Endep

Recognition and treatment of tremor disorders is an important and gratifying component to any clinical practice. In a managed care setting, the role of the family physician in treating these potentially disabling conditions will become increasingly prominent. Recently, a group of neurologists met to develop an algorithm for the treatment of Parkinson's disease in an effort to better control symptoms of this neurodegenerative disease and improve communication between neurologists and primary care physicians.[1]

In contrast to the head and limb tremor of essential, or familial, tremor, the tremor of Parkinson's disease occurs when the patient is at rest, involves the face, tongue and limbs and is often asymmetric. It is usually slower in frequency than essential tremor, and has been described as a "pill rolling" motion in the hands. Parkinson's disease is also associated with bradykinesia (slow movement), postural instability and rigidity.[2] Patients may report nightmares, depression, excessive salivation, difficulty turning in bed, buttoning clothes or cutting food, and problems with walking. Other features of more advanced Parkinson's disease include orthostatic hypotension, constipation, cognitive impairment, micrographia, hypophonia, urinary incontinence and impotence.

Educational materials are readily available from the American Parkinson's Disease Association, the National Parkinson's Foundation, the Parkinson's Disease Foundation and the United Parkinson's Foundation and International Tremor Foundation. In most communities, one of these organizations is easily accessible, and support groups offer patients an opportunity to learn coping strategies (Table 1).

Functional Impairment without Cognitive Impairment

Pharmacologic intervention in Parkinson's disease depends on the severity of the patient's symptoms and the preferences of the treating physician. However, if a patient has only a tremor of the nondominant hand, both the patient and physician may be comfortable avoiding medications.

In the mildly symptomatic or tremordominant patient, levodopa-sparing strategies may be used to postpone use of levodopa or decrease the dosage needed (Table 3). This treatment rationale is based on clinical and scientific data suggesting that both endogenous and exogenous dopamine hasten the progression of symptoms of Parkinson's disease.[22,23]

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ANTICHOLINERGIC MEDICATIONS

The tremor-dominant patient may respond dramatically to anticholinergic medications (e.g., trihexyphenidyl [Artane], 2 to 5 mg three times daily), but most patients report benefit for only three to four months.[24] Anticholinergic drugs are believed to restore an "imbalance" between reduced dopamine and uninhibited cholinergic interneurons in the striatum. The exact mechanism of tremor suppression is unknown, but perhaps anticholinergics alter the rates of spontaneous interneuronal cell discharge associated with nigrostriatal destruction.[25]

Amitriptyline (Elavil, Endep) an antidepressant with anticholinergic properties, is useful in patients with Parkinson's disease, especially those with sleep difficulty and excessive salivation. Benztropine (Cogentin) may also be useful, in dosages of 0.5 mg to 6 mg daily.

Side effects of anticholinergics include dry mouth, urinary retention, constipation, visual problems, confusion and psychosis, and these agents should be used with caution, especially in elderly patients.[25]

AMANTADINE

Amantadine may be used in monotherapy or as an adjunctive medication, particularly when patients report wearing-off difficulties or problems with sleeping.[26] The starting dosage is 100 mg daily, but the dosage may be gradually increased to 100 mg twice or three times daily Although its mechanism of action is unknown, amantadine has been shown to affect both presynaptic and postsynaptic dopamine receptors and has some anticholinergic properties as well. Side effects are similar to those of anticholinergic drugs and also include ankle edema and, rarely, a purple mottling of the skin (livedo reticularis).[19]

DOPAMINE AGONISTS

Only two dopamine agonists are currently available in the United States. Pergolide (Permax) and bromocriptine (Parlodel) act at the postsynaptic membrane and have been shown to be useful in decreasing the amount of levodopa needed. Bromocriptine (starting at 1.25 mg daily, gradually increasing to 10 to 30 mg per day) is a potent D2 dopamine agonist, while pergolide (0.75 to 3 mg per day in three divided doses) acts at both D1 and D2 receptors.[27,28] Pergolide has a longer half-life and may be given less often than bromocriptine, but titration from the 0.05-mg tablet to the 1.0-mg tablet requires frequent dosage adjustment.

Clinical trials are currently under way to evaluate the use of cabergoline, a D2 dopamine agonist. The dosage of this agent ranges from 1 to 6 mg each morning.[29]

Side effects are common in this class of antiparkinsonian drugs and include somnolence, confusion, hallucinations, orthostatic hypotension, nausea and depression. Pergolide is associated with an increased incidence of sinus tachycardia and premature atrial contractions. Long-term therapy with dopamine agonists is associated with the possible development of shortness of breath secondary to pulmonary fibrosis. Headache, back pain and a painful, reddish discoloration of the skin over the shins are also reported.[21]

Final Comment

Treatment of the patient with early Parkinson's disease is often gratifying because of the noticeable improvement in the patient's ability to perform daily routines. However, if a patient does not respond adequately to initial treatment, or if these treatments become less effective, referral to a neurologist or a movement disorders center may be beneficial.

The authors acknowledge Steven Zweig, M.D., for his careful and thoughtful critique of the manuscript.

