Association of adverse effects with monoamine oxidase type B inhibitor and catechol-o-methyl transferase inhibitor combination therapy in Parkinson’s disease patients

doi:10.4236/apd.2012.11002

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Vol.1, No.1, 5-10 (2012) Advances in Parkinson’s Disease

doi:10.4236/apd.2012.11002

Association of adverse effects with monoamine

oxidase type B inhibitor and catechol-o-methyl

transferase inhibitor combination therapy in

Parkinson’s disease patients

Rui Zhang, Danielle C. Spengler, Marie-Helene Saint-Hilaire*, Anna D. Hohler

Department of Neurology, Boston University School of Medicine, Boston, USA;

*Corresponding Author: Marie.Saint-Hilaire@bmc.org

Received 1 July 2012; revised 24 July 2012; accepted 22 August 2012

ABSTRACT

Currently, levodopa is the most effective and

commonly used medication to control motor

symptoms in Parkinson’s disease (PD). However,

its long-term use is associated with adverse effects

(AEs). Combination therapy of a monoamine

oxidase type B inhibitor (MAOBI) with levodopa

or a catechol-O-methyl transfer ase inhibitor (COMTI)

with levodopa provides benefits to PD patients.

Direct comparison of efficacy and side effect

profiles is complex. The aim of this study is to

investigate the different AE profiles of MAOBI

and COMTI combination therapies. Data used to

analyze the AEs of different PD medications

were retrieved from “The Boston University Me-

dical Center’s Parkinson’s Disease and Move-

ment Disorder Database”. Ten categories of AEs

were compared between patients receiving

MAOBI and COMTI combination treatment. In

total, 87 subjects were included in the analysis.

Out of ten AEs, the presence of dementia was

signifi- cantly different between the MAOBI and

COMTI groups with an OR of 6.9 (COMTI vs

MAOBI, 95% CI 1.3 - 37.0). Motor fluctuations

were also found to be differently distributed in

the two medication groups with an OR of 3.1

(COMTI vs MAOBI, 95% CI 1.0 - 9.8). In this ret-

rospective database analysis of patients treated

with combination treatment for PD, combination

therapy of a COMTI with levodopa was more

likely to be associated with dementia and motor

fluctuations than a MAOBI with levodop a.

Keywords: Catechol-O-Methyl Transferase

Inhibitors; Dementia; Monoamine Oxidase Type B

Inhibitors; Motor Fluctuations; Parkinson ’s Disease

1. INTRODUCTION

Parkinson’s disease (PD) is a neurodegenerative disorder

[1], characterized by resting tremor, rigidity or stiffness,

bradykinesia and postural instability [2]. While the eti-

ology of PD remains uncertain [3,4], the progressive loss

of dopaminergic neurons in the substantia nigra (SN) is

considered a marker of the motor disorder of PD [5].

Currently, medication therapy is the most widely used

treatment for PD. Several types of medications have been

approved by the US Food and Drug Administration (FDA)

for the treatment of PD, including levodopa (L-Dopa)/

carbidopa (dopa-decarboxylase inhibitor), rasagiline and

selegiline (monoamine oxidase type B inhibitors, MAOBIs),

entacapone and tolcapone (catechol-o-methyl transferase

inhibitors, COMTIs), ropinirole and pramipexole (non-

ergolin dopamine agonists), and amantadine (which has

both anticholinergic and antiglutaminergic properties)

[6-11].

Levodopa is the most effective and commonly used

medication to control motor symptoms in PD [12]. The

long-term treatment of PD using levodopa, however, has

been shown to induce several adverse effects (AEs). The

most common AEs include motor fluctuations (“on-off”

phenomenon), dyskinesia, and psychosis [8,13]. As a

result, other classes of medication, including COMTIs,

MAOBIs, and dopamine agonists, have been widely used

as alternatives or adjuncts in treating PD [14].

Combination therapy of a MAOBI with levodopa has

been proven to decrease the required dosage of levodopa,

improve symptom relief, and reduce “off” time [8,14-17].

However, the combination of a MAOBI with levodopa

has been observed to cause more frequent AEs than levodopa

monotherapy, including dyskinesia, hypotension, nausea,

dizziness, dry mouth, psychiatric abnormalities, and bal-

ance difficulties [7,8,16,18-20].

