindan, a nonamphetamine compound. Rasagiline is well tolerated with infrequent cardiovascular or psychiatric side effects, and at the recommended therapeutic dose of 1 mg once daily, tyramine restriction is unnecessary. In addition to MAO-B inhibition, the propargylamine chain also confers dose-related antioxidant and antiapoptotic effects, which have been associated with neuroprotection in multiple experimental models (258259).


Therapeutic Efficacy


Selegiline Monotherapy with oral selegiline (10 mg/day) reduces symptom severity and, during prolonged therapy, delays the need to start L-dopa in previously untreated patients with early PD (260265). These symptomatic effects of selegiline are considered modest. In a meta-analysis (266), it has been estimated that the differences versus placebo at 3 months follow-up is about 2.78 points on the total UPDRS score and close to 2 on the motor part of the UPDRS.


The standard oral formulation has been shown to improve PD symptoms in patients with motor fluctuations, but a consistent effect in reducing off time in patients with wearing-off has not been shown (106). A recent study with orally disintegrating tablets of selegiline (267) showed that this formulation of selegiline significantly reduces off time when used as adjunctive therapy with L-dopa in patients with motor fluctuations.


Trials with selegiline have looked into the effect of selegiline in preventing or delaying motor complications (268,269). It was concluded that selegiline is not efficacious in preventing dyskinesias. In a follow-up trial with the original DATATOP cohort, freezing of gait occurred more commonly in placebo than in selegiline-treated patients (28.9% versus 15.5%; p = 0.003) (269).


Rasagiline For the management of PD, rasagiline is efficacious across the span of PD stages ranging from monotherapy in early disease (270) to adjunctive treatment in patients with advancing disease and motor fluctuations.


In a double-blind randomized trial on monotherapy in early PD (271), rasagiline or placebo was given to patients during 26 weeks. Patients receiving rasagiline 1 or 2 mg/day showed improvement in parkinsonism (UPDRS scores) relative to the placebo group. The outcome for the ADL subscale was also in favor of the rasagiline 2 mg/day group, and the proportion of responders in the rasagiline groups was significantly higher than for placebo recipients. Compared with placebo, patients receiving rasagiline had significantly improved quality-of-life measures during the 26 weeks of the study.


In patients with motor complications, rasagiline given as a once-daily medication without titrations reduced off time by approximately 1 hour, a reduction of about 20%. Two double-blind, placebo-controlled, randomized clinical trials have assessed the efficacy of rasagiline in patients with PD experiencing L-dopa–related motor fluctuations, the Parkinson’s Rasagiline: Efficacy and Safety in the Treatment of “Off” (PRESTO) and the Lasting Effect in Adjunct Therapy with Rasagiline Given Once-Daily trials (LARGO) (272,273). Both studies were placebo-controlled. The LARGO study also included an active comparator arm, for which patients received entacapone 200 mg administered with each L-dopa dose. Primary efficacy variable in both trials was the change from baseline in daily off time assessed by patient’s diaries. A significant reduction in daily off time occurred in both trials in patients receiving rasagiline relative to placebo. Although the LARGO study was not designed to directly compare rasagiline and entacapone, the results demonstrate that the clinical effects on off time were similar with these two compounds.


MAO-B Inhibitors and Neuroprotection


In the hope that selegiline might afford neuroprotection, clinical trials have compared the effect of selegiline with that of placebo on the evolution of disability in de novo patients. One trial compared selegiline with placebo in 54 untreated patients (274), and the DATATOP study (260) investigated both selegiline and vitamin E in a double-blind prospective study of 800 PD patients. Both studies demonstrated that selegiline significantly delayed the development of disability requiring L-dopa therapy. Although a neuroprotective effect of selegiline cannot be ruled out, it is generally considered that these beneficial effects are due to a symptomatic amelioration of PD by selegiline.


