Treatment of "On-Off Effect" With A Dopa Decarboxylase Inhibitor Richard D. Sweet, MD; Fletcher H. McDowell, MD; Claude G. Wasterlain, MD; Peter H. Stern, MD
Irregularities in motor response after continuing levodopa therapy of Parkinson disease (the "on-off effect") were assessed with the addition of l-\g=a\-methydopa hydrazine (carbidopa) in a doubleblind study. Thirteen of 20 patients improved while receiving carbidopa and levodopa while only four of 17 patients improved while receiving placebo and levodopa. Twenty-three of 37 patients improved in a subsequent non-blind trial of carbidopa plus levodopa. Improvement was not dependent on an increase in dose or frequency of levodopa administration. Adverse effects included
dyskinesia, imbalance, and confusion; nausea was eliminated. One patient died of glomerulonephritis that predated the drug trial, but worsened progressively during and after it. Carbidopa's suppression of the "on-off effect" suggests that extracerebral factors may be important in this phenomenon. (Arch Neurol 32:560-563, 1975)
publication Oct 14, 1974. From the Department of Neurology, Cornell University Medical College, New York. Reprint requests to Department of Neurology, Cornell University Medical College, 1300 York Ave, New York, NY 10021 (Dr. Sweet). Accepted
for
unpredictable oscillations in motor performance from hour to hour have emerged as one of the most troublesome effects of contin¬ uing treatment with levodopa for Parkinson disease.13 The change in a given patient from mobility with dyskinesia and imbalance to akinesia and vice versa is so striking that im¬ age of a switch has been invoked and the phenomenon has been termed the "on-off effect." The mechanism of this effect is not fully known. Barbeau4 attributes it to excessive levodopa dosage, and this has been partially supported by oth¬ ers.5·6 Determinations of plasma con¬ centrations of levodopa during "on" (mobile) and "off" (akinetic) spells have shown high dopa values with "on" and low values with "off" epi¬ sodes.79 Patients with the effect often feel as if levodopa's effect "wears out" too soon, and they would like to take the medication more often were it not for the consequent dyskinesia and imbalance. Extracerebral inhibitors of the en¬ zyme dopa decarboxylase have been used to potentiate the therapeutic ef¬ fect of orally administered levodopa and limit its extracerebral adverse effects, such as nausea, hypotension,
Rapid,
Downloaded From: http://archneur.jamanetwork.com/ by a University of Iowa User on 06/08/2015
and cardiac arrhythmias.1013 These compounds inhibit the conversion of dopa to dopamine outside the central nervous
system and, therefore, might
be expected to prolong plasma halflife of dopa, making it more con¬ stantly available to the brain. This, in turn, might aid in the treatment of the "on-off effect." We have, there¬ fore, studied the use of a-methyldopa
hydrazine (carbidopa), an extracere¬ bral inhibitor of dopa decarboxylase, in patients with this effect. METHODS
Thirty-nine patients who had taken levo¬ dopa continually for Parkinson disease were selected for study. They had bother¬ some fluctuations in motor performance ("on-off effect") that were unresponsive to simple time or dose adjustments of levo¬ dopa. Twenty patients were randomly as¬ signed to group A, which received carbi¬ dopa plus levodopa throughout the eightweek study. The other 19 patients were randomly assigned to group B, which re¬ ceived levodopa plus placebo for carbidopa
for the first four weeks of study and carbi¬ dopa plus levodopa for the second four weeks. The carbidopa dosage was 100 mg per day in four divided doses. Patients tak¬ ing carbidopa or its placebo substitute were given levodopa tablets of identical
containing 100 mg or 500 mg. They took as many new levodopa tablets at the start of the study as they had standard 500 mg levodopa tablets before the study. Therefore, the carbidopa patients took one fifth of their prior dose of levodopa while the placebo patients' doses were not changed. The physicians could change a patient's levodopa dose by one tablet every other day if changes in motility or adverse effects warranted it. Patients and physi¬ appearance
cians
were
Patients were seen every two weeks in the outpatient clinic of the New York Hos¬ pital or the Burke Rehabilitation Center, White Plains, NY, The Cornell Weighted Scale14 was completed at each visit, but was not satisfactory because scores for "on" and "off" periods were radically different in individual patients. Patients were, therefore, questioned about the fre¬ quency and severity of fluctuations in mo¬ bility. They also completed a diary grid sheet designating each hour as "on" or "off."2 The physician used these sheets to rate each patient's fluctuations (not sever¬ ity of disease) as mild, moderate, or severe. During the treatment trial, a comparison of the patient's "on-off effect" was made with the base-line status. Ratings were assigned on a five-point scale: much worse, somewhat worse, unchanged, some¬ what better, and much better. Clinical ad¬ verse effects were assessed by standard questions and observations.1415 Hémato¬ logie, hepatic, renal, and cardiovascular laboratory determinations were made at the four- and eight-week visits.
