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Parkinsonology: Dosage Strategies for Controlling Symptoms by Dr. Mark Stacy

Dr. Mark Stacy is well respected parkinsonologist, researcher and teacher. He is highly sought after to speak on dosing strategies to control symptoms. He is affiliated with the Barrow Neurological Institute, in Phoenix, AZ.

The Neurosciences Institute, which is associated with Good Samaritan Hospital in Los Angeles, sponsored a symposium on Nov. 2-3, 1996 in Rancho Mirage, CA. Dr. Stacy made his presentation there.

I thank Carole Hilton for making this information available to the Parkinsn archives.

Patients and care-givers should take note of the mention of diaries in this paper. A diary allows the parkinsonologist to see graphically when the medicine is taken and when when complications develop.

Symptom Management in Parkinson's Disease by Mark Stacy, M.D. Director, National Parkinson Foundation Center of Excellence at Barrow Neurological Institute

Address Correspondence to:

Mark Stacy, M.D
Barrow Neurological Institute
222 W Thomas Rd
Phoenix, AZ 65260
(602)406-6330

Introduction:

Treatment of Parkinson's disease (PD) assumes several phases in the course of this illness. Initially, both the physician and the patient are concerned with diagnosis. The next phase is treatment initiation, and the last and longest involves treatment optimization. Referals "early" in the course of a parkinsonian type illness, are most often for a second opinion regarding diagnosis. At this time patients and families sense inconsistencies with the clinical diagnosis when compared to others with PD or descriptions found in literature. Often, further medical evaluation is necessary to eliminate other parkinsonism "masqueraders." Other causes of parkinsonism include Parkinsonism-Plus syndromes, drug-induced parkinsonism, and other heredodegenerative conditions. Drugs known to cause or worsen PD are major tranquillizers, anti-emetics, and the antihypertensive agent, alpha-methyl-dopa. In addition, environmental toxins such as carbon monoxide, cyanide, carbon disulfide, manganese, lithium, and alcohol withdrawal have been associated with parkinsonian features. The next major concern for patients and families with PD is when to begin therapy. This discussion should include a discussion of "neuroprotective" therapy, "levodopa sparing" strategies, and other drugs. The last phase, treatment optimization, is often frustrating, because symptoms primarily attributable to PD and secondly a result of medication complications are often difficult to separate. This manuscript will attempt to address a method of defining cyclical, medication problems in PD; a patient example and the importance of dosing diaries will be stressed. Any potential changes in your medical regimen should be discussed appropriately with your doctor.

Diagnosis:

The diagnosis of PD is highly dependent on assessment by a physician; there are no confirmatory tests for this condition. The most straightforward patient exhibits the "classic" characteristics of PD (slowness, resting tremor, stiffness, and balance difficulty). Often one side is affected more than another, and patients may also report symptoms of nightmares, sleep difficulty, trouble being heard over the telephone, drooling at night, difficulty turning in bed, trouble cutting food, poor and small handwriting, and a tendency to favor one side. There are several "red flags" that may prompt a physician to look for other conditions that may mimic the signs of parkinsonism. A tremor that is more prominent with action (spilling soup, trouble using a screwdriver or other tools), has been present for many years, and has been noticed in other family members, strongly suggests the diagnosis Benign Essential Tremor. A lack of resting tremor also prompts investigation into other parkinsonian disorders. Frequent falls and "freezing" at the initial presentation suggests a number of disorders (including PD), and magnetic resonance imaging (MRI) of the brain is important. Furthermore, lack of response to levodopa should be cause to reconsider the diagnosis of idiopathic PD.

Early Treatment Response:

In the initial PD presentation treatment options become a major focus of the discussion. A number of questions must be considered. The first is to treat or not to treat. This is a patient and family decision, and depends on both the severity of symptoms and the wish to begin medication. Eventually, treatment options must be discussed, and should center around

1) "neuroprotective" drugs to slow the progression of the disease,

2) drugs to improve PD symptoms, and

3) whether early levodopa treatment increases the risk of patient progression in the future.

Neuroprotection has been a confusing issue in the last decade. Selegeline (Eldepryl^®) has been shown to delay the need for levodopa, and some investigators believe this drug delays PD progression. More recent data suggests that this compound is useful in the early patient for the first three years after diagnosis, but the "neuroprotection" potential in the advanced patient is unknown. The role of selegeline should be detenmined by the patient and the clinician; cost and severity of PD symptoms should play major roles in this decision.