Two studies have assessed an effect of rasagiline on disease progression. The TVP-1012 in Early Monotherapy for Parkinson’s Disease Outpatients (TEMPO) study (271) used a delayed-start design, in which one arm initiated active treatment with a 6-month delay. The results of this study suggest that there might be a benefit to starting treatment early (275). Olanow et al. assessed the effect of rasagiline 1 mg, 2 mg, and placebo also in a delayed-start design study in an attempt to separate symptomatic from neuroprotective or disease-modifying effects (ADAGIO study). Patients were randomized to receive 1 or 2 mg of rasagiline daily for the entire 72-week study (early start) or placebo for 36 weeks followed by rasagiline (delayed start) for the second 36-week period. To prove disease modification attributable to rasagiline, the investigators used three hierarchical endpoints in their primary analysis, based on magnitude and rate of change of UPDRS scores during different periods of the study. The 1-mg daily dose results fulfilled all three criteria, suggesting a disease-modifying effect. However, the 2-mg dose failed to meet all three of the predetermined criteria for disease modification. Based on the TEMPO and ADAGIO studies, the MDS Evidence-Based Review recently concluded that there is insufficient evidence for a role of rasagiline in prevention/delay of clinical progression of PD (276).


Safety and Tolerability of MAO-B Inhibitors


Both selegiline and rasagiline when employed as monotherapy or combined with L-dopa have proven to be well-tolerated drugs. Due to their selective MAO-B inhibition, both are devoid of a “cheese effect” (the tyramine increase observed with MAO-A inhibitors) when administered at currently recommended doses.


No major differences with respect to adverse events were detected between the inhibitors and placebo in several clinical trials when given to de novo patients.


The clinical relevance of the amphetamine and metamphetamine metabolites of selegiline is not fully clear, but they are considered to underlie the occurrence or worsening of neuropsychiatric problems and insomnia sometimes observed with selegiline. Insomnia may improve when the drug is administered early in the day.


When administered with L-dopa, both MAO inhibitors may increase dopaminergic effects, which include nausea, orthostatic hypotension, increase in dyskinesias, confusion, and hallucinations. These symptoms are reversible with reduction of L-dopa or the MAO inhibitor. In the LARGO and PRESTO studies, where L-dopa could be adjusted during the first weeks of treatment, dyskinesias were not significantly modified.


MAO inhibitors are listed among agents that can induce the serotonin syndrome when coadministered with serotonin-enhancing agents, including antidepressants such as the tricyclics, tetracyclics, selective serotonin reuptake inhibitors (SSRIs), serotonin, and noradrenaline reuptake inhibitors. Serious adverse experiences following the combined use of selegiline or rasagiline and antidepressants seem very rare, but it seems prudent, in general, to avoid the combination of MAO-B inhibitors with these drugs. Overall, the available MAO-B inhibitors are well tolerated and considered safe. One large prospective study in de novo patients reported increased mortality after 2 and 4 years of treatment with L-dopa plus selegiline compared with L-dopa alone (175). Although altered cardiovascular responses have been demonstrated in patients on selegiline and L-dopa (277,278), a clinically relevant impact of these findings has not been confirmed in any other trials, and the initial finding of increased mortality is generally regarded as a statistical artifact (155,266).


AMANTADINE


Amantadine hydrochloride (ATD) was originally introduced as an antiviral agent effective against A2 Asian influenza (279) and was fortuitously noted to be useful in relieving clinical symptoms in a patient with PD in 1969 (280). Since then, several clinical trials have established the drug as a useful, well-tolerated agent for the symptomatic treatment of PD. The finding that ATD is a noncompetitive antagonist of the N-methyl-D-aspartate (NMDA) receptor with its implications on the glutamatergic toxic hypothesis on PD and the putative antidyskinetic action of the drug have renewed clinical and theoretical interest in ATD.


The drug is readily absorbed (blood levels peak 1–4 hours after an oral dose of 2.5 mg/kg) and poorly metabolized in humans (more than 90% of an ingested dose can be recovered unchanged in the urine) (281284).


