Chapter 6 Medical treatment of Parkinson disease
Introduction
If treatment of Parkinson disease (PD) with levodopa, the most efficacious drug available for this disorder, were uniformly successful and free of complications, there would be no controversies or complexities, and treatment of this disease would be easy. Moreover, treatment with levodopa would begin when the diagnosis of PD was made. But because of levodopa’s propensity to cause motor complications (wearing-off and dyskinesia), which can impair a patient’s quality of life, strategies have been developed to avoid or delay these motor complications. Also, strategies have been developed to overcome these complications once they have appeared. Thus, treatment strategies have evolved to deal with the different phases of the natural history of PD and also the presence of the motor complications. The natural history of PD is one of gradual worsening, not only of the cardinal motor symptoms, but also increasing prominence of nonmotor features; these are discussed in Chapter 8, which covers nonmotor symptoms due to the illness as well as those due to the medication. The natural history of the prototypical person who develops PD is someone who develops the first symptoms around age 60 and lives approximately 20 years, and has clinical problems as illustrated in Figure 6.1. The early stages, including problems of motor complications from medications, are largely treatable. It is the later stages with intractable motor symptoms and dementia that are virtually untreatable at present.
Therapeutic principles
Give priority to any therapies, such as drugs or surgery, that have been established as protective
If any drug could slow the progression of the disease process, it would make sense to use it as soon as the disease is diagnosed. As of this writing, no proven protective or restorative effect of a drug has been demonstrated with certainty. But studies are in progress looking at various agents to determine if they have such an effect. Drugs that have been specifically evaluated in controlled clinical trials for slowing disease progression have been selegiline and tocopherol (Parkinson Study Group, 1989b, 1993a), selegiline alone (Myllyla et al., 1992; Parkinson Study Group, 1996a; Palhagen et al., 1998, 2006), riluzole (Rascol et al., 2003), neuroimmunophilin (NINDS NET-PD Investigators, 2007), coenzyme Q10 (Shults et al., 2002; NINDS NET-PD Investigators, 2007), glial-derived neurotrophic factor (GDNF) (Lang et al., 2006), and rasagiline (Parkinson Study Group, 2004a; Olanow et al., 2009). Two antiapoptic drugs that that were studied in controlled trials were a propargyline that inhibits glyceraldehyde 3-phosphate dehydrogenase (Waldmeier et al., 2000) and an inhibitor of the mixed lineage kinase-3 family that lies upstream of the c-Jun N-terminal kinase signal transduction pathway to apoptotic cell death (Xia et al., 2001). Both studies failed to show benefit (Olanow et al., 2006; Parkinson Study Group PRECEPT Investigators, 2007). Controlled trials with an antibiotic, minocycline, and an energy enhancer, creatine, using a futility design (Tilley et al., 2006), failed to show these drugs to be superior to their comparison placebo group (NINDS NET-PD Investigators, 2006, 2008). The same results were obtained for coenzyme Q10 and neuroimmunophylin (NINDS NET-PD Investigators, 2007). The MAO-B inhibitors, selegiline and rasagiline, have been studied in clinical trials, with positive results suggesting they may modify disease progression, and many neurologists utilize one of these agents at the time of diagnosis, but whether either would delay the long-term, dopa-nonresponsive features is unknown. A discussion of the results of these completed studies is presented in the section “Treatment of early-stage PD.”
Encourage patients to remain active and mobile
PD leads to decreased motivation and increased passivity. An active exercise program, even early in the disease, can often avoid this. Furthermore, such a program involves patients in their own care, allows muscle stretching and full range of joint mobility, and enhances a better mental attitude towards fighting the disease. By being encouraged to take responsibility in fighting the devastations of the disease, the patient becomes an active participant. Physical therapy, which can be implemented in the form of a well-constructed exercise program, is useful in all stages of disease. In early stages, a physical therapy program can instruct the patient in the proper exercises, and the regimen forces the patient to exercise if he or she lacks the motivation to exercise on his or her own. In advanced stages of PD, physical therapy may be even more valuable by keeping joints from becoming frozen, and providing guidance on how best to remain independent in mobility. Therefore, exercise is beneficial in both the early and later stages. It has been shown that PD patients who exercise intensively and regularly have better motor performance (Reuter et al., 1999; Behrman et al., 2000; Craig et al., 2006) and quality of life (Rodrigues de Paula et al., 2006). If exercise is not maintained, the benefit is lost (Lokk, 2000).
