Cheaper, Simpler, and Better: Tips for Treating Seniors With Parkinson Disease

In truth, treating seniors with PD can be greatly simplified. Seniors, defined in this article as those older than 60 years, do not require complex polypharmacy during the early years of PD. Even later, a simple approach, reinforced by understanding of just a few drugs, may be best for the patient. Herein, a dozen basic principles, or “tips,” for treatment of seniors with PD are provided, which should facilitate primary care clinicians becoming effective PD providers. Parkinson disease (PD) is common, with US prevalence estimates of approximately 1 million patients. Many primary care and internal medicine clinicians defer treatment to neurologists. This may be appropriate if the problems become complex with advancing disease. However, even then, having a knowledgeable primary clinician as an active member of the care team can have a major impact on the patient’s quality of life. TIPS FOR TREATMENT OF SENIORS WITH PD 1. No Drugs Are Proven to Slow PD Progression Many agents have been proposed to slow PD progression, but no compelling evidence has surfaced in clinical trials. The American Academy of Neurology reviewed the evidenced-based literature in 2006 and concluded that, “No treatment has been shown to be neuroprotective.”1 Since that publication, the only published clinical trial that challenges this statement assessed rasagiline in early PD; a statistically significant effect was documented with the lower of 2 rasagiline doses.2 However, this was a very controversial study with multiple potential confounding factors, leading others to conclude that evidence was insufficient for a rasagiline “neuroprotective” effect.3 Thus, treatment of PD remains symptomatic. 2. Dopamine Replenishment Remains the Key to Symptomatic Treatment Parkinson disease has long been synonymous with cerebral dopamine depletion, and dopamine replenishment remains the fundamental substrate for medical treatment. Both motor and nonmotor symptoms reflect loss of the nigrostriatal dopaminergic system, and these symptoms often respond dramatically to dopamine restoration. However, it is now well-recognized that PD involves much more than loss of dopamine. Other neurotransmitter systems are not only affected late in PD (eg, dementia, levodopa-refractory motor symptoms, dysautonomia) but also early, preceding PD motor symptoms. Early symptoms such as rapid eye movement sleep behavior, olfactory loss, anxiety, or dysautonomia (constipation) may develop 20 or more years before recognizable PD.4 The temporal course of PD, spanning decades, has been formalized in the Braak staging scheme.5 Although PD is now understood to be much more than a dopamine deficiency state, most of the therapeutic gains are achieved through restoring brain dopamine neurotransmission. Understanding how best to accomplish this is key to managing PD. 3. Carbidopa/Levodopa: Most Efficacious and a Good First Choice The advent of carbidopa/levodopa nearly 4 decades ago was associated with substantially increased longevity, documented in multiple studies of PD cohorts,6 and presumably due to mobilizing akinetic patients. This drug remains the most efficacious treatment. Although new PD drugs are sometimes advocated for initial treatment, they are much more expensive and, for seniors with PD, have few advantages over carbidopa/levodopa. The oral dopamine agonists pramipexole and ropinirole are the primary alternatives to carbidopa/levodopa as initial treatment. They are efficacious but substantially less so than levodopa.7,8 Moreover, they have troublesome adverse effects, including sedation/sleep attacks9 and pathological behaviors,10 plus an approximately 3-fold risk of hallucinations, compared to carbidopa/levodopa.7,8 Uncommonly, PD patients sometimes experience massive lower limb edema provoked by agonists.7,8 The primary argument for starting therapy with these agonists is to reduce dyskinesia and motor fluctuation risks in early PD (see subsequent discussion). However, during the early years of PD in seniors, dyskinesias and motor fluctuations are not very frequent and usually are unimportant problems.11-13 Of course, the opposite is true in very young people with PD; disease onset before age 40 years is nearly always associated with at least some dyskinesias by 5 years of levodopa treatment.14 However, PD onset before age 40 years is extremely uncommon. 4. You Cannot Save the Best Response for Later Carbidopa/levodopa is often dramatically beneficial during the initial years of PD, with a very stable (long-duration) response.15 Throughout subsequent years, the response becomes less stable and complete, plus it is often marked by dyskinesias. Without proof, some argue for “saving” the beneficial responses of carbidopa/levodopa for later. However, there is no compelling evidence that deferring treatment allows the benefit to be “cashed in” later. Rather, this likely represents a lost opportunity. It appears that later-developing levodopa response instability is primarily related to PD progression, rather than the duration of levodopa treatment.11,16 Actually, deferring treatment may have longer-term detrimental consequences. If PD patients experience sufficient symptoms to reduce activities, it may be difficult to