The exact mechanism of action of ATD in PD still remains unclear. Most of the behavioral and neurochemical studies indicate that ATD can interact with catecholamines, especially DA. ATD may act presynaptically and postsynaptically. Presynaptically, it enhances the release of stored catecholamines from intact dopaminergic terminals by an amphetamine-like mechanism (285288). It also inhibits catecholamine reuptake processes at the presynaptic terminal (289291).


Postsynaptically, it can activate DA receptors directly (292) and can produce changes in the DA receptor conformation that fixates the receptor in a high-affinity (agonist-like) configuration (293,294). Nondopaminergic properties of ATD also have been proposed, including an anticholinergic action (295,296) and an NMDA receptor-blocking effect (297). The therapeutic benefit of ATD in PD may be mediated in part by this blockade of glutamate receptors. ATD is able to displace the noncompetitive NMDA receptor antagonist MK-801 from the NMDA receptor complex (298). Importantly, this NMDA receptor antagonistic action is exerted at therapeutic levels (299).


ATD was first given to a large group of patients with PD by Schwab et al. (280). In this uncontrolled study, 107 (66%) of 163 patients treated with a maximum daily dosage of 200 mg showed improvement consisting of a reduction in akinesia and rigidity and some lessening of tremor. One-third of the patients who experienced remarkable initial reduction of symptoms, particularly in akinesia and rigidity, showed a slow but steady loss of benefit after 4 to 8 weeks. In another 58%, benefit was sustained over 3 to 8 months of treatment. In a subsequent publication (300), it was observed that the beneficial effect of ATD usually occurred within the first 24 hours, sometimes following the first 100-mg capsule. When treatment with the drug was stopped, there was a prompt reappearance of symptoms within 24 hours.


Subsequent studies have confirmed the antiparkinsonian properties of ATD. The degree of improvement described in these trials, however, has varied, with open trials giving much more favorable results. In these trials, ATD was compared with placebo either as single therapy or as add-on in patients on anticholinergics. These studies indicated a useful if modest antiparkinsonian effect (301304).


The effect of ATD on the different elements of the parkinsonian syndrome has been repeatedly described as qualitatively similar to that of L-dopa in that it improves all cardinal manifestations of the illness. A detailed analysis of these studies, however, discloses disparate results. Two studies (280,305) described a modest effect on akinesia and a lesser effect on tremor. Other authors (303,305307) reported greater effects on tremor than on akinesia. Judging from the studies reported, there are no clear predictors of a positive response to ATD.


Although direct comparative studies are lacking, it can be concluded that the antiparkinsonian potency of ATD is clearly inferior to that of L-dopa but, at least, similar to that of the anticholinergics. The degree of improvement achieved tends to be similar whether or not the patients are taking anticholinergic drugs. Most open-label studies report that the conditions of one-third to two-thirds of patients improve and that the drug causes few side effects. Acceptance by patients was good in most of the trials, and improvement in functional disability was greater than improvement in physical signs. The reverse was true in a few studies.


ATD also has been studied as an adjunctive treatment to L-dopa. In one study in patients without motor complications, ATD was found beneficial when compared with baseline and with placebo, although the follow-up was short (308). Improvement was more noticeable in patients on low doses of L-dopa in another trial (309). The effect of ATD on motor fluctuations has been studied in two double-blind randomized clinical trials. In one study, a significant decrease in off time versus placebo was described (310). Another study (311) found no significant differences in hours on or off, but this study included only 11 patients and was powered to detect differences in dyskinesias.