A number of basic science studies have discovered that exercise, particularly enriched exercise, can reduce the loss of dopaminergic neurons after 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) exposure. When such exercise is initiated shortly after rodents were given experimental lesions of the nigrostriatal dopamine pathway, the result was a significantly less amount of damage to the dopamine pathway (Tillerson et al., 2001, 2002, 2003; Cohen et al., 2003; Bezard et al., 2003; Fisher et al., 2004; Mabandla et al., 2004). The mechanism appears to be the induction of increased trophic factors, such as GDNF (Smith and Zigmond, 2003) and brain-derived neurotrophic factor (BDNF) (Bezard et al., 2003).
Keep the patient functioning independently as long as possible
There are a number of drugs that have a favorable impact on the clinical features of the disease by reducing its symptoms, but to date none have been shown to stop the progression of the disease. Since PD is a progressive disease and since no medication prevents ultimate worsening, the long-term goal in treating PD is to keep the patient functioning independently for as long as possible. Clearly, if medications that provide symptomatic relief can continue to be effective and without producing adverse effects, this would be excellent. For example, if levodopa therapy could persistently reverse parkinsonian signs and symptoms, we would not have a problem with therapeutic strategy. The difficulty is that 75% of patients have serious complications after 5 years of levodopa therapy (Table 6.1) (Fahn, 1992a), and younger patients (less than 60 years of age) are particularly prone to develop the motor complications of fluctuations and dyskinesias (Quinn et al., 1987; Kostic et al., 1991; Gershanik, 1993; Wagner et al., 1996). Some physicians therefore recommend utilizing dopamine agonists in younger patients, rather than levodopa, when beginning therapy, in an attempt to delay the onset of these problems (Quinn, 1994b; Fahn and Przedborski, 2010). Controlled clinical trials comparing dopamine agonists and levodopa as the initial therapeutic agent have proven that motor complications are less likely to occur with dopamine agonists (Parkinson Study Group, 2000; Rascol et al., 2000; Oertel et al., 2006). But each of these studies also showed that levodopa was more effective in improving parkinsonian symptoms and signs as measured quantitatively by the Unified Parkinson’s Disease Rating Scale (UPDRS) (Fahn and Elton, 1987). But ultimately symptoms develop that are not responsive to levodopa or other dopaminergic agents (Hely et al., 2005, 2008).
Table 6.1 Five major responses to >5 years of levodopa therapy (n = 330 patients)
| No. | % | |
|---|---|---|
| 1.Smooth, good response | 83 | 25 |
| 2.Troublesome fluctuations | 142 | 43 |
| 3.Troublesome dyskinesias | 67 | 20 |
| 4.Toxicity at therapeutic or subtherapeutic dosages | 14 | 4 |
| 5.Total or substantial loss of efficacy | 27 | 8 |
Thirty-six patients had troublesome fluctuations and troublesome dyskinesias.
Data from Fahn S. Adverse effects of levodopa. In Olanow CW, Lieberman AN, eds: The Scientific Basis for the Treatment of Parkinson’s Disease. Carnforth, England: Parthenon Publishing Group, 1992; pp. 89–112.
Individualize therapy
Also, keep in mind that younger patients are more likely to develop motor fluctuations and dyskinesias; older patients are more likely to develop confusion, sleep–wake alterations, and psychosis from medications. We have divided the severity of PD into five stages and describe treatment for each of them except end stage, which is resistant to treatment: early, mild, moderate, advanced, and end stage (Table 6.2).
Table 6.2 Individualizing treatment according to disease severity
Therapeutic choices available for Parkinson disease
Treatment of patients with PD can be divided into three major categories: physical (and mental health) therapy, medications, and surgery. Physical exercise and physiotherapy were discussed in a previous paragraph. Speech therapy plays a similar role in those with problems of communication. Dysarthria, palilalia, and tachyphemia are difficult to treat, but hypophonia can be overcome by training the patient to shout, known as the Lee Silverman Voice Treatment (Ramig et al., 2001). Psychiatric assistance may be required to handle depression and the social and familial problems that can develop with this chronic, disabling illness. Electroconvulsive therapy (ECT) may have a role in patients with severe, intractable depression; some psychiatrists have been promoting it to help overcome the motor symptoms of PD, but at best ECT provides only short-term motor benefit, and it may not be replicated on repeat treatments. The current practice parameters on treatment of depression, psychosis, and dementia in patients with PD have been summarized in the 2006 report by the American Academy of Neurology Quality Standards Subcommittee (Miyasaki et al., 2006); this topic is covered in Chapter 8.