reverse the established disability. Moreover, emerging literature suggests that staying physically active may actually have a favorable influence on brain integrity and neuroplasticity, possibly neuroprotective in PD. 5. Generic Immediate-Release 25/100 Carbidopa/Levodopa Is an Excellent Choice Carbidopa/levodopa dosage is given as 2 numbers, with the first representing the carbidopa component. Carbidopa protects against nausea, and hence formulations with more carbidopa are usually preferable and only slightly more expensive (ie, 25/100 vs 10/100). If nausea is absent, then the amount of carbidopa per dose or per day can be ignored. The controlled-release formulation has less bioavailability than the immediate-release drug18; it generates more erratic responses and is much slower to “kick in.”19 It is also more expensive than the immediate-release formulation and has complex interactions with food.18 Thus, for routine daytime use, immediate-release carbidopa/levodopa is a better option. The role for controlled-release carbidopa/levodopa is very limited in my practice and will not be addressed further in this article. Recently, the addition of the catechol-O-methyltransferase inhibitor entacapone has been advocated for initial therapy as a combination drug with carbidopa/levodopa (Stalevo, Novartis Pharma, Basel, Switzerland). However, a recent randomized clinical trial failed to demonstrate advantages that would offset the considerable additional expense, compared to carbidopa/levodopa alone. 20 The bottom line is this: start therapy with 25/100 immediate-release carbidopa/levodopa. 6. Carbidopa/Levodopa Must be Taken on an Empty Stomach Levodopa is a large neutral amino acid that crosses the blood-brain barrier via a molecular transporter, which selectively binds all amino acids from that class. Obviously, digestion of dietary proteins liberates amino acids into the circulation, and these compete with levodopa for transport across the blood-brain barrier. This transport system is easily saturated, and administration of carbidopa/levodopa with meals substantially reduces efficacy. To ensure that levodopa passage across the blood-brain barrier is not compromised, patients should be advised to take their carbidopa/levodopa doses an hour or more before, and 2 or more hours after eating. Pharmacists may dispense carbidopa/levodopa with labeling stating, “Take with meals,” which obviously is incorrect. However, for patients who experience nausea, it is acceptable to take carbidopa/levodopa with dry bread, soda crackers, a banana portion, or some other nonprotein product. 7. There Is no Reason to Restrict Levodopa Dosage: Use What Works Best Although some advocate keeping the levodopa doses as low as possible, no evidence shows that this strategy has any long-term benefit; clearly, it may result in short-term disability. Once PD patients become sedentary, it may be difficult to reverse this. As mentioned previously, increasing evidence shows that ongoing physical activity and exercise may have a favorable influence on PD progression. Notably, some PD symptoms respond to carbidopa/levodopa in an “all-or-none” fashion. For example, rest tremor may not resolve with the lower doses on this schedule but may be controlled as higher doses are taken. Hence, patients should not become discouraged and abandon the scheme if the initial doses are not effective. 8. EArly Levodopa Adverse Effects Primarily Relate to Nausea and Orthostatic Hypotension Carbidopa/levodopa typically has only limited adverse effects as it is initiated. As mentioned previously, severe nausea is uncommon, and mild nausea usually abates with continued treatment. When nausea is provoked by carbidopa/levodopa, it is due to the premature conversion of levodopa to dopamine in the bloodstream. Circulating dopamine does not cross the blood-brain barrier, except for limited regions and notably the brainstem chemoreceptive trigger zone; this is the substrate for nausea. Hence, such nausea is not a sign of gastrointestinal pathology, such as gastritis or ulcers. Obviously, levodopa-related nausea should not be treated with centrally acting dopamine-blocking drugs such as metoclopramide or prochlorperazine. Medication options for nausea include supplementary carbidopa (Lodosyn [Merck, Whitehouse Station, NJ], 25 mg), 1 to 2 tablets administered with each dose of carbidopa/levodopa. Trimethobenzamide and ondansetron are antiemetics that can be administered to PD patients because these agents do not block dopamine receptors; however, they are not highly efficacious in this setting. Outside the United States, domperidone is available; it blocks dopamine receptors but does not cross the blood-brain barrier. Parkinson disease is associated with variable degrees of dysautonomia, and hence there is potential for orthostatic hypotension. This may be primed by drugs already on patients’ medication lists, such as antihypertensives, α1 blockers for prostatism (eg, tamsulosin), or diuretics. Obtain the standing blood pressure before starting carbidopa/levodopa, and if it is less than 100 mm Hg systolic, defer starting the drug until this is addressed. Patients with initially low-normal blood pressure should be advised to monitor their pressure as carbidopa/levodopa doses are increased; systolic values