Several clinical trials have shown that ATD has a potent antidyskinetic effect in patients taking L-dopa(312). The clinical relevance of several of these studies is limited because they assessed the antidyskinetic effect of acute challenges of ATD (310,313,314). In one recent study concerning amantadine use in controlling dyskinesia in advanced PD (315), amantadine increased on time when compared with placebo, whereas off time decreased, although not significantly. Several subjects treated with ATD experienced a rebound in dyskinesia severity after drug discontinuation. ATD was found to decrease dyskinesia scores by 45% compared with placebo. This decrease in dyskinesia, though, was reported to last only from 3 to 8 months. Although in some cases the beneficial effects of this NMDA antagonist wane, amantadine appears to have relatively long-term antidyskinetic effects as evidenced by recurrence of dyskinesia when amantadine is discontinued after years of treatment, which was shown in two randomized, controlled studies (316,317). Amantadine is currently the best available medication for the treatment of L-dopa–induced dyskinesias.


Safety and Tolerability


Side effects of ATD in patients with PD are usually mild. In the original report (280) on a group of 163 patients treated with maximal daily dosages of 200 mg/day, 22% experienced some type of side effect. The most common side effects are livedo reticularis and ankle edema (318), dryness of mouth, and difficulty focusing vision. Persistent bilateral ankle edema occurred in 22% of patients in one study and tends to occur within 2 to 8 weeks of starting ATD treatment (305). Livedo reticularis is a common undesirable side effect at therapeutic dosages and is probably related to the vasoconstrictor effect of catecholamines released by ATD (319). It generally appears in the legs and occasionally on the buttocks and arms. Patients usually do not complain about livedo reticularis, and it is generally found on routine inspection of the skin. One report described this in 90% of the patients in the study (305). Occurrence of livedo reticularis does not require discontinuation of the drug.


Dryness of mouth, blurred vision, and, when present, palpitations and jitteriness are considered atropine-like side effects related to the anticholinergic properties of ATD. More uncommon but more troublesome are mental aberrations such as confusion, depression, nightmares, insomnia, agitation, visual hallucinations, and psychosis. Objective neurologic findings can include ataxia, slurred speech, and, rarely, convulsion.


An evidence-based review of the literature (106) concluded that ATD for PD “has an acceptable risk, without specialized monitoring.”


In conclusion, ATD hydrochloride is useful in the treatment of the motor symptoms of PD. It leads to an improvement in all cardinal symptoms. Patients’ acceptance is usually good, and the incidence of significant side effects is low when it is administered in the 200 to 300 mg/day range (106). Administered alone or in combination with MAO-B inhibitors (or anticholinergics), ATD has a definite place in the treatment of symptoms in the early, mild stages of PD when it may allow for a delay in the introduction of DA agonists or L-dopa. There is some evidence, however, that the therapeutic efficacy of ATD tends to diminish after months of continuous administration, thus adding ATD to optimal L-dopa treatment to improve motor fluctuations in advanced PD is of questionable value but can be tried if additional therapeutic effects are desired.


The results of recent double-blind studies show that ATD is useful in reducing L-dopa–induced dyskinesias and support the antidyskinetic potential of NMDA antagonism as a possibility of modifying dyskinesias.


ANTICHOLINERGIC MEDICATIONS FOR PD


Anticholinergic substances have formed the mainstay of the medical treatment of PD for more than half a century, since Ordenstein, 1867 (320), following the observations of his professor Jean-Martin Charcot, first described the beneficial effect of the belladonna alkaloids (mainly containing atropine as active component) on tremor and other PD symptoms. Anticholinergics improve symptoms of PD through a central anticholinergic effect exerted in the striatum. Duvoisin showed that cholinesterase inhibitors, which can penetrate the brain, increase the severity of PD symptoms (321,322), an effect that can be reversed by anticholinergics, such as benzotropine. This observation provides a rationale for the use of anticholinergics in PD and supports the notion that a state of striatal cholinergic preponderance exists in PD (323). It is thought that the antimuscarinic properties of the anticholinergics mediate their antiparkinsonian properties (324,325). Another proposed mechanism of action is the inhibition of DA reuptake in the striatum (326).