Neurosurgery for PD is becoming increasingly available as the technique of deep brain stimulation has been developed. This major topic is covered in Chapter 7, and is only mentioned here to be complete in understanding the choices available.
Medications available for Parkinson disease
A great many drugs have been developed for PD. Tables 6.3 through 6.6 classify them according to their mechanisms of action. Selection of the most suitable drugs for the individual patient and deciding when to utilize them in the course of the disease are challenges to the treating clinician. In many of the parkinsonism-plus disorders, the response to treatment is not satisfactory, but the principles for treating PD are the basis for treating these disorders as well. Because PD is a chronic progressive disease, patients require lifelong treatment. Medications and their doses will change over time as adverse effects and new symptoms are encountered. Tactical strategy is based on the severity of the disease.
Table 6.5 Nondopaminergic agents for motor symptoms
Table 6.6 Nondopaminergic agents for nonmotor symptoms
| Behavioral |
| Sleep-related |
| Autonomic |
| Gastrointestinal |
Almost all drug trials evaluate a drug’s short-term symptomatic benefit, but the leading unmet need is to stop or slow progression. Dopaminergic medications usually are effective in controlling the early motor symptoms of PD, but ultimately many patients develop new symptoms that do not respond to dopaminergic medication. The Sydney Multicenter Study of Parkinson disease has reported the problems experienced by people who survived 15 years (Table 6.7) (Hely et al., 2005) and 20 years (Table 6.8) (Hely et al., 2008) from diagnosis. The major problems are the development of symptoms that are not responsive to dopaminergic therapy (Tables 6.7 and 6.8), with dementia reaching 81% in 20-year survivors. Only 26% survived 20 years. The standardized mortality ratio, although less than in the pre-levodopa era of 3.0 (Hoehn and Yahr, 1967), was still significantly elevated at 1.86 at 15 years, but was 3.1 between 15 and 20 years. None were employed. Nonmotor symptoms were prevalent.
Table 6.7 Major symptoms after 15 years of PD
| Living in aged care facility – 40% | Employed – 0% |
|---|---|
| Motor symptoms | Nonmotor symptoms |
| Choking – 50% | Symptomatic orthostasis – 35% |
| Falls – 84% | Urinary incontinence – 41% |
| Fractures – 24% | Depression – 50% |
| Motor complications – 95% | Hallucinations – 50% |
| Cognitive decline – 84% | |
| Dementia – 48% |
Data from Hely et al. (2005) on following subjects enrolled in a study comparing bromocriptine and levodopa therapies. Although approximately 95% of subjects have experienced dopa-induced dyskinesia/dystonia and wearing-off, in the majority these symptoms were not disabling. Dyskinesia and dystonia were delayed by early use of bromocriptine, but wearing-off appeared at a similar time once levodopa was added. The most disabling long-term problems of PD relate to the emergence of symptoms that are not improved by levodopa.
Table 6.8 Major symptoms after 20 years of PD
| Living in aged care facility – 48% | Living independently – 1/36 |
|---|---|
| Motor symptoms | Nonmotor symptoms |
| Choking – 48% | Symptomatic orthostasis – 48% |
| Falls – 87% | Urinary incontinence – 71% |
| Fractures – 35% | Depression – 70% |
| Freezing – 81% | Hallucinations – 74% |
| Moderate dysarthria – 81% | Dementia – 83% |
| Excessive daytime sleepiness – 70% |
Data from Hely et al. (2008) on following subjects enrolled in a study comparing bromocriptine and levodopa therapies. The most disabling long-term problems of PD relate to the emergence of symptoms that are not improved by levodopa, particularly dementia.
