The Use of COMT Inhibitors in Older Patients
by Cheryl Waters, M.D., F.R.C.P.(C), and Anne Constantino, M.D.
| Geriatric Times |
 |
March/April 2001 |
|
Vol. II |
|
Issue 2 |
Catechol-O-methyltransferase (COMT) inhibitors are a new class of drugs that
provide an alternate therapeutic option to patients with Parkinson's disease
(PD) (Figure). They are most useful for
"wearing-off" (end-of-dose deterioration) motor fluctuations and are used in
conjunction with levodopa. Tolcapone (Tasmar) and entacapone (Comtan) are two
well-studied COMT inhibitors. Side effects of COMT inhibitors include
dyskinesias, hallucinations, diarrhea, hypotension and urine discoloration.
With tolcapone, liver toxicity is also a possible side effect, limiting its
use.
To understand the function of the COMT inhibitors, it is important to
discuss the pharmacology of levodopa.
Levodopa as the Gold Standard
The motor symptoms of PD are due to dopamine deficiency. Dopamine
replacement by levodopa improves some of the motor functions, such as
bradykinesia, that impact activities of daily living. Levodopa is transported
across the small intestine by the aromatic and branched L-chain amino acid
system. It is then decarboxylated to dopamine in the periphery so only about 1%
crosses the blood-brain barrier and reaches the striatal neurons.
Carbidopa, a peripheral inhibitor of dopa decarboxylase, is given together
with levodopa to prevent decarboxylation in the periphery and thus increases
the amount of unmetabolized drug that can cross the blood-brain barrier.
Carbidopa also reduces the side effects of levodopa, which include nausea and
vomiting, postural hypotension, and cardiac arrhythmias. Levodopa is the
preferred initial therapy for older patients with PD because of the propensity
of other drugs to cause more central side effects.
COMT is the second enzyme involved in the metabolism of levodopa to produce
3-O-methyldopa (3-OMD). The COMT inhibitors lengthen the duration of action of
levodopa by inhibiting its conversion to 3-OMD. This increases the
bioavailability of levodopa in the circulation, allowing a larger amount of the
drug to cross the blood-brain barrier. The COMT inhibitors are always given
with levodopa.
In order to clearly define the indications of COMT inhibitors, the motor
complications of PD should be understood (Table
1). The most common of these complications is the wearing-off
phenomenon. This occurs because of the increase in dopamine neuronal loss and
the inability of remaining neurons to store dopamine. The symptoms of wearing
off include recurrence of parkinsonian symptoms-pain, autonomic features,
shortness of breath, confusion and panic. The patient can also fluctuate
between an "on" state, when the plasma levodopa concentration controls the
symptoms, and an "off" state, which is related to plasma levodopa decline.
Other motor complications worth mentioning are dyskinesias or dystonia. The
presence of dyskinesia indicates a change in the striatal bioavailability of
levodopa. Fluctuating levels of levodopa are associated with motor
complications, and prolonging the duration of each dose of levodopa to a more
consistent level may be achieved by several strategies. These include
increasing the amount or frequency of levodopa administered, using a
controlled-release preparation, using a monoamine B inhibitor, or using a COMT
inhibitor (Table 2).
COMT Inhibitors
The two available COMT inhibitors are most useful for wearing-off motor
fluctuations and are compared in Table 3.
Both drugs were found to reduce fluctuations in plasma levodopa levels, thereby
lowering patients' daily levodopa requirements while increasing their "on"
time.
Pharmacological studies of entacapone show that it prolongs the elimination
half-life of levodopa by 56%, thus extending the percentage of days "on." Side
effects include dyskinesias and diarrhea (Ruottinen and Rinne, 1996). A
multicenter, placebo-controlled, randomized, 24-week study of 205 patients
conducted by the Parkinson Study Group (1997) showed that the "on" time was
increased by 5% (approximately one hour per day), and the Unified Parkinson's
Disease Rating Scale (UPDRS) score improved by 10% at week 24 in patients
taking entacapone.
Levodopa requirements were also reduced by an average of 100 mg/day. When
entacapone was withdrawn, the beneficial effects of the drug were rapidly lost.
Adverse reactions included dyskinesias (which were reported most frequently
during the first eight weeks), urine discoloration, dizziness, nausea and
constipation. The Nordic Study Group had similar results, with an increase in
daily "on" time of 1.3 hours (Rinne et al., 1998).
Patient Selection Criteria
The indications for use of COMT inhibitors are for patients with simple
wearing-off phenomena. Patients with PD who have cognitive problems, especially
those in nursing homes, may benefit from COMT inhibitors if motor fluctuations
occur.