Centrally active anticholinergics (muscarinic receptors antagonists) exert a modest improvement, but the percentage of patients reported to improve with these drugs has varied greatly, from 43% to 77% in open trials (327,328) and from 20% to 40% in double-blind studies (302). Studies of trihexyphenidyl (329), benzotropine (330), and bornaprine (331) in L-dopa–treated patients indicate that adjunctive anticholinergics have only a minor effect on PD symptoms in patients on L-dopa therapy.


It is frequently stated that anticholinergics are more effective in alleviating resting tremor and rigidity than akinesia (327,332). Reports suggesting that anticholinergics do not have a specific antitremor effect, however, abound in the literature (333,334), and two reviews (106,335) indicate that data suggesting such a tremor-specific effect are inconclusive. Therapeutic differences among the various synthetic anticholinergics are probably minor, but some patients may tolerate one better than the other.


Today, the anticholinergics are occasionally used as initial treatment in the early stages of the disease. However, they are no longer used as first-line drugs, since they have been replaced gradually by other medications such as the MAO-B inhibitors or the modern DA agonists. These latter drugs have shown a reduced incidence of motor complications when compared to L-dopa, with nearly comparable clinical efficacy in the case of DA agonists. No such studies have been performed with the anticholinergics. Furthermore, no trials have compared the symptomatic effects of DA agonists directly with those of the anticholinergics. Despite a lack of definite data to confirm a special role in the management of tremor, anticholinergics are also recommended in patients in whom other therapies such as the agonists, amantadine, or L-dopa have failed to sufficiently control tremor.


In patients on long-term L-dopa therapy and more advanced disease, for example, patients with associated motor complications such as fluctuations or dyskinesias, the beneficial effect from adding anticholinergics has been questioned (329), but some authors believe that in some instances, the addition of anticholinergics may convey some benefit (302,330,334).


Development of tolerance to the beneficial effects of anticholinergics is said to occur frequently, but some loss of therapeutic benefit is indeed a common clinical observation after months of treatment, that could be attributed, at least in part, to disease progression. Withdrawal of anticholinergics, though, even in patients in whom it is thought that these drugs are no longer effective, invariably results in worsening of the parkinsonian symptoms, at times to a level worse than the patients’ baseline state (336,337).


Anticholinergic drugs have been reported to alleviate dystonic spasms in PD resulting from chronic L-dopa administration, as is the case of early-morning dystonia (338).


Safety and Tolerability


The clinical use of this class of drugs is limited by a considerable spectrum of frequent adverse effects. Peripheral adverse effects include tachycardia, constipation (rarely leading to paralytic ileus), urinary retention, blurred vision, and dry mouth (332,339). Reduced sweating may interfere with body temperature regulation.


These effects are reversible when diminishing or with discontinuation of the drug and can even show some tolerance after prolonged exposure. Rarely, some of these side effects can be beneficial, as is the case for dry mouth, which can be advantageous in patients with prominent drooling. Caution must be exercised in elderly male patients with comorbid prostate hypertrophy, due to a risk for urinary retention. Blurred vision is a common side effect, attributed to reduced accommodation due to parasympathetic blockade.


The usefulness of anticholinergics is also limited by central side effects. These include sedation, confusion, and psychiatric disturbances, such as hallucinations and psychosis. Impaired mental function (mainly immediate memory and memory acquisition) is a well-documented central side effect that resolves after drug withdrawal. Impaired neuropsychiatric function has been demonstrated even in patients without cognitive impairment (340,341). These central effects are more likely to occur with advanced age and in patients with dementia. The marked involvement of the cholinergic system (i.e., nucleus basalis of Meynert) in PD pathology (342,343) is probably the basis of the cognitive changes induced by anticholinergics.


Overall, due to the propensity of anticholinergics to induce adverse effects and due to the wider choice of alternative antiparkinsonian drugs with better tolerability, the importance of these drugs in the management of PD has declined in recent years. If they are prescribed, caution must be exercised especially when administered to elderly patients, in order to detect any adverse effects early, in particular with respect to cognition.