Dopaminergic agents
Because most of the major motoric symptoms of PD are related to striatal dopamine deficiency (Hornykiewicz, 1966), dopamine replacement therapy is the major medical approach to treating these features of the disease. Table 6.3 lists these dopaminergic drugs. The most powerful drug is levodopa. It is usually administered with a peripheral decarboxylase inhibitor. In Table 6.3, both carbidopa and benserazide are listed as peripheral dopa decarboxylase inhibitors, although in the United States only carbidopa is available. In many other countries, benserazide is also available. Carbidopa/levodopa is marketed as Sinemet or as a generic drug; the combination is available in immediate-release (e.g., Sinemet standard) and extended-release (e.g., Sinemet CR) formulations. The former allows a more rapid “on” and shorter half-life, and the latter allows for a delayed “on” and a slightly longer plasma half-life. Benserazide/levodopa is marketed as standard Madopar and Madopar HBS (for slow release). The peripheral decarboxylase inhibitors potentiate levodopa, allowing about a four-fold reduction of levodopa dosage to obtain the same benefit. Moreover, by preventing the formation of peripheral dopamine, which can act at the area postrema (vomiting center with a lack of a blood–brain barrier), they block the development of nausea and vomiting. If additional carbidopa is needed for patients in whom nausea persists, it can be prescribed, and patients can obtain it from their pharmacy; the additional peripheral decarboxylase inhibitor may overcome the nausea. Keep in mind that levodopa is absorbed only in the proximal small intestine. The slow release of levodopa from the extended-release versions is such that only about two-thirds to three-quarters of levodopa is absorbed per tablet compared to standard Sinemet. This is because some of the levodopa in the slow-dissolving tablet has not been released before the tablet reaches the large intestine. Levodopa is not absorbed from the rectum, so suppository administration is not useful. There is also an immediate-release formulation of carbidopa/levodopa that dissolves in the mouth and is swallowed with saliva, with the trade name of Parcopa. It can be taken without water, which may be an advantage for some patients, e.g., those who have trouble swallowing or who need to be without food or water pre- and postsurgery.
Levodopa is universally accepted as the most effective drug available for symptomatic relief of many of the motor features of PD. If it were uniformly and persistently successful and also free of complications, new strategies utilizing other treatments would not be needed. Unfortunately, 75% of patients have serious complications after 5 years of levodopa therapy (Table 6.1). Fahn (2008) has reviewed the discovery of levodopa as a useful drug and the history of dopamine’s role in PD.
The absorption of levodopa may be increased by eradicating gastric Helicobacter pylori with omeprazole, amoxicillin, and clarithromycin in PD patients documented to be infected with this bacterium (Pierantozzi et al., 2006; Lee et al., 2008). About 50% of the general population is infected with the bacterium.
The question of whether to use levodopa in a patient who has a history of malignant melanoma needs to be considered. Levodopa is an intermediary metabolite in the synthesis of skin melanin, so the concern is whether lurking melanoma cells can be activated by the use of levodopa therapy. A review of the literature does not provide evidence of a definite relationship between treatment with levodopa and the development or reemergence of malignant melanoma (Pfutzner and Przybilla, 1997; Zanetti et al., 2006; Olsen et al., 2007). Epidemiologic studies have shown that people with PD have an increased prevalence of malignant melanoma (Olsen et al., 2006). A clinical trial in which the development of melanoma was a secondary outcome measure showed that patients with PD on the placebo arm of the trial had a much higher rate of developing malignant melanoma than would have been predicted; no association between levodopa therapy and the incidence of melanoma was found (Constantinescu et al., 2007). Yet, it is would seem prudent not to treat with levodopa in a patient with a history of a malignant melanoma if other antiparkinson agents remain effective. Once it becomes necessary to use levodopa to improve quality of life, the patient needs to be informed that he should be observed carefully for changes in or development of new pigmented lesions.
Besides being metabolized by aromatic amino acid decarboxylase (also called dopa decarboxylase), levodopa is also metabolized by catechol-O-methyltransferase (COMT) to form 3-O-methyldopa. Two COMT inhibitors are currently available – tolcapone and entacapone. These agents extend the plasma half-life of levodopa without increasing its peak plasma concentration, and can thereby prolong the duration of action of each dose of levodopa. These drugs are used in conjunction with levodopa to reduce the wearing-off effect, a common motor fluctuation adverse effect of levodopa therapy. The net effect with multiple dosings a day, though, is to elevate the average plasma concentration but smooth out the variations in the concentration. Tolcapone has two potential adverse effects that need to be explained to the patient. The most serious is that a small percentage of patients will develop elevated liver transaminases, and patients need to have baseline and follow-up liver function tests. Death from hepatic necrosis has occurred in three patients who had no liver function surveillance (Watkins, 2000). Entacapone has not shown these hepatic changes. With tolcapone, a small percentage of patients will develop diarrhea, which does not appear until about 6 weeks after starting the drug. The diarrhea can be explosive, so the patient might not have any warning. Entacapone appears not to have these adverse effects. Many clinicians believe that tolcapone is more effective than entacapone in reducing motor fluctuations, but one should not prescribe the former unless the latter has not been effective in relieving wearing-off. Patients on entacapone can be easily switched to tolcapone if the former had less than the desired effect, and a double-blind comparison showed tolcapone to be slightly more effective in reducing the amount of “off” time (Entacapone to Tolcapone Switch Study Investigators, 2007). We advise starting tolcapone at a low dose of 100 mg/day and increasing gradually to 100 mg three times daily.
