What is the impact of catechol-O-methyltransferase (COMT) on Parkinson’s disease treatment?

KEYWORDS:

• Entacapone
• tolcapone
• opicapone
• Parkinson’s disease
• COMT

1. Introduction

Parkinson’s disease (PD) is the second most common neurodegenerative disorder worldwide [1]. From the pathological perspective, the etiology of the disease is the death of the dopaminergic cells in the substantia nigra pars compacta [1]. The main cardinal features of the disease are bradykinesia, muscle rigidity and rest tremor [1]. The gold standard of the treatment is still the levodopa substitution [2]. However, wearing off and other motor complications appear sooner or later during the treatment, which requires further therapeutic steps [2]. Regarding the management of wearing-off, catechol-O-methyl transferase (COMT) inhibitors are one of the molecular groups, which help to maintain the levodopa concentration stable [2]. The three most important COMT inhibitors are entacapone, tolcapone, and opicapone [3]. The mechanism of action of these drugs is based on the inhibition of COMT enzyme, which results in a higher levodopa concentration in the blood without peripheral degradation to 3-O-methyldopa (3-OMD) [3]. Table 1 compares the key properties of the three molecules. The aim of this paper is to present the clinically relevant, previously identified [3] studies (Table 2) on each COMT inhibitor. Furthermore, based on the key findings of these studies, the manuscript is intended to help clinicians to make evidence-based decisions during the medical care. In the expert opinion section, the authors also draw attention to the main decision-making aspects between COMT inhibitors and suggest the optimal therapeutic algorithm (take home message section).

Table 1. Comparison of the main properties of COMT inhibitors

	Entacapone	Tolcapone	Opicapone
Approved indication	‘end-of-dose’ motor fluctations	‘end-of-dose’ motor fluctuations, other COMT inhibitors ineffectivity	‘end-of-dose’ motor fluctations
Starting dose	200 mg/levodopa dose	100 mg t.i.d.	50 mg q.d.
Maximum dose	2000 mg	200 mg t.i.d.	no data
Peak plasma concentration (Tmax)	1 h	2 h	1–2.5 h
Half life	30 min	2 h	0.7–3.2 h
Metabolism	CYP450 2C9	CYP450 3A4 and 2A6	CYP450 2C8 and 2C9
Site of action	Periphery	Periphery, central	Periphery

Abbreviations: CYP – cytochrome, t.i.d. – three times a day, q.d. – once a day.

Table 2. Summary of the most relevant aspects of the randomized controlled studies

COMT inhibitor	Study design	Number of participants (treatment group and placebo group)	Characteristics of patients	Duration of the study	Dose/dose frequency	Outcome measures	Key findings	Reference
Entacapone	Randomized, placebo controlled, double blind	115 (Treatment) vs. 57 (Placebo) (fluctuating patients)	Both fluctuating and non-fluctuating	24 weeks	200 mg entacapone or an identical placebo tablet, taken concomitantly with each daily levodopa dose	Primary: daily ON time (%). Secondary: absolute ON and OFF times; daily levodopa dosages	Levodopa treatment resulted in increasing ON time	Brooks et al., 2003 [4]
	Randomized, placebo controlled, double blind	99 (Treatment) vs. 63 (Placebo)	Wearing-off motor fluctuations	12 weeks	Entacapone 200 mg or placebo, administered with each dose of levodopa	‘ON’ and ‘OFF’ time while awake. Investigator’s Global Assessment. The SF-36 Health Survey. Changes in levodopa dosages	Entacapone provides additional antiparkinsonian benefits to levodopa therapy	Fénelon et al., 2003 [5]
	Randomized, placebo controlled, double blind	197 (Treatment) vs. 104 (Placebo)	Majority with motor fluctuations	24 weeks	Entacapone (200 mg) or placebo with each daily dose of standard or controlled- release (CR) levodopa	‘ON’ and ‘OFF’ times. Unified Parkinson’s Disease Rating Scale (UPDRS) and changes in levodopa dosages	Entacapone is an effective and safe levodopa extender and enhancer	Poewe et al., 2002 [6]
	Randomized, placebo controlled, double blind	174 (Treatment) vs. 96 (Placebo)	Motor fluctuations	13 weeks	Entacapone 200 mg or placebo with each dose of current levodopa treatment	Primary: UPDRS part II, activities of daily living, PDQ-39. Secondary: UPDRS parts I, III–VI, Global Assessment of Change, PDQ-39 subscores, SF-36, EQ-5D	Levodopa combined with entacapone has good efficacy in terms of ADL	Reichmann et al., 2005 [7]
	Randomized, placebo controlled, double blind	85 (Treatment) vs. 86 (Placebo)	Wearing-off