PRACTICAL APPROACH TO THE MEDICAL TREATMENT OF DE NOVO AND STABLE PD


Until agents with proven disease-modifying effects become available, the choice of initial treatment must be tailored to each patient’s requirements. When symptoms are noticed but not troublesome, it is acceptable to withhold treatment, if the patient so desires (344), but it should be kept in mind that untreated patients have been shown to experience a greater deterioration in quality of life over time than treated patients (197). The judgment to initiate symptomatic drug treatment is made in discussions between the patient and the treating physician. Available treatments include amantadine, MAO-B inhibitors, DA agonists and L-dopa, and anticholinergics (whose use is often limited by an unfavorable side-effect profile). There is general consensus that in the early stage of PD, when the symptoms are noticed but are not troublesome, treatment with L-dopa is not necessary. As outlined in this chapter, early treatment with L-dopa is associated with good functional improvement but carries a risk of eventually leading to the development of motor complications in many patients. This is particularly so in younger patients, and it is therefore reasonable to use an L-dopa sparing strategy in this group of patients. There is no general cut off age for agonists vs l-dopa as initial treatment.


In mildly affected patients, MAO-B inhibitors, amantadine, and, sometimes, anticholinergics may be sufficient as initial treatment. Although comparative trials are lacking, these drugs are likely to have less symptomatic effect than DA agonists. The agonists are used widely as initial therapy because of their symptomatic effect and because they have been shown to delay the onset of motor complications compared with L-dopa treatment. These trials have not shown, however, that starting treatment with a DA agonist reduces the risk for the development of disabling dyskinesias or motor response fluctuations at later disease stages. When treatment is initiated with an agonist, L-dopa can then be added when its superior symptomatic effect becomes necessary to maintain full functioning.


While this initial approach is currently considered to be the most appropriate for the majority of younger PD patients, individual factors must be taken into account. DA agonists have a higher risk of causing ICDs, somnolence, hallucinations, and orthostatic hypotension, including in early PD. The risk of ever-developing motor complications is considerably smaller in patients with older age at onset (11), and concern for these treatment-related complications is therefore less prominent in elderly patients.


Conversely, while younger-onset patients have a higher risk of motor complications, their ability to remain employable or physically active may be an important goal. DA agonists will often be the first choice in these patients, but in certain circumstances, L-dopa should be considered early, either as monotherapy or in combination with other drugs. Slow-release L-dopa preparations or starting L-dopa therapy in association with a DDC inhibitor plus entecapone does not confer any benefit with respect to the risk of motor complications when compared to standard L-dopa. When prescribing a DA agonist, nonergot ones are recommended to avoid the risk of cardiac valvular fibrosis associated with the use of ergot derivatives (345).


Currently, DA agonist treatment is frequently initiated with ER formulations given once-daily that have a prolonged dopaminergic effect (pramipexole, ropinirole), or transdermal preparations (rotigotine). These formulations are not more effective or better tolerated than the standard orally administered t.i.d. DA agonists, but they may be more convenient for the patient and likely to provide better drug adherence.


Recent studies have shown that the drugs used for the treatment of motor symptoms can influence some nonmotor manifestations of PD. Such proposed effects sometimes drive the selection of the drugs one uses in the initial stages. A favorable influence of DA agonists on depressive symptoms or pain, for example, or on nocturnal disabilities, best documented for pramipexole (346) and rotigotine respectively, (248) has been described. L-dopa’s effects upon NMS, such as cognition or autonomic symptoms, are generally minimal, but it can improve sleep quality (347), RBD (348), and central pain (349).


ONGOING MANAGEMENT IN STABLE DISEASE


In most patients with PD, initial treatment is followed by a period of good response, which may variably last from months to decades. However, even during this stable phase, repeated adjustments of treatment according to tolerability and requirements are necessary as the neurodegenerative process continues.