should be maintained above 90 mm Hg. 9. Levodopa Pharmacodynamics Change After Several Years: The Short-Duration Response During the first several years of PD, the response to levodopa is stable and unvarying throughout the course of the day. This is termed the long-duration response, taking a week or 2 to slowly develop after a dose change.15,21 However, after several years, part of the benefit becomes time-locked to each dose, characterized as the short-duration response.15 Typically, patients then complain about response fluctuations. For example, they may have difficulty initially walking in the early morning, only to experience normalization an hour or so after their first morning carbidopa/levodopa dose. This benefit then fades after a few hours, with recurrence of gait problems. These short-duration responses may last from 1 to 6 hours. Patients may be oblivious to these temporal fluctuations, reporting only that they generally “can’t walk,” while overlooking the fact that parkinsonism may be well controlled during major portions of the day. Short-duration levodopa responses rarely benefit from higher individual levodopa doses; increasing the dose does not translate into substantially longer responses. The appropriate strategy is to determine the duration of the response and adjust the dosing intervals to match the response duration. Clinicians are sometimes instructed to reduce individual levodopa doses if administering carbidopa/levodopa more frequently; however, this is not an advisable strategy. The carbidopa/levodopa dose should be the one that produces the most benefit. The number of doses or tablets per day is not important, as long as they are appropriate to the patient’s needs. 10. Levodopa Dyskinesias Are Often Benign and Treatable Around the same time that the short-duration levodopa responses become apparent, patients may experience hyperkinetic movements, primarily manifest as chorea; these are termed dyskinesias. Just as too little brain dopamine translates into motor slowness, too much dopamine results in excessive movements, ie, dyskinesias. Because dyskinesias represent an excessive response to dopamine replenishment, they can be abolished by reducing the individual doses of carbidopa/levodopa. Note that dyskinesias are tied to the most recent dose; thus, carbidopa/levodopa doses taken more than 6 hours previously have lost this dyskinesia potential. Dyskinesias in this sense are manifest as predominant chorea, characterized by nonpatterned flowing or dancing movements of a limb, trunk, head/neck, or combinations of body areas. This differs from simple dystonia, which is often painful, like cramps. Pure dystonia, especially if painful, typically represents a levodopa-underdosed state, rather than an excessive levodopa effect. A common example is the dystonic toe curling or foot inversion often experienced by PD patients, reflecting wearing-off of the levodopa effect, or inadequate levodopa. Unfortunately, reduction of levodopa to abolish dyskinesias may result in reemergence of parkinsonism. Some patients have a narrow therapeutic window between necessary and excessive levodopa effects. For such patients, the old drug amantadine works well to attenuate dyskinesias. If levodopa adjustments cannot control dyskinesias without inducing unacceptable parkinsonism, then the addition of 100 mg of amantadine twice daily is worth considering. It can be increased to 3 and then 4 times daily if necessary (dose-related response). In susceptible individuals, amantadine may contribute to confusion or hallucinations, but it is tolerated in most PD patients. It commonly causes livedo reticularis, but this is not concerning. 11. Anxiety, Akathisia, and Panic Are Common in PD and Are Levodopa-Responsive Symptoms of PD extend well beyond motor problems. Thus, anxiety, restlessness, and even panic may reflect inadequate dopamine replenishment. Some patients may experience these as the most troublesome components of their condition. As mentioned previously, certain PD symptoms respond in an all-or-none fashion, and anxiety typically behaves that way. Waxing and waning anxiety that develops after PD onset often reflects levodopa “off” states and requires adjustment of the dosing interval. 12. Insomnia in PD Often Responds to Levodopa Commonly, PD patients develop difficulty initiating sleep or staying asleep due to such parkinsonian symptoms as akathisia, stiffness (rigidity), inability to turn in bed, and tremor. Such insomnia typically responds to dopamine replenishment with carbidopa/levodopa. Among patients with recent-onset PD with a long-duration levodopa effect, daytime doses of carbidopa/levodopa may adequately treat insomnia. Among patients with short-duration levodopa responses, bedtime or nighttime levodopa doses will be necessary. Note that insomnia is a symptom that typically completely responds, or not at all. Hence, whatever dose has been identified as optimal for daytime use should be the same dose used at night. Parenthetically, not all PD-related sleep disorders are linked to dopamine deficiency. Rapid eye movement sleep behavior disorder is a primary symptom of Lewy body disorders,22 manifest as acting-out dreams. It may precede PD by many years23 and is treated with a bedtime dose of a benzodiazepine (clonazepam).