REFERENCES

[1.] Koller WC, Silver DE, Lieberman A. An algorithm for the management of Parkinson's disease. Neurology 1994;44(12 Suppl 10):1-52. [2.] Stacy M, Jankovic J. Differential diagnosis of Parkinson's disease and the parkinsonism plus syndromes. Neurol Clin 1992;10:341-59. [3.] Mayeux R, Chen J, Mirabello E, Marder K, Bell K, Dooneief G, et al. An estimate of the incidence of dementia in idiopathic Parkinson's disease, Neurology 1990;40:1513-7. [4.] Jankovic J, McDermott M, Carter J, Gauthier S, Goetz C, Golbe L, et al. Variable expression of Parkinson's disease: a base-line analysis of the DATATOP cohort. Neurology 1990,40:1529-34. [5.] Biggins CA, Boyd JL, Harrop FM, Madeley P, Mindham RH, Randall JI, et al. A controlled, longitudinal study of dementia in Parkinson's disease. J Neurol Neurosurg Psychiatry 1992;55:566-71. [6.] Saint-Cyr JA, Taylor AE, Lang AE. Neuropsychological and psychiatric side effects in the treatment of Parkinson's disease. Neurology 1993(12 Suppl 6):47-52. [7.] Friedman JH, Lannon MC. Clozapine in the treatment of psychosis in Parkinson's disease. Neurology 1989;39:1219-21. [8.] Stacy M, Jankovic J. Current approaches in the treatment of Parkinson's disease. Ann Rev Med 1993;44:431-40. [9.] Calne DB. Treatment of Parkinson's disease. N Engl J Med 1993;329:1021-7. [10.] Nutt JG. Levodopa-induced dyskinesia: review, observations, and speculations. Neurology 1990; 40:340-5. [11.] Rajput AH. Clinical features and natural history of Parkinson's disease. In: Calne DB, ed. Neurodegenerative diseases. Philadelphia: Saunders, 1994:555-82. [12.] Tetrud JW, Langston JW. The effect of deprenyl (selegiline) on the natural history of Parkinson's disease. Science 1989;245:519-22. [13.] Effect of deprenyl on the progression of disability in early Parkinson's disease. The Parkinson Study Group. N Engl J Med 1989;321:1364-71. [14.] Rinne JO. Nigral degeneration in Parkinson's disease in relation to clinical features. Acta Neurol Scand Suppl 1991;136:87-90. [15.] Effects of tocopherol and deprenyl on the progression of disability in early Parkinson's disease. The Parkinson Study Group. N Engl J Med 1993; 328:176-83. [16.] Landau WM. Clinical neuromythology IX. Pyramid sale in the bucket shop: DATATOP bottoms out. Neurology 1990,40:1337-9. [17.] Myllyla VV, Sotaniemi KA, Vuorinen JA, Heinonen EH. Selegiline as initial treatment in de novo parkinsonian patients. Neurology 1992;42:339-43. [18.] Schulzer M, Mak E, Calne DB. The antiparkinson efficacy of deprenyl derives from transient improvement that is likely to be symptomatic. Ann Neurol 1992;32:795-8. [19.] Pahwa R, Koller WC. A rational polypharmacy approach to Parkinson's disease. Intern Med 1994;15:53-64. [20.] Package insert. Eldepryl. September 1994. [21.] LeWitt PA, Segel SA, Mistura KL, Schork MA. Symptomatic anti-parkinsonian effects of monoamine oxidase-B inhibition: comparison of selegiline and lazabemide. Clin Neuropharmacol 1993;16:332-7. [22.] Markham CH Diamond SG. Evidence to support early levodopa therapy in Parkinson disease. Neurology 1981;31:125-31. [23.] Rajput AH Rozdilsky B, Rajput A, Ang L. Levodopa efficacy and pathological basis of Parkinson syndrome. Clin Neuropharmacol 1990;13:553-8. [24.] Fitzgerald PM Jankovic J. Nondopaminergic therapy in Parkinson's disease. In: Koller WC, Paulson GW, eds. Therapy of Parkinson's disease. New York: Marcel Dekker, 1990:369-97. [25.] Graybiel AM, Aosaki T, Flaherty AW, Kimura M. The basal ganglia and adaptive motor control. Science 1994;265:1826-31. [26.] Jankovic J, Marsden CD. Therapeutic strategies in Parkinson's disease. In: Jankovic L Tolosa E, eds. Parkinson's disease and movement disorders. Baltimore: Williams & Wilkins, 1993:115-37. [27.] Nakanishi T, Mizuno Y, Goto I, Iwata M, Kanazawa I, Kowa H, et al. Nationwide collaborative study on the long-term effects of bromocriptine in patients with Parkinson's disease. The fourth interim report. Eur Neurol 1991;31(Suppl 1):3-16. [28.] Olanow CW, Fahn S, Muenter M, Klawans H, Hurtig H, Stem M, et al. A multicenter double-blind placebo-controlled trial of pergolide as an adjunct to Sinemet in Parkinson's disease. Mov Disord 1994;9:40-7. [29.] Jori MC, Franceschi M, Giusti MC, Canal N, Piolti R, Frattola L, et al. Clinical experience with cabergoline, a new ergoline derivative, in the treatment of Parkinson's disease. Adv Neurol 1990;53:539-43.

The Authors

MARK STACY, M.D. is assistant professor in the Department of Neurology at the University of Missouri-Columbia School of Medicine, where he earned a medical degree. Dr. Stacy completed a residency in neurology at Hahnemann University Medical Center in Philadelphia, and a fellowship in movement disorders at Baylor College of Medicine in Houston.

H. JAMES BROWNLEE, M.D. is chairman of the Department of Family Medicine at South Florida College of Medicine, Tampa. Dr. Brownlee obtained his medical degree at the State University of New York Health Sciences Center in Syracuse and completed a residency in family practice at the Williamsport (Pa.) Hospital.

Address correspondence to Mark Stacy, M.D., Division of Neurology, M741, University of Missouri-Columbia School of Medicine, One Hospital Drive, Columbia, MO 65212.

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