Case 1: A 64-year-old man who has had PD for four years has been on
levodopa/carbidopa 100 mg/50 mg (1.5 tabs) three times a day at 6 a.m., noon
and 5:30 p.m. He develops wearing-off fluctuations for 1.5 hours between doses.
This patient is a candidate for entacapone, whichcan be given three times daily
together with the levodopa/carbidopa medication. Most patients at this stage
will respond. Side effects are uncommon, and the adjustment of the levodopa
dosage is not necessary.
COMT Inhibitors in the Elderly
The COMT inhibitors have the potential to increase the dopaminergic adverse
events in patients receiving levodopa. A number of patients treated with COMT
inhibitors develop peak-dose dyskinesias, nausea or hallucinations. Although
studies show that COMT inhibitors are well-tolerated, in clinical trials of
tolcapone there was a need to decrease the dose of levodopa if the daily
levodopa dose was more than 600 mg or if moderate to severe dyskinesias were
present before beginning tolcapone treatment (Rajput et al., 1997). The average
reduction in daily levodopa dose was 30%.
Case 2: A 60-year-old man who has had PD for 10 years has presented
with wearing-off fluctuations and moderate peak dose dyskinesias. His
levodopa/carbidopa dosage is 100 mg/25 mg, 1.5 tabs four times daily,
pramipexole (Mirapex) 0.5 mg tid and selegiline (Eldepryl) 5 mg bid. Although
this patient may benefit from a COMT inhibitor, he will have an increase in
dyskinesia. The patient should be forewarned before starting the medication
that the dyskinesias might worsen and, if this occurs, he may have to reduce
the dose of levodopa to one tablet four times daily. Another dopamine agonist
might also be used.
The nondopaminergic side effects of tolcapone include diarrhea, which was
the most frequent reason given for patients' withdrawal from long-term trials.
The other serious adverse event that occurs between six to 12 weeks after the
start of tolcapone is the elevation of alanine aminotransferase and aspartate
aminotransferase, with three times the normal elevation. Enzyme levels return
to normal in two to four weeks without adverse events, although three deaths
from acute fulminant hepatic failure have been reported in association with the
use of tolcapone. The mechanism of toxicity is thought to be mitochondrial
dysfunction. Prescribing requirements include liver-function testing before
starting the drug and monitoring every two weeks for one year and every four
weeks for six months and every two months for the lifetime of the patient.
Rhabdomyolysis can also occur and, thus, the drug is not used in patients
with severe dyskinesias. Entacapone has been documented to cause hypotension,
benign urine discoloration, constipation and diarrhea (Parkinson Study Group,
1997). No liver toxicity has been reported.
Conclusion
The COMT inhibitors are adjunctive agents for PD that prolong the duration
and action of levodopa by inhibiting peripheral COMT, thus decreasing
metabolism of levodopa. They are indicated mainly for wearing-off phenomena and
for increasing the patients' "on" time. Dopaminergic side effects that occur
with the use of COMT inhibitors usually can be reduced or eliminated by
decreasing the levodopa dose.
Dr. Waters is professor of clinical neurology at Columbia University,
specializing in research and care of patients with Parkinson's disease.
Dr. Constantino is a fellow in the Division of Movement Disorders at
Columbia University.
References
Parkinson Study Group (1997), Entacapone improves motor fluctuations in
levodopa-treated Parkinson's disease patients. [Published erratum appears in
44(2):292.] Ann Neurol 42(5):747-755 [see comments].
Rajput AH, Martin W, Saint-Hilaire MH et al. (1997), Tolcapone improves
motor function in parkinsonian patients with the "wearing-off" phenomenon: a
double-blind, placebo-controlled, multicenter trial. Neurology
49(4):1066-1071.
Rinne UK, Larsen JP, Siden A, Worm-Petersen J (1998), Entacapone enhances
the response to levodopa in parkinsonian patients with motor fluctuations.
Nomecomt Study Group. Neurology 51(5):1309-1314.
Ruottinen HM, Rinne UK (1996), Entacapone prolongs levodopa response in a
one month double blind study in parkinsonian patients with levodopa related
fluctuations. J Neurol Neurosurg Psychiatry 60(1):36-40.
Waters CH (1997), Managing the late complications of Parkinson's disease.
Neurology 49(1 suppl 1):S49-S57.
Waters CH (1999), Diagnosis and Management of Parkinson's Disease, 2nd ed.
Caddo, Okla.: Professional Communications Inc.