Elevated total plasma homocysteine, a risk factor for strokes, heart attacks, and dementia, has been found in PD patients using levodopa. The increase of plasma homocysteine with levodopa therapy is thought to be due to the utilization of the methyl group from methionine in the COMT reaction, converting levodopa to 3-O-methyldopa, while converting methionine to homocysteine. A study evaluating the immediate effects of initiating levodopa therapy found a modest elevation of homocysteine and a modest lowering of vitamin B12 levels (O’Suilleabhain et al., 2004). These investigators did not see a reversal with levodopa reduction, agonist treatment, or entacapone treatment. In another study, entacapone also did not reduce homocysteine levels (Nevrly et al., 2010). Another study reported that levodopa treatment does not affect B12 levels, but does reduce folate levels (Lamberti et al. 2005). These investigators found that the addition of COMT inhibitors could reduce the amount of homocysteine, but other investigators did not. Whether the increase in plasma homocysteine with levodopa therapy puts the patient at a greater risk for other medical problems is unknown (Postuma and Lang, 2004).
Adding entacapone to levodopa for patients who are not experiencing motor fluctuations did not add any improvement to motor performance in one study (Olanow et al., 2004), but improved the activities of daily living (ADL) score in another (Brooks and Sagar, 2003). In the FIRST-STEP study, levodopa/carbidopa/entacapone (LCE) 100/25/200 mg three times daily was compared with levodopa/carbidopa (LC) 100/25 mg three times daily in patients with early PD for 39 weeks (Hauser et al., 2009). LCE treatment resulted in slightly better UPDRS Part II activities of daily living (ADL) scores (P = 0.025), but not Part III motor scores.
The concept that intermittent brain levels of levodopa and dopamine contribute to the development of motor complications (see below in discussion of advanced PD) has led to the concept that continuous dopaminergic stimulation may avoid these complications from levodopa. So far, one study (STRIDE-PD) testing this hypothesis has yielded the opposite effect, i.e., an earlier onset of dyskinesias (Stocchi et al., 2010). A total of 747 patients with early PD were randomized to LCE 100/25/200 mg or LC 100/25 mg with flexible dosing to reach 400 mg/day, with a dose 3.5 h apart. The results showed that time to dyskinesia was statistically significantly shorter in LCE-treated patients compared to LC-treated patients. The incidence of dyskinesia during the study period was higher in LCE-treated patients in comparison to the LC group.
The next most powerful drugs, after levodopa, in treating PD symptoms are the dopamine agonists. Of those listed in Table 6.3, bromocriptine, pramipexole, ropinirole, and apomorphine are available in the United States, and these are discussed below. Lisuride, pergolide, cabergoline, rotigotine and piribedil are marketed in some countries. Lisuride is water soluble and can be infused subcutaneously; it has considerable 5-HT agonist activity. Cabergoline is the longest acting and could be taken just once a day (Ahlskog et al., 1996; Hutton et al., 1996); it might prove to be the most important in terms of preventing or reducing the “wearing-off” effect. Piribedil is relatively weak, but has been touted as having an anti-tremor effect. Rotigotine is a dopamine agonist that is utilized as a transdermally applied skin patch (Parkinson Study Group, 2003; Poewe and Luessi, 2005; LeWitt et al., 2007; Poewe et al., 2007; Watts et al., 2007) and was marketed in summer 2007. After the discovery that crystals of rotigotine appear on the patch, the drug was withdrawn from the USA.
