The Role of COMT and Neurotransmitters
Catechol-O-methyltransferase (COMT) is a naturally occurring enzyme in the body responsible for breaking down catecholamines, which are neurotransmitters like dopamine, norepinephrine, and epinephrine. In the context of Parkinson's disease, COMT is of particular interest because it also metabolizes levodopa, the most effective drug for treating Parkinson's symptoms. Without intervention, COMT and another enzyme called AADC (aromatic L-amino acid decarboxylase) degrade a significant portion of levodopa before it can cross the blood-brain barrier and be converted into dopamine.
Parkinson's disease is characterized by the loss of dopamine-producing neurons in the brain, leading to motor symptoms such as tremors, rigidity, and bradykinesia (slowness of movement). The primary strategy for treating these symptoms is to replenish dopamine levels in the brain using levodopa. To maximize levodopa's effectiveness, it is typically administered with carbidopa, an AADC inhibitor, to reduce its peripheral breakdown. However, the effect of levodopa can still wear off between doses, leading to motor fluctuations or 'OFF' time.
How COMT Inhibitors Work
A COMT inhibitor is a medication that blocks the action of the COMT enzyme, primarily in the periphery (outside the brain). By doing so, it effectively reduces the breakdown of levodopa, allowing more of the drug to reach the brain. This results in several therapeutic benefits for Parkinson's patients:
- Prolonged Levodopa Effect: The half-life of levodopa is extended, leading to more stable plasma levels of the drug.
- Reduced 'OFF' Time: Patients experience less time with worsened motor symptoms as the levodopa's effects are sustained for longer.
- Increased 'ON' Time: This directly translates to more time where symptoms are well-controlled and movement is smoother.
- Lower Total Levodopa Dosage: In some cases, the enhanced effectiveness of levodopa allows for a reduction in the total daily dose, which can help manage levodopa-related side effects like dyskinesia.
COMT inhibitors do not have a direct symptomatic effect on their own. They must be used as an adjunct therapy in combination with levodopa and carbidopa.
Comparison of Common COMT Inhibitors
| Feature | Entacapone (Comtan) | Opicapone (Ongentys) | Tolcapone (Tasmar) |
|---|---|---|---|
| Dosing Frequency | Taken with every dose of carbidopa/levodopa | Once daily at bedtime | Typically three times daily |
| Site of Action | Peripherally selective | Peripherally selective | Acts both peripherally and centrally |
| Liver Toxicity | Not associated with hepatotoxicity | Not associated with hepatotoxicity | Rare but potentially lethal hepatotoxicity risk |
| Monitoring | No routine liver function test (LFT) monitoring required | No routine LFT monitoring required | Requires regular LFT monitoring |
| Clinical Use | Most commonly prescribed, often first-line adjunctive therapy | Approved in 2020, offers convenience with once-daily dosing | Used as a last resort due to liver risk, if others fail |
Key Considerations and Side Effects
The most common side effects associated with COMT inhibitors are typically related to the increased dopaminergic stimulation in the brain. As more levodopa is converted to dopamine, this can lead to new or enhanced side effects.
Potential Side Effects:
- Dyskinesia: Involuntary, uncontrolled movements are a common side effect of increased dopamine activity and may require a reduction in the levodopa dose.
- Gastrointestinal Issues: Diarrhea and nausea are frequent complaints, and diarrhea is a common reason for discontinuation.
- Urine Discoloration: Entacapone and tolcapone can cause harmless, orange-brown urine discoloration.
- Orthostatic Hypotension: Dizziness or lightheadedness when standing up due to low blood pressure.
- Hallucinations and Confusion: These psychiatric side effects can occur with heightened dopamine levels.
Interactions with other Medications:
- MAO-B Inhibitors: While both COMT and MAO-B inhibitors are used in Parkinson's, they work differently. COMT inhibitors extend the duration of levodopa's effect, whereas MAO-B inhibitors prevent the breakdown of dopamine in the brain. Combining them requires careful management to avoid excessive dopaminergic stimulation and potential side effects.
- Dietary Iron: Iron supplements can reduce the absorption of entacapone. It is often recommended to take iron 2-3 hours before or after an entacapone dose.
The Importance of the Right Treatment
Choosing the correct medication and dosage is a complex process that depends on the individual patient's symptoms, overall health, and response to treatment. For many years, entacapone has been the standard for COMT inhibition. The introduction of opicapone offers a convenient once-daily alternative, which can improve adherence for patients. Tolcapone remains an option, but its use is limited to situations where other treatments are ineffective due to its rare but serious liver risks.
Conclusion
In conclusion, a COMT inhibitor is a vital class of medication that significantly improves the effectiveness of levodopa therapy for people with Parkinson's disease. By inhibiting the enzyme that breaks down levodopa, these drugs help manage motor fluctuations and prolong the time patients experience good symptom control. The choice between entacapone, opicapone, and tolcapone depends on the patient's clinical profile, weighing factors such as dosing convenience and risk of side effects. For patients experiencing troublesome 'OFF' times, adding a COMT inhibitor to their treatment regimen can be a highly effective strategy to improve their quality of life. As always, medication decisions should be made in close consultation with a healthcare team to determine the most appropriate course of treatment. The Davis Phinney Foundation offers additional resources for people living with Parkinson's disease and their families.