The concern of many investigators in treating PD surrounds the potential that levodopa may hasten the progression of the disease. For this reason "levodopa sparing strategies," or therapeutic approaches to limit this drug may be tried. Since selegeline has been shown to delay the need for levodopa, it is an important drug at this juncture. In addition, amantadine (Symmetrel^®) or trihexyphenidyl (Artane^®) may be used. A new class of medications, catechol-0-methyl transferase (COMT) inhibitors, such as tolcapone and entacapone, hold promise in reducing levodopa dosages, and tolcapone may be useful in treating PD when used alone. Eventually, all PD patients require levodopa, the most effective medication for treating symptoms of PD. This drug is combined with carbidopa (Lodosyn^®) to form Sinemet^® and is available in a variety of ratios (25/100, 25/250 and 10/100). There is also a controlled release form (Sinemet CR^®) that is available as CR 25/100 and CR 50/200 tablets. At least 75 mgs of carbidopa per day is necessary to prevent levodopa metabolism outside the brain. The patient with nausea, vomiting, light headedness may require additional carbidopa; this drug is available from the manufacturer at no charge. The "immediate-release" carbidopa/levodopa 25/100 formulation is begun one tablet every morning for one week, then one tablet twice a day for one week, then one tablet three times a day (e.g. 8:00, noon, 4:00). The 25/250 and 10/100 preparations should be used in the advancing patient, and initially, bedtime levodopa should be avoided. The control-release (CR) form is begun: one tablet every morning for one week, and then one tablet at 7:00 am and noon thereafter. If a patient does not respond to these doses of levodopa, the diagnosis of idiopathic PD must be reconsidered.

Treatment Optimization:

Treatment of advancing PD is mainly concerned with medication response. In each clinic visit medication schedule and response is most important. Symptoms occurring at a certain period of the day cannot be treated without this knowledge. The following example illustrates one simple problem, and treatment options that may be applied to other PD symptoms.

--------------------- Figure 1

Dosing Diary Response Curve

ON=moving normally; C=cramping of the leg; OFF=Parkinson's symptoms limit mobility; 25/100= Sinemet^® 25/100

-----------------------

This patient demonstrates a typical "wearing-off" dystonia, a side effect of low levels of levodopa. The "dosing diary" demonstrates cramping at the end of the levodopa dosing cycle. The daytime problems may be treated by increasing the dose of 25/100 to 1+ tablets at 8:00, noon and 4:00 and adding a tablet at 8:00 pm. Another approach could be giving the medication more often (7:00, 10:00, 1:00, 4:00 and 7:00), and finally the patient could be placed on the CR 50/200 tablet one at 7:00, noon, and 5:00. Daily levodopa doses would be 530 mgs in the first example, 500 mgs in the second, and 600 mgs in the third.

In this instance the medication is adjusted to 1 1/2 tablets of 25/l00 at 8,12,4 and 1 tablet at 8pm. She returns in one month to report less leg cramping during the day, but continued sleep difficulty and cramping at night. In addition, she now has involuntary movements (dyskinesias) of her head at 2:00 and 6:00 every day. [Figure 2)

--------------------- Figure 2

Dosing Diary Response Curve

DYS=dyskinesia; ON=moving normally; C=cramping of the leg; OFF=Parkinson's symptoms limit mobility; 25/100= Sinemet^® 25/100

-----------------------

On this regimen the patient exhibits simple motor fluctuations that are easily correlated to levodopa dosing. At this time there are three choices: give smaller doses of 25/l00 carbidopa/levodopa more frequently, change to controlled release carbidopa/levodopa, or return to the previous levodopa dose and add another drug. (Figure 3) Since 1 1/2 tablets of 25/100 produce dyskinesias and 1 tablet does not last a full four hours, a reasonable change would be to give one tablet every 3 to 3+ hrs. A change to the controlled- release tablet will allow for a slower absorption, but a more sustained level of drug. This would potentially eliminate "peak dose" dyskinesias and "wearing-off' problems, but the slow rate of onset in the morning would prolong the time for "kick-in" each morning. Therefore, a change to this formulation would be a CR tablet at 7:00, noon, 5:00 and 1/2 tablet of 25/100 every morning. The last alternative would be to return to the previous 25/100 regimen, and add another drug. In this instance amantadine, selegeline, tolcapone or entacapone may improve symptoms. However, many parkinsonologists would add a dopamine agonist (pergolide (Permax^®) or bromocriptine (parlodel^®)). Several dopamine agonists, pramipexole and cabergoline, may be available in US markets in the near future.

--------------------- Figure 3

Dosing Diary Response Curve

ON=moving normally; 25/100=Sinemet^® 25/100; CR=Sinemet CR^® 50/200; The figure attempts to illustrate the 3 different dosing strategies discussed above, and these are listed separately. Permax^® is titrated over 4-6 weeks.

* in this example the patient may have some off symptoms until "kick-in" at 8:00.

-----------------------

With improvement of her motor ability during the day, the patient now strongly desires to address her sleep problems and early morning foot cramping. In this instance the addition of amitriptyline (Elavil^®) 10-25 mgs may help both the sleep and foot cramping problem, and would be a reasonable choice. If, however the patient had memory difficulties or problems with urinary retention this drug should be avoided. Baclofen (Lioresol^® 20mgs bedtime and in the early morning may alleviate symptoms of foot cramping. Clonazepam (Klonapin^®) 0.5-1.0 mgs may be useful in treating sleep problems in some patients.

Conclusion:

The treatment of PD is highly dependent on interaction between a patient and a physician. Improvement may be seen once a patient is able to communicate a problem to a physician. It is important for a patient to direct an office visit to symptoms of major concern, such as, "I cannot sleep, if I could sleep, I could feel better." This limits a doctor visit to a more realistic amd patient desired endpoint. In the case reviewed in this article, this lead to a teasing out of the problems this patient was experiencing, and a logical approach to solving a complicated problem. In advancing PD every effort should be made to correlate fluctuating symptoms with medication dosages; with proper recognition, rational changes in a drug regimen may be made.

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