COMT inhibitors: Uses, common brands, and safety info

Dopamine is a neurotransmitter that helps the brain function properly. Many people recognize it for its role in creating feelings of pleasure and reward. However, it has many other important functions, such as helping our brain communicate with our muscles. Recently, scientists have hypothesized that dopamine can directly influence voluntary movement through nerves in the motor cortex of the brain. Furthermore, scientists believe that depletion of dopamine in the midbrain causes movement disorders in patients with Parkinson’s Disease. A class of drugs called COMT inhibitors was developed to increase dopamine levels in Parkinson’s Disease patients. This article will discuss how COMT inhibitors work, describe their common side effects, outline important safety points.

What are COMT inhibitors?

Catechol-o-methyltransferase inhibitors, or COMT inhibitors for short, were developed during the 1990’s to aid in the treatment of Parkinson’s disease. The motor symptoms associated with Parkinson’s Disease, such as tremors, muscle rigidity, slow movement, and gait and balance problems occur when certain neurons in the brain deteriorate. These neurons are called dopaminergic neurons because they supply dopamine to certain areas of the brain, such as the substantia nigra. 

Dopamine released by these cells play an important role in controlling movement and coordination. Thus, treatment for Parkinson’s Disease has largely focused on restoring dopamine to this area of the brain. The drug levodopa is the most effective agent for restoring dopamine to the substantia nigra and is the primary treatment for Parkinson’s Disease. In fact, it has been the primary agent for treating Parkinson’s disease for over 40 years. One issue with levodopa is that its effectiveness wears off. A new class of drugs, called COMT inhibitors, were developed to prolong the effectiveness of levodopa. Therefore, COMT inhibitors are always used as an adjunct therapy, meaning their purpose is to assist a primary treatment. They are never used alone to treat Parkinson’s Disease.

How do COMT inhibitors work?

COMPT inhibitors prevent the breakdown of levodopa, a naturally occurring amino acid that gets converted into dopamine. Levodopa can be synthesized in a lab and is commonly used as a treatment for Parkinson’s Disease. Dopamine cannot be administered as a treatment because it does not cross the blood-brain barrier, so it would not reach the intended site of action within the brain. Levodopa can travel from the bloodstream to the brain, where it is then converted into dopamine. However, some of the administered levodopa breaks down in the body before it can reach the brain. COMT is the primary enzyme that breaks down levodopa, thus inhibiting it increases the amount of levodopa available to the central nervous system. COMT inhibitors must be used in combination with the drug levodopa to have any benefit.

What are COMT inhibitors used for?

• Parkinson’s Disease

Currently, the only known application of COMT inhibitors is in the treatment of Parkinson’s Disease. COMT inhibitors are not prescribed as part of an initial treatment for Parkinson’s Disease. Carbidopa/levodopa is typically used as the initial treatment, although dopamine agonists such as Mirapex may also be used as initial treatment, usually among patients younger than sixty years old. Wearing-off usually occurs after a couple of years, with 80% of patients experiencing wearing-off within four years of starting initial therapy. According to multiple studies, wearing-off is more likely among patients who develop Parkinson’s Disease at a younger age.

Who can take COMT inhibitors?

Can children take COMT inhibitors?

COMT inhibitors are approved by the U.S. Food and Drug Administration (FDA) for adult use only. COMT inhibitors have not been studied in children. The safety and efficacy of COMT inhibitors have not been established in pediatric patients.

Can adults take COMT inhibitors?

COMT inhibitors are typically prescribed to adults who have experienced a “wearing-off” of initial treatment effects, meaning their initial treatment is no longer working as well to control the motor symptoms of Parkinson’s Disease. Since COMT inhibitors are never used as an initial treatment, adults will not take them until they have been on carbidopa/levodopa for a few years. Every patient will experience wearing-off at some point in their treatment, however, not all patients experience wearing-off as early as others. Younger patients with Parkinson’s Disease may be prescribed dopamine agonists as an initial treatment before eventually adding levodopa. This may delay the need for COMT inhibitors. However, since wearing-off is more prevalent among patients with younger-onset Parkinson’s Disease, adults who develop the disease before sixty are more likely to require COMT inhibitors.

Can seniors take COMT inhibitors?

Parkinson’s Disease is primarily a disease that occurs late in life. The average age of diagnosis is 60 years old. Therefore, all treatments for Parkinson’s Disease are safe for use in the elderly. However, there may be certain side effects or risks that are more pronounced in older patients. For example, patients older than 75 years are more likely to develop hallucinations when using Tasmar. Older patients are also more likely to have kidney or liver impairment that necessitates dose adjustments or discontinuation of COMT inhibitors.

Can women who are pregnant or breastfeeding take COMT inhibitors?