The combination therapy of levodopa with a COMTI can

increase levodopa duration of action [21], regulate the

R. Zhang et al. / Advances in Parkinson’s Disease 1 (2012) 5-10

motor fluctuations, and reduce levodopa dose [8,14,22-26].

Adjunct therapy with a COMTI is also associated with

increased frequency of dopaminergic AEs, including

dyskinesia, nausea, postural hypotension, and hallucina-

tions [8,20,24].

There have been some comparative studies involving

MAOBIs and COMTIs. One randomized, double-blinded

trial involving 687 subjects on levodopa compared the

efficacy and safety between the additions of rasagiline

(MAOBI), entacapone (COMTI), or placebo (levodopa

monotherapy), and found that the overall relative fre-

quency of dopaminergic AEs was similar among the

three groups. Rasagiline was, however, better tolerated

with less early-discontinuation than entacapone and pla-

cebo [27]. A meta-analysis study evaluated the efficacy

and safety of MAOBIs or COMTIs as adjunct therapies

with levodopa. It concluded that the efficacy of combina-

tion therapy was superior to monotherapy with levodopa,

but the incidence of dyskinesia was observed to be

higher in both combination therapy groups than with

monotherapy. However, no direct comparison between

the two adjunct therapy groups was reported [20]. A

meta-analysis review study of 44 clinical trials demon-

strated, through indirect comparison of the drugs, more

dyskinesia and higher overall incidence of AEs with

COMTIs than with MAOBIs [14].

Although these studies have been helpful in elucidat-

ing the differences in the safety profiles of these combi-

nation therapies (MAOBI vs COMTI), available data are

too limited to directly compare them. The aim of this

study is to investigate and compare the difference be-

tween the AE profiles of MAOBIs and COMTIs when

used in combination with levodopa for the treatment of

PD.

2. METHODS

Data were taken from “The Boston University Medical

Center’s Parkinson’s Disease and Movement Disorder

Database”, a collection of information acquired from

movement disorder patients seen at the Boston Univer-

sity Neurological Associates Clinic. The data collection

form contains three major sections: demographic infor-

mation, relevant disease information and medications.

The relevant disease information section includes the

neurological diagnosis with onset and diagnosis dates,

family history of related disease, and common complica-

tions of disease/therapy. These include compulsive be-

havior, dyskinesia, dementia, depression, freezing, hallu-

cinations, motor fluctuations, orthostatic hypotension,

psychosis, and other autonomic dysfunction. Subjects

were asked about their current and previous medication

use. In addition, subjects were asked about surgical in-

terventions such as Deep Brain Stimulation (DBS) and

pallidotomy to treat their movement disorders.

To be included in the analysis for this study, subjects

had to meet the following inclusion and exclusion crite-

ria. The subject must have a diagnosis of PD in “The

Boston University Medical Center’s Parkinson’s Disease

and Movement Disorder Database”, and have been be-

tween the ages of 18 and 89. (Subjects who were over 89

years old were excluded in order to meet the privacy

regulation for de-identified data research.) Furthermore,

the subject must have been able to provide medication

information, and have had history of current or prior use

of levodopa combined with a MAOBI but never used a

COMTI, or vice versa. Potential subjects were excluded

if they were diagnosed with any movement disorder

other than PD. Subjects who fit the criteria and who were

entered in the database between January 2007 and Janu-

ary 2011 were included in the final analysis. In addition

to complications and medication use, other variables

were included in the analysis as covariates, including

gender, family history, occupation, ethnicity, education

level, other PD medication use, age, and disease dura-

tion.

Fisher’s exact test was applied to test whether different

AEs were associated with the different PD medications

(MAOBI vs COMTI). Multivariate logistic regression

models were applied to test whether discovered associa-

tions would still exist after controlling for other possible

confounding factors, such as age, disease duration, edu-

cation level, and other PD medication use. Two models

of multivariate logistic regression were applied: general

model (including all the potential covariates) and step-

wise model (only including those covariates with statis-

tical significance with entry criterion p ≤ 0.1 and removal

criterion p > 0.1). Odds ratio (OR) and 95% confidence

interval of OR were calculated to show the strength of

association. To account for occasional missing data in the

database, relative frequency, mean and interquartile

range (IQR) were used to compare distributions of vari-

ous variables in non-missing cohort and sample cohort.