If a patient has started on an MAO-B inhibitor, amantadine, anticholinergic, or a combination of these drugs, a stage will come when, because of worsening motor symptoms, there is a requirement for adding either L-dopa or a DA agonist. As with initial treatment, each patient’s individual circumstances and treatment goals must be considered before deciding on changes in dosage or agents used. Again, the patient’s age and the desire to minimize motor complications must be weighed against early tolerability and improved motor disability (both of which are better with L-dopa).


If a patient is on DA agonist therapy, it is usually best practice to increase the DA agonist dose in accordance with tolerability. However, even when the DA agonist dose is increased over time, these agents cannot control parkinsonian symptoms for more than about 1 to 3 years of follow-up in most patients, and L-dopa must be added at some stage in nearly all patients.


If a patient is on L-dopa already, the choice whether to increase L-dopa dose or to add a MAO-B inhibitor or a DA agonist will depend on the same deliberations already outlined above. Recent data have shown that adding a DA agonist instead of increasing L-dopa may delay the onset of dyskinesia in patients who started treatment on L-dopa and subsequently require additional dopaminergic treatment for motor control (179).


PRACTICAL APPROACH TO THE MEDICAL TREATMENT OF RESPONSE FLUCTUATIONS AND DYSKINESIAS


The term advanced PD usually refers to patients suffering from the classical motor syndrome of PD along with other motor or nonmotor complications, either disease-related (e.g., freezing) or treatment-related (e.g., fluctuations, dyskinesias, or hallucinations).


The goal in management of motor fluctuations is to increase “on” time during the day without inducing unacceptable treatment-related side effects. It often requires a determined patient and a doctor with patience to achieve significant improvements.


WEARING-OFF


In patients with wearing-off, optimizing L-dopa treatment is often the first step. This includes adjusting individual dosages according to the patients’ needs and shortening the intervals between doses. Increasing the daily doses of L-dopa to more than three times a day soon becomes a necessity, and some patients with very short duration of effect of each L-dopa dose may need L-dopa dosing every 2 to 3 hours during the waking day, with additional doses at night. Switching from standard L-dopa to a CR formulation can also improve the wearing-off and is not uncommonly used to treat nocturnal or early morning akinesia, although a definite benefit of this common approach has never been proven. It should be kept in mind that the GI absorption of slow-release preparations is lower and can be less predictable than with standard L-dopa; if this occurs, switching back to standard formulations should be considered (Table 10.5).


Response to L-dopa varies with meals. Intake with meals may delay L-dopa absorption and result in a weaker response to it. In many patients, intake of L-dopa 1 hour before meals may enhance absorption and induce a more reliable on. While this strategy is unnecessary during the stable phase of treatment, it may be useful in patients describing delayed ons when taking L-dopa during or after meals. Rarely will competition with other amino acids in the diet interfere with L-dopa efficacy. In such cases, reduction in concomitant dietary protein may provide a more stable response to L-dopa throughout the day.












TABLE 10.5


 


Options Available to Improve Wearing-Off Fluctuations




1.Improve l-dopa absorption and transport


     Avoid competition for intestinal absorption: avoid l-dopa intake with meals; dietary protein restrictions.


     In selected cases:
Enhance gastric motility (domperidone).
Soluble l-dopa: as rescue medication when regimen otherwise optimized, e.g., early morning offs


     In selected refractory cases: duodenal l-dopa infusions


2.Stabilize l-dopa plasma levels


     Adjust l-dopa dose.


     Adjust intervals between intakes.


     Add COMT inhibitors.


     Use sustained-release formulations (for nocturnal akinesia and, in selected cases, during daytime).


3.Enhance striatal dopamine concentrations


     Add MAO-B inhibitor.


4.Add dopamine agonists


     Oral dopamine agonist


     Transdermal dopamine agonist


     Intermittent subcutaneous apomorphine injections; as rescue medication when regimen otherwise optimized


     Continuous apomorphine treatment: when fluctuations and dyskinesias are refractory to oral adjustments

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Jun 28, 2016 | Posted by in NEUROLOGY | Comments Off on Pharmacologic Management of Parkinson’s Disease

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