RESULTS Patient Selection
patients in groups A and similar in respect to sex, age, stage of Parkinson disease (Hoehn and Yahr16), and duration of disease (Table 1). One person in group A and had a history of en¬ two in group cephalitis. Four in group A and six in had undergone stereotaxic group surgery for parkinsonism. Two pa¬ tients in group elected to leave the study during the first week, while they were taking placebo and levo¬ dopa. Both were distressed by a loss of therapeutic effect with their new pills. Twenty patients in group A and 17 patients in group completed the The
study.
Stage of
Duration of
Age
Disease
Group
II
III
A
6
12
blind to the type of medication
during the first four-week double-blind pe¬ riod of study. The second four-week period was "open." All patients were given carbi¬ dopa, 100 mg/day, and commercial 100-mg levodopa tablets.
were
Table 1.—Characteristics of Patients Studied
the
IV
Sex Male Female Male Female
Number
Validity of Rating Method
15
Mean 62.3 61.6 57.7
61.3
Median 63 59 60 60
'
Changes in the "On-Off Effect"
The physicians' base-line evalua¬ tions of fluctuations in mobility are shown in Table 2. Four patients were rated mild, 20 moderate, and 13 severe.
Carbidopa plus levodopa produced improvement of the "on-off effect" in 13 of 20 patients during the fourweek double-blind trial (Table 3, group A). In contrast, only four pa¬ tients taking placebo plus levodopa were rated as improved (group B).
The differences between groups A and were significant (P < .05, square, 1 df). When all patients were treated with carbidopa plus levodopa during the second four-week period, 23 of 37 patients were better, 13 from group A and 10 from group B. The square test showed no significant dif¬ ference among the results of the three carbidopa plus levodopa trials (group A, double-blind and open peri¬ ods, and group B, open period). Akinetic episodes were completely abolished in only two patients. The remainder of patients noticed a short¬ ening of "off" periods as well as
Downloaded From: http://archneur.jamanetwork.com/ by a University of Iowa User on 06/08/2015
Mean
yr
Median
9.5 6.2 9.5 12.2
Table 2.—Base-Line Evaluation of Irregularity of Clinical Response
Physicians' ratings of the change in the "on-off effect" at the end of the eight-week study were compared ret¬ rospectively with the percent change in number of "off" hours recorded by patients. The weeks prior to the base¬ line and the eight-week visits were used, and 31 patients' diary grid sheets were complete enough for this determination. Analysis of variance showed a significant correlation be¬ tween the physicians' ratings and percent change in "off" hours (P
Irregularities in motor response after continuing levodopa therapy of Parkinson disease (the "on-off effect") were assessed with the addition of l-\g=a\-methydopa hydrazine (carbidopa) in a doubleblind study. Thirteen of 20 patients improved while receiving carbidopa and levodopa while only four of 17 patients improved while receiving placebo and levodopa. Twenty-three of 37 patients improved in a subsequent non-blind trial of carbidopa plus levodopa. Improvement was not dependent on an increase in dose or frequency of levodopa administration. Adverse effects included
dyskinesia, imbalance, and confusion; nausea was eliminated. One patient died of glomerulonephritis that predated the drug trial, but worsened progressively during and after it. Carbidopa's suppression of the "on-off effect" suggests that extracerebral factors may be important in this phenomenon. (Arch Neurol 32:560-563, 1975)
publication Oct 14, 1974. From the Department of Neurology, Cornell University Medical College, New York. Reprint requests to Department of Neurology, Cornell University Medical College, 1300 York Ave, New York, NY 10021 (Dr. Sweet). Accepted
for
unpredictable oscillations in motor performance from hour to hour have emerged as one of the most troublesome effects of contin¬ uing treatment with levodopa for Parkinson disease.13 The change in a given patient from mobility with dyskinesia and imbalance to akinesia and vice versa is so striking that im¬ age of a switch has been invoked and the phenomenon has been termed the "on-off effect." The mechanism of this effect is not fully known. Barbeau4 attributes it to excessive levodopa dosage, and this has been partially supported by oth¬ ers.5·6 Determinations of plasma con¬ centrations of levodopa during "on" (mobile) and "off" (akinetic) spells have shown high dopa values with "on" and low values with "off" epi¬ sodes.79 Patients with the effect often feel as if levodopa's effect "wears out" too soon, and they would like to take the medication more often were it not for the consequent dyskinesia and imbalance. Extracerebral inhibitors of the en¬ zyme dopa decarboxylase have been used to potentiate the therapeutic ef¬ fect of orally administered levodopa and limit its extracerebral adverse effects, such as nausea, hypotension,
Rapid,
Downloaded From: http://archneur.jamanetwork.com/ by a University of Iowa User on 06/08/2015
and cardiac arrhythmias.1013 These compounds inhibit the conversion of dopa to dopamine outside the central nervous
system and, therefore, might
be expected to prolong plasma halflife of dopa, making it more con¬ stantly available to the brain. This, in turn, might aid in the treatment of the "on-off effect." We have, there¬ fore, studied the use of a-methyldopa
hydrazine (carbidopa), an extracere¬ bral inhibitor of dopa decarboxylase, in patients with this effect. METHODS
Thirty-nine patients who had taken levo¬ dopa continually for Parkinson disease were selected for study. They had bother¬ some fluctuations in motor performance ("on-off effect") that were unresponsive to simple time or dose adjustments of levo¬ dopa. Twenty patients were randomly as¬ signed to group A, which received carbi¬ dopa plus levodopa throughout the eightweek study. The other 19 patients were randomly assigned to group B, which re¬ ceived levodopa plus placebo for carbidopa
for the first four weeks of study and carbi¬ dopa plus levodopa for the second four weeks. The carbidopa dosage was 100 mg per day in four divided doses. Patients tak¬ ing carbidopa or its placebo substitute were given levodopa tablets of identical
containing 100 mg or 500 mg. They took as many new levodopa tablets at the start of the study as they had standard 500 mg levodopa tablets before the study. Therefore, the carbidopa patients took one fifth of their prior dose of levodopa while the placebo patients' doses were not changed. The physicians could change a patient's levodopa dose by one tablet every other day if changes in motility or adverse effects warranted it. Patients and physi¬ appearance
cians
were
Patients were seen every two weeks in the outpatient clinic of the New York Hos¬ pital or the Burke Rehabilitation Center, White Plains, NY, The Cornell Weighted Scale14 was completed at each visit, but was not satisfactory because scores for "on" and "off" periods were radically different in individual patients. Patients were, therefore, questioned about the fre¬ quency and severity of fluctuations in mo¬ bility. They also completed a diary grid sheet designating each hour as "on" or "off."2 The physician used these sheets to rate each patient's fluctuations (not sever¬ ity of disease) as mild, moderate, or severe. During the treatment trial, a comparison of the patient's "on-off effect" was made with the base-line status. Ratings were assigned on a five-point scale: much worse, somewhat worse, unchanged, some¬ what better, and much better. Clinical ad¬ verse effects were assessed by standard questions and observations.1415 Hémato¬ logie, hepatic, renal, and cardiovascular laboratory determinations were made at the four- and eight-week visits.
RESULTS Patient Selection
patients in groups A and similar in respect to sex, age, stage of Parkinson disease (Hoehn and Yahr16), and duration of disease (Table 1). One person in group A and had a history of en¬ two in group cephalitis. Four in group A and six in had undergone stereotaxic group surgery for parkinsonism. Two pa¬ tients in group elected to leave the study during the first week, while they were taking placebo and levo¬ dopa. Both were distressed by a loss of therapeutic effect with their new pills. Twenty patients in group A and 17 patients in group completed the The
study.
Stage of
Duration of
Age
Disease
Group
II
III
A
6
12
blind to the type of medication
during the first four-week double-blind pe¬ riod of study. The second four-week period was "open." All patients were given carbi¬ dopa, 100 mg/day, and commercial 100-mg levodopa tablets.
were
Table 1.—Characteristics of Patients Studied
the
IV
Sex Male Female Male Female
Number
Validity of Rating Method
15
Mean 62.3 61.6 57.7
61.3
Median 63 59 60 60
'
Changes in the "On-Off Effect"
The physicians' base-line evalua¬ tions of fluctuations in mobility are shown in Table 2. Four patients were rated mild, 20 moderate, and 13 severe.
Carbidopa plus levodopa produced improvement of the "on-off effect" in 13 of 20 patients during the fourweek double-blind trial (Table 3, group A). In contrast, only four pa¬ tients taking placebo plus levodopa were rated as improved (group B).
The differences between groups A and were significant (P < .05, square, 1 df). When all patients were treated with carbidopa plus levodopa during the second four-week period, 23 of 37 patients were better, 13 from group A and 10 from group B. The square test showed no significant dif¬ ference among the results of the three carbidopa plus levodopa trials (group A, double-blind and open peri¬ ods, and group B, open period). Akinetic episodes were completely abolished in only two patients. The remainder of patients noticed a short¬ ening of "off" periods as well as
Downloaded From: http://archneur.jamanetwork.com/ by a University of Iowa User on 06/08/2015
Mean
yr
Median
9.5 6.2 9.5 12.2
Table 2.—Base-Line Evaluation of Irregularity of Clinical Response
Physicians' ratings of the change in the "on-off effect" at the end of the eight-week study were compared ret¬ rospectively with the percent change in number of "off" hours recorded by patients. The weeks prior to the base¬ line and the eight-week visits were used, and 31 patients' diary grid sheets were complete enough for this determination. Analysis of variance showed a significant correlation be¬ tween the physicians' ratings and percent change in "off" hours (P
