A Closer Look at COMT Inhibitors: Helping Levodopa Get to Where It’s Needed

For many years, Levodopa has been the “gold standard” for treating Parkinson’s symptoms, and many people find it very effectively manages many of their Parkinson’s symptoms. But  levodopa is not without potential complications. For example, stomach upset, including nausea and sometimes vomiting, is common with levodopa taken in isolation, so levodopa is taken with a “helper” drug, called carbidopa, which eases this effect. 

Carbidopa is not the only levodopa “helper.” Researchers have spent years developing and testing other medications that might make levodopa more effective and reduce its side effects. One class of “helpers” is the category of medications known as catechol-o-methyl transferase inhibitors, better known as COMT inhibitors, which can impact motor symptoms by reducing your OFF time. 

Why Levodopa Needs ‘Help’ and How COMT Inhibitors Provide It 

Before we take a closer look at COMT inhibitors, it may help to understand more about why companion medications are prescribed with levodopa generally. 

Dopamine, a chemical found in the brain, is important for regulating your movement body movements, and people with Parkinson’s don’t have enough of it. Levodopa eases your Parkinson’s symptoms because it can be converted to dopamine in the brain, but it has to get there first, and it’s a long way from the gut, where your levodopa pill ends up after you swallow it, to the regions of the brain that control movement. 

Drugmakers have developed different types of medication to make levodopa’s journey from the gut to the brain as smooth as possible. Selective MAO-B inhibitors (rasagiline, selegiline, and safinamide) are one class of medications that do this, and COMT inhibitors are another. 

Researchers discovered COMT—catechol-o-methyl transferase—in the late 1950s. COMT, which is found in the intestines, liver, and throughout the nervous system, contributes to the breakdown of dopamine. Because people with Parkinson’s have too little dopamine, researchers developed a way to decrease COMT’s activity to help treat Parkinson’s. COMT inhibitors are not used in isolation as a treatment for Parkinson’s. 

COMT Inhibitors Today 

COMT inhibitors can decrease OFF time for people with Parkinson’s. COMT inhibitors may also contribute to more predictable patterns in your medication effectiveness. These pattern help your care team to make different decisions about the dosage and timing of your levodopa to further improve your response to symptoms. You may, for example, be able to hold off on higher doses of levodopa if a COMT inhibitor makes the levodopa dose you’re takes now works longer. 

There are three COMT inhibitors on the market in the United States, accounting for four drug formulations: 

• Entacapone (Comtan® in the US) tablets have been approved in the US since 1999 and are often the first COMT inhibitor a person with Parkinson’s will be prescribed. It is taken at the same time as your carbidopa/levodopa, each time. In addition to dyskinesia, commonly reported adverse effects of entacapone include discolored (orange, reddish or brown) urine as well as diarrhea; it has sometimes interfered with impulse control. 
• Carbidopa/levodopa/entacapone (Stalevo® in the US), available since 2003, is simply carbidopa/levodopa combined with entacapone in a single tablet. 
• Opicapone (Ongentys® in the US), the most recently approved (2020) COMT inhibitor for people with Parkinson’s, is taken once daily by capsule. It is often prescribed for its convenience or if entacapone has not produced the desired effects. 
• Tolcapone (Tasmar® in the US) is a tablet that has been available for some time as an alternative to entacapone, but it is associated with rare but serious side effects on the liver. Today, it is prescribed only when other COMT inhibitors have not worked and when the risk of liver damage has been thoroughly assessed. 

The most recent research on COMT inhibitors typically centers on opicapone, the newest COMT inhibitor. For example, a phase IV study in South Korea, the ADOPTION study, explored whether an additional dose of levodopa or opicapone resulted in less OFF time. In this study, adding 50 mg of opicapone resulted in a ~45 minute reduction in OFF time compared to adding an additional 100 mg dose of levodopa. While dyskinesia was more common with opicapone 50 mg than with an additional levodopa dose, the dyskinesia was not considered troublesome by participants who experienced it.

Additionally, a study published in January 2025 study found opicapone improved motor impairment without bringing on motor complications in people with early-stage Parkinson’s. The study saw a “significantly greater proportion of patients who self‐reported an improvement in their condition relative to baseline.” 

An important consideration may be cost. As the newest drug in this class and one that is available only in its brand-name form (Ongentys), opicapone is significantly more expensive than entacapone.  

Alternatives, Risks, and Side Effects 

Since COMT inhibitors are intended to improve levodopa uptake and prolong levodopa’s effects, the side effects of levodopa, such as dyskinesia, may come into play.  

A 2021 study compared the effects of the three most common add-on Parkinson’s therapies: COMT inhibitors, MAO-B inhibitors and dopamine agonists. This study aimed to compare the effects of the different classes of drugs.  

Key takeaways from this study: 

• Dopamine agonists yielded statistically slightly better mobility scores than the inhibitors as a group. These differences were so small that they were not scientifically meaningful, but you might want to know about them. 
• A small, but more meaningful, difference was seen in quality-of-life outcomes, with MAO-B inhibitors performing a little better than COMT inhibitors. 
• The study compared reasons why people discontinued use of the medication they were on. For dopamine agonists and MAO-B inhibitors, reasons for discontinuing use were more likely to be psychiatric. For COMT inhibitors, gastrointestinal impacts were more likely to contribute to discontinuation. 
• The study was not able to assess differences across different racial or ethnic groups. 

One more note for some readers: an analysis published in 2023 flagged considerations regarding COMT inhibitors that are specific to those receiving levodopa/carbidopa by pump. 

OFF Time Can Be Difficult, But There are Multiple Options to Help 

The medications described in this post are not the only options you might consider to help.  For example, three medications were also recently approved for use in the US: Crexont® (an oral capsule of extended-release carbidopa/levodopa), Onapgo™ (a continuous infusion apomorphine formulation), and Vyalev™ (a continuous infusion foscarbidopa/foslevodopa formulation). So keep in mind that COMT inhibitors are one option that may help improve effectiveness of levodopa and decrease OFF time, but they may not be the best choice for you.  

If you experience troublesome OFF times or motor fluctuations where your medication doses have less reliable effects on your symptoms, talk with your care team bout whether a medication addition or change would be best for you. As we described above, there are multiple different options you may be able to try.  

ADDITIONAL RESOURCES 

Entacapone (Comtan) Prescribing Information 

Carbidopa/levodopa/entacapone (Stalevo) Prescribing Information 

Opicapone Prescribing Information 

Tolcapone Prescribing Information 

On the History of COMT Inhibitors 

Parkinson’s Podcast Episode about OFF