Other than apomorphine and rotigotine, the other dopamine agonists in Table 6.3 are effective orally. Apomorphine needs to be injected subcutaneously or sprayed intranasally. Bromocriptine is the weakest clinically in comparison to the others. Pergolide, pramipexole, and ropinirole appear to be comparable in clinical practice, but some patients will respond better to one than the others. There are some differences between these agonists in their affinity for the dopamine receptor subtypes, as depicted in Tables 6.4 and 6.9. Only apomorphine (strong) and pergolide and lisuride (modest) have agonist activity at the D1 receptor. The activation of the D2 receptor is known to be important in obtaining an anti-PD response, whereas it is unknown how important D3 receptor activation is for improving the anti-PD response. Bromocriptine, pergolide, pramipexole, and ropinirole activate the dopamine D3 as well as the D2 receptor, but their ratios of affinities for these two receptors are different (Table 6.9) (Perachon et al., 1999). All dopamine agonists are less likely to induce dyskinesias compared to levodopa (Schrag et al., 1998). The agonists can be used as adjuncts to levodopa therapy (e.g., Lieberman et al., 1998; Pinter et al., 1999) or as monotherapy (e.g., Kieburtz et al., 1997b; Brooks et al., 1998; Kulisevsky et al., 1998; Rinne et al., 1998a; Sethi et al., 1998). Adverse effects that are more common with dopamine agonists than with levodopa are drowsiness, sleep attacks, confusion, orthostatic hypotension, nausea, and ankle/leg edema associated commonly with erythema (Parkinson Study Group, 2000; Rascol et al., 2000). Edema can spread to involve other areas of the body including the arms and face.
Having several dopamine agonists to choose from allows the opportunity to find one that is better tolerated as well as one that might have more effect. Adverse effects may be the deciding factor as to which drug a patient will do best on. Unfortunately, all these drugs can induce confusion and hallucinations in elderly patients. Leg edema occurs in some patients, usually after a few years. Pramipexole and ropinirole, and other dopaminergics as well, though with probably less frequency, can cause sleepiness and sleep attacks. This could be dangerous for the patient who drives an automobile, and motor vehicle accidents have occurred when patients fell asleep at the wheel (Frucht et al., 1999; Ferreira et al., 2000; Hoehn, 2000; Schapira, 2000). So when deciding to place a patient on pramipexole or ropinirole, the physician should determine the extent of the driving to be done by the patient, and warn the patient about this potential hazard. Short trips, e.g., 10 minutes or so, should be without risk. Should sudden falling asleep occur in any non-driving activity, this event can serve as a warning against driving or else it would be best to taper and even discontinue these medications if driving is necessary. Dopamine agonists also are more likely to induce impulse control problems, such as gambling, hypersexuality, shopping, and binge eating (see Chapter 8) (Weintraub et al., 2010).
Monoamine oxidase (MAO) inhibitors offer mildly effective symptomatic benefit. Type B MAO inhibitors eliminate concern about the “cheese effect” that can occur with type A inhibitors and a high tyramine meal. Although there is debate about possible protective benefit with selegiline, it does have mild symptomatic effects when used alone (Parkinson Study Group, 1993a, 1996a, 1996b) and also potentiates levodopa when used in combination with it (Lees, 1995). A more thorough discussion of selegiline’s possible protective effect is presented below in the section entitled “Selegiline, rasagiline, and antioxidants.” Selegiline has a mild ameliorating effect for mild “wearing-off” from levodopa (Golbe et al., 1988). Zydis selegiline is a form of selegiline that dissolves in the mouth and is absorbed through the oral mucosa, avoiding first pass metabolism in the liver (Waters et al., 2004). This preparation of selegiline, formulated in a freeze-dried tablet that contains a fast dissolving selegiline (Zelapar), has been approved by the Food and Drug Administration in 2006 for clinical use (Clarke and Jankovic, 2006).
Like selegiline, rasagiline is another irreversible type B MAO inhibitor with mild symptomatic benefit (Rabey et al., 2000; Parkinson Study Group, 2002a, 2004a) and with a similar chemical structure; both are propargylamine compounds. Rasagiline is available for use in both early and advanced stages of PD and has a good safety record (Goetz et al., 2006). Both the TEMPO trial and the subsequent larger ADAGIO trial using a delayed-start design showed that starting earlier with rasagiline allows a better clinical outcome than starting later (Parkinson Study Group, 2004a; Olanow et al., 2009). A more thorough discussion of rasagiline’s possible protective effect is presented below in the section entitled “Selegiline, rasagiline, and antioxidants.”
