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Special Report


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.