SAS (Statistical Analysis System) 9.1.3, provided by

SAS Institute Inc., was employed to conduct all the data

analysis. Results were considered significant if the two-

tailed p value was < 0.05. This study (H-31069) was de-

termined to be exempt from review by the IRB of Bos-

ton University Medical Campus and Boston Medical

Center.

3. RESULTS

Of the 577 subjects in the database, 87 met all inclu-

sion and exclusion criteria and were included in the data

analysis (Table 1). The reasons for excluding subjects

included: never used a MAOBI or a COMTI (140, 51%),

used both a MAOBI and a COMTI (78, 28%), and were

prescribed a MAOBI or a COMTI without levodopa (58,

21%). In those 87 subjects, 39 took a MAOBI with

R. Zhang et al. / Advances in Parkinson’s Disease 1 (2012) 5-10 7

levodopa currently or previously, and the remaining 48

subjects took a COMTI with levodopa currently or pre-

viously (Ta b l e 2 ). In the MAOBI group, an equal num-

ber of subjects took rasagiline and selegiline, in com-

parison with the COMTI group, where the majority took

entacapone (37 out of 47) and only 10 subjects took tol-

capone. In the study cohort, 57% of the subjects were male,

and the majority of subjects were Caucasian (91%), which

is consistent with the incidence disparity of PD in the gen-

eral population [28,29].

Of the 10 recorded AEs, the most frequent was dyski-

nesia (59%), and the least frequent was psychosis (4.6%)

(Figure 1). In this sample cohort, 16 (18%) subjects did

not experience any of the recorded AEs. However, 43%

of subjects were reported to have 3 or more AEs and as

many as 8 AEs were reported in one subject (Table 3).

Table 1. Demographic characteristics of categorical variables

in sample cohort (N = 87).

Items Category Frequency N (%)

Female 37 (43)

Gender

(N = 86) Male 49 (57)

Yes 28 (32)

Family History

(N = 87) No 59 (68)

Yes 66 (76)

Other PD medications1

(N = 87) No 21 (24)

Caucasian 78 (91)

Ethnicity

(N = 86) others 8 (9)

Not in the Labor Force 59 (71)

Occupation

(N = 83) Others 24 (29)

Public insurance 45 (58)

Insurance

(N = 77) Private insurance 32 (42)

Below college 26 (32)

College or associate degree 32 (40)

Education

(N = 81)

Graduate or Professional 23 (28)

No AE 16 (18)

1 AE 12 (14)

2 AEs 22 (25)

AEs2

(N = 87)

≥3 AEs 37 (43)

1Other PD medications included anticholinergics, apomorphine, amantadine,

botulinum toxin, dopamine agonists. 2AEs included compulsive behavior,

hallucinations, dyskinesia, motor fluctuations, dementia, orthostatic hy-

potension, depression, other autonomic dysfunction, freezing and psychosis.

Table 2. MAOBI and COMTI medication distributions in sam-

ple cohort.

Combined medication

(N = 87)

Frequency

N (%)

Medication

(N = 85)*

Frequency

N (%)

Rasagiline 19 (22)

MAOBI 39 (45)

Selegiline 19 (22)

Entacapone 37(43)

COMTI 48 (55)

Tolcapone 10 (11)

*Excluded 1 subject, who had taken both entacapone and tolcapone and 1

subject, who had both taken rasagiline and selegiline.

Figure 1. Relative frequency of ten recorded adverse effects.

Table 3. Distributions of adverse effects in MAOBI and

COMTI groups.