The FDA has assigned all COMT inhibitors with a pregnancy risk of “Category C.” There is not enough data from human studies to determine the developmental risks associated with COMT inhibitor use during pregnancy. However, animal studies suggest the possibility of fetal harm, although animal reproduction studies are not always predictive of human response. Animal studies demonstrated an increase in birth defects resulting from Tasmar. Entacapone demonstrated an increased risk of abortions, decreased fetal weight, and birth defects when studied in animals. Ongentys (opicapone) demonstrated an increase in structural abnormalities at all doses when tested in rabbits. Finally, all COMT inhibitors must be used with levodopa, which is known to cause fetal malformations in rabbits. Because it is unknown how these studies translate to human response, COMT inhibitors should only be used during pregnancy when a doctor determines the potential benefits justify the possible risks to the fetus.

Are COMT inhibitors safe?

Recalls

There have been no recent recalls of any COMT inhibitors.

Restrictions

COMT inhibitors should never be taken with a class of drugs called monoamine oxidase inhibitors (MAOIs). Examples include phenelzine, tranylcypromine, and others. The only exceptions are the MAO-B inhibitors, which selectively target monoamine oxidate Type B. These include selegiline (Eldepryl, Zelapar) and Rasagiline (azilect). Using COMT inhibitors with any other MAO inhibitors can result in life-threatening increases in blood pressure. Patients must wait two weeks after stopping MAOIs before starting therapy with COMT inhibitors.

A black box warning, or “boxed warning,” is an FDA warning to alert consumers about serious or life-threatening side effects the drug may have. These are found on the package insert for prescription drugs, this is the most serious warning given by the FDA. The only COMT inhibitor that carries a black box warning is Tasmar. The warning is listed below:

Tasmar: Use of Tasmar (tolcapone) increases the risk of hepatic (liver) failure which may be fatal. It should only be used for patients on levodopa/carbidopa who have motor symptoms that cannot be treated by an alternative adjunct treatment. Stop using tolcapone if there is no clear benefit after three weeks. Avoid use in patients with liver disease or elevated liver enzymes, and do not continue use if liver enzymes are greater than twice the upper limit of normal (ULN). Monitor liver enzymes every two to four weeks for six months following imitation or a dose increase. If treatment must be stopped due to liver injury risk, do not restart therapy.

Tasmar is also contraindicated in patients with a history of nontraumatic rhabdomyolysis (breakdown of muscle tissue) or very high fever (hyperpyrexia) and confusion that was possibly caused by any medication.

While Tasmar is contraindicated in patients with liver dysfunction, other COMT inhibitors may be used in patients with liver disease, though dosage adjustments may be required. For example, Ongentys (opicapone) is another COMT inhibitor that requires dosage adjustment based on kidney and liver function. Patients with moderate liver impairment (Child-Pugh Class B) should not take more than 25 mg of Ongentys daily, and patients with Class C liver impairment should avoid use altogether. Patients should avoid using Ongentys if they have kidney injury and a creatinine clearance less than 15 mg/mL. Patients with kidney injury should use caution when taking Ongentys if their creatinine clearance is between 15 mg/mL.

Finally, Ongentys should not be used in patients with a history of pheochromocytoma, paraganglioma, or other catecholamine secreting tumors.

Are COMT inhibitors controlled substances?

No, COMT inhibitors are not controlled substances.

Common COMT inhibitors side effects

Most adverse events in the use of COMT inhibitors are caused by an increase in dopamine levels. For example, dyskinesia, constipation, and dry mouth are attributed to dopaminergic effects. Some of these can be managed by lowering the dose of levodopa since COMT inhibitors do not increase dopamine levels in the absence of levodopa. However, not all adverse events are associated with levodopa. One example is diarrhea, which may be severe and may not manifest until six to 12 weeks after initiating a COMT inhibitor. Diarrhea is one of the most frequent causes for discontinuing tolcapone and entacapone. Patients who experience diarrhea from a COMT inhibitor should drink fluids to maintain adequate hydration and monitor themselves for weight loss. Opicapone is the only COMT inhibitor that is not associated with diarrhea.

Common side effects of COMT inhibitors are listed below:

• Nausea

• Postural hypotension

• Dyskinesia(small involuntary ‘tics’)

• Insomnia

• Dystonia (involuntary, sustained muscle contractions)

• Dizziness

• Anorexia/ weight loss

• Muscle cramps

• Somnolence (drowsiness)

• Diarrhea

• Confusion

• Constipation

• Fatigue

• Urinary tract infection

• Abdominal pain

• Hallucinations

The adverse effects listed above are not a comprehensive list. Individual COMT inhibitors may carry additional side effects. Always consult a healthcare provider if you have questions about medication side effects.

How much do COMT inhibitors cost?

COMT inhibitors vary in price. Entacapone is available as a generic drug which makes it more affordable, especially with a SingleCare discount. A month’s supply of entacapone costs $230 on average without insurance. However, a free entacapone coupon from SingleCare can lower the price to less than $35 for the same amount of medication. 

Stalevo, a combination drug that includes entacapone, carbidopa, and levodopa, costs around $400 for a month supply without insurance. A SingleCare coupon for the generic alternative can lower the price down to approximately $35 at participating pharmacies.