Lazabemide is another type B MAO inhibitor, but is a reversible inhibitor. It shows the same symptomatic effect in PD (Parkinson Study Group, 1993b) as does selegiline and rasagiline. It is not known whether it has a neuronal rescue effect. Lazabemide is not commercially available in the United States. In contrast to selegiline, neither lazabemide nor rasagiline is metabolized to methamphetamine. Type B MAO inhibitors should not require a tyramine-restricted diet, provided that the dose remains no higher than the FDA-authorized dose. Higher doses will begin to inhibit MAO type A, and could cause severe hypertension (the so-called “cheese effect”) if the diet contained too much tyramine. A controlled tyramine challenge showed that rasagiline up to 2 mg/day did not induce a significant blood pressure or pulse change when tyramine was added (deMarcaida et al., 2006). Inhibitors of both type A and type B MAO would offer greater inhibition of dopamine oxidation in the brain and thus the combination would theoretically be more capable of reducing oxidative stress as well as providing more symptomatic effect (Fahn and Chouinard, 1998). But tranylcypromine and phenelzine (both nonselective inhibitors of types A and B MAO) cannot be taken in the presence of levodopa therapy because of the “cheese effect,” and even in the absence of levodopa, patients on these drugs need to adhere to a reduced tyramine diet (Gardner et al., 1996).
We will return to discuss MAOIs and antioxidants below in their possible role in treating early-stage PD. Next, we will review the nondopaminergic drugs that are useful in treating PD, both the motor problems (Table 6.5) and the nonmotor problems (Table 6.6).
Nondopaminergic agents for motor symptoms
Nondopaminergic agents (Table 6.5) are also useful to treat motoric PD symptoms, particularly antimuscarinic drugs (commonly referred to as anticholinergics), which have been widely used since the 1950s, but these are much less effective than the dopaminergic agents, including amantadine. Antimuscarinic drugs have been thought to be somewhat helpful in reducing all symptoms of PD, but they have found special favor in reducing the severity of tremor. But because of sensitivity to memory impairment and hallucinations in the elderly population, antimuscarinic drugs should usually be avoided in patients over the age of 70 years. The antihistaminics, tricyclics, and cyclobenzaprine (Flexeril) have milder anticholinergic properties that make them useful in PD, particularly in older patients who should not take the stronger anticholinergics.
Amantadine, listed in Table 6.3 as a dopaminergic agent, is listed also in Table 6.5 because it has antiglutamatergic effects; this property might account for its usefulness in reducing choreic dyskinesias induced by levodopa (Rajput et al., 1997; Metman et al., 1998a). Dextromethorphan is another antiglutamatergic agent, and it has been found effective in reducing the severity of dyskinesias by 50% (Metman et al., 1998b). Another useful class of drugs is the benzodiazepines to reduce anxiety, and thereby decrease parkinsonian tremor that is exacerbated by stress. Diazepam is usually well tolerated and does not exacerbate parkinsonian symptoms, whereas chlordiazepoxide can (Schwarz and Fahn, 1970). Lorazepam and alprazolam are other useful benzodiazepine agents; the latter has the added benefits of being short-acting and having antidepressant effects. The muscle relaxants listed in Table 6.5 might help in treating “off” and peak-dose dystonias. Because oxidative stress appears to play a role in the pathogenesis of PD, high doses of antioxidant vitamins have been tried for patients with PD. The DATATOP study showed that tocopherol by itself has no effect, but the combination of ascorbate and tocopherol may be more effective than either of these two vitamins alone (Fahn, 1992b; Yoshikawa, 1993). Ascorbate has proven effective in blocking degeneration of nerve cells in vitro induced by levodopa (Mena et al., 1993; Mytilineou et al., 1993; Pardo et al., 1993, 1995; Lai and Yu, 1997). Adenosine A2A receptors are located on GABA neurons in the striatum and antagonize the effect of dopamine on these neurons (Benarroch, 2008). Antagonizing adenosine A2A receptors has a behavioral effect similar to enhancing dopaminergic transmission. One of these receptor antagonists, istradefylline, has undergone clinical trials for patients with motor fluctuations (Bara-Jimenez et al., 2003; Hauser et al., 2003, LeWitt et al., 2008; Stacy et al., 2008), but the results were mixed, with insufficient relief of fluctuations while enhancing dyskinesias. Another adenosine A2A receptor antagonist, preladenant, is currently undergoing clinical trials.
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