AEs CategoryMAOBI N (%) COMTI N (%)p

Yes 3 (8) 2 (4)

Compulsive

behavior No 36 (92) 46 (96) 0.65

Yes 8 (21) 18 (38)

Hallucinations No 31 (80) 30 (63) 0.10

Yes 23 (59) 28 (58)

Dyskinesia No 16 (41) 20 (42) 1.00

Yes 17 (44) 30 (63)

Motor

fluctuations No 22 (56) 18 (38) 0.09*

Yes 2 (5) 16 (33)

Dementia No 37 (95) 32 (67) 0.0012**

Yes 5 (13) 9 (19)

Orthostatic

hypotension No 34 (87) 39 (81) 0.56

Yes 7 (18) 9 (19)

Depression No 32 (82) 39 (81) 1.00

Yes 2 (5) 7 (15)

Other

autonomic

dysfunction No 37 (95) 41 (85) 0.18

Yes 5 (13) 12 (25)

Freezing No 34 (87) 36 (75) 0.18

Yes 2 (5) 2 (4)

Psychosis No 37 (95) 46 (96) 1.00

No AE9 (23) 7 (15)

1 AE 7 (18) 5 (10)

2 AEs10 (26) 12 (25)

Combined AEs

≥3 AEs13 (33) 24 (50)

0.37

*Fisher’s exact test p < 0.1; **Fisher’s exact test p < 0.05.

R. Zhang et al. / Advances in Parkinson’s Disease 1 (2012) 5-10

Using Fisher’s exact test to compare the AE profiles of

the different combination treatments, only the frequency

of dementia was found to be statistically significantly

different between the MAOBI and COMTI groups (p =

0.0012, Table 3): subjects who took a COMTI with

levodopa had a higher relative frequency of dementia

compared to subjects who took a MAOBI (33% versus

5%). Motor fluctuations also showed a different distribu-

tion between the two medication groups (p = 0.09): the

COMTI subjects had a higher relative frequency of mo-

tor fluctuations than the MAOBI subjects (63% versus

44%). The differences of relative frequency of other AEs

between the two groups were not statistically significant

in the sample cohort (Table 3).

As subjects could not be randomized as part of this

study design, the distributions of other potential con-

founding factors were compared with available informa-

tion in the database and were included in multivariable

logistic regressions.

Two multivariable logistic models were applied to test

the association between dementia and PD medication

use. Only those subjects with complete data were re-

tained in the analysis (n = 61). The stepwise model only

contained those variables with at least p = 0.1 signifi-

cance level.

Variables of treatment (MAOBI or COMTI) and age

were retained in the stepwise logistic regression model.

The OR of developing dementia was 6.9 (COMTI vs

MAOBI, 95% CI: 1.3 - 37.0).

Based on the general logistic regression model, which

included all of the potential confounding factors with

recorded information, the OR of developing dementia

was 8.0 (COMTI vs MAOBI, 95% CI: 1.2 - 52.6), marking

an increase from 6.9 in the stepwise model. This indi-

cated that after controlling for the potential confounding

factors, the association between dementia and COMTI

was still statistically significant.

Multivariable logistic models were also employed to

test the association between PD medication use and mo-

tor fluctuations. In the stepwise model, with at least p =

0.1 significance level, 2 variables, treatment of MAOBI

or COMTI, and disease duration, were retained in step-

wise logistic regression model. The OR of developing

motor fluctuations was 3.1 (COMTI vs MAOBI, 95% CI:

1.0 - 9.8, p = 0.05). The stepwise statistical model also

suggested that, for a PD subject treated with MAOBI

combination therapy with an average disease duration of

10 years, the probability of experiencing motor fluctua-

tions was 44.8% compared to 71.1% in a similar subject

treated with COMTI combination therapy.

After taking into account all of the potential con-

founding factors with available information in general

regression analysis, the OR of developing motor fluctua-

tions was 3.7 (COMTI vs MAOBI, 95% CI: 1.01 - 13.8),

indicating that the association between motor fluctua-

tions and COMTI became stronger and statistically sig-

nificant after controlling for the potential confounding

factors. Twenty-six subjects were removed from the lo-

gistic regression models because data were incomplete.

Upon examination of the distribution of all testing vari-

ables, no major differences were observed in the two

groups, and all the variables were similarly distributed

between non-missing data cohort and sample cohort.

4. DISCUSSION

Results from other studies have indicated that com-

pared to levodopa monotherapy, MAOBI and COMTI

adjunct therapies increase therapeutic effects, reduce

levodopa dose, and are more effective in controlling mo-

tor fluctuations [8,14,16,21-23]. However, the combined

therapies have also been associated with more frequent

AEs, especially dyskinesia [8,14,20]. Despite the wide

use of these medication regimens, few studies have di-

rectly and systematically compared their AE profiles, as

this one has. The results are interesting and incite further

questions and ideas for future prospective comparative

trials.

Based on the results of Fisher’s exact test, out of the

10 recorded complications analyzed, only dementia

showed a statistically significant difference among pa-

tients on MAOBI and COMTI combination therapies

with levodopa. Patients on COMTI had a higher relative

frequency of dementia than patients on MAOBI (33% vs

5%) (Table 3).

There are various estimates of the prevalence of de-

mentia (8% - 93%) in PD patients. Cognitive difficulties

can greatly impact the PD treatment plan and influence

the quality of life of PD subjects [30]. In the current

sample cohort, the subjects on COMTI were slightly

older than the MAOBI group; the middle 50% percent of

subjects were 60 - 77 years old in the COMTI group,

versus 59 - 74 years old in the MAOBI group. Since age

is known to be an important risk factor for dementia

[31,32], this difference could slightly impact the associa-

tion of the medications with dementia found in the cur-

rent study. The logistic regression model took the sub-

ject’s age into account. The OR age was 1.1 in the step-

wise logistic regression model, which indicated that, with

an increase of 1 year in age, the risk of dementia would

increase 10%, regardless of the treatment group.

Severity of motor symptoms is also considered to be a

risk factor for dementia [30,31]. This, however, cannot

be estimated using the current database. The Hoehn and

Yahr stage information was only collected for some sub-

jects to record the severiy of PD, and only 25 out of 87

(29%) subjects had an “off” Hoehn and Yahr score, and

therefore provides limited information.

Motor fluctuations, also known as deterioration at the

R. Zhang et al. / Advances in Parkinson’s Disease 1 (2012) 5-10 9

end of a dose or wearing-off, consist of fluctuations be-

tween “on” and “off” states. They are prevalent in long-

term PD patients and appear to be an inevitable outcome

of levodopa treatment [33]. In our sample cohort, 54% of

subjects had motor fluctuations. This proportion was

higher in the group on combination treatment with a

COMTI compared to the group treated with an MAOBI

(63% vs 44%, p = 0.09) (Table 3).

Because motor fluctuations increase with the progres-

sion of PD and long-term usage of levodopa, disease

duration should be considered a risk factor for these

fluctuations. In this study, disease duration was signifi-

cantly associated with motor fluctuations with an OR of

1.2 (p < 0.05). This suggests a 20% increase in the risk of

motor fluctuations for every 1 year after the diagnosis of

the disease.

Both COMTI and MAOBI combination regimens with

levodopa have been found to reduce “off” time and mo-

tor fluctuations [8,14-17,22-24]. Our study showed that

COMTI subjects had a higher relative frequency of mo-

tor fluctuations with an OR of 2.2 in the single variable

model (95% CI: 0.9 to 5.1). This association became

significant and stronger (OR = 3.7) after controlling for

confounding factors. These results suggest that compared

to COMTI combination therapy, MAOBI combination

therapy may be better able to control motor fluctuations.

This study relied on available data in the movement

disorders database, which occasionally lacked specific

data points. The current and previous medication use had

to be taken into account as a factor over time. In this

study all AEs included both side effects from medication

and symptoms/signs of the underlying illness; we were

therefore unable to specifically link the causality be-

tween a specific AE and PD medication.

The study design did not allow subjects to be random-

ized into medication groups, which would have ensured

that they were comparable at baseline with respect to

confounding factors. To control for this, we applied mul-

tivariable logistic regression models, which incorporated

potential confounding factors.

5. CONCLUSION

Based on the available data, combination therapy with

a COMTI combined with levodopa was more likely to be

associated with dementia and motor fluctuations than a

MAOBI combined with levodopa in PD patients. Physi-

cians pay close attention to side effect profiles when

prescribing medications. These study results may impact

decision making related to PD medication choice in pa-

tients with concomitant dementia or motor fluctuations.

Prospective head to head trials would be useful to further

assess the significance of these adverse effects in vul-

nerable populations.

6. ACKNOWLEDGEMENTS

This work did not receive outside financial support. A. D. Hohler

wishes to disclose that she is currently on the speaker’s bureau for

TEVA pharmaceuticals. The remainder of the authors has no conflicts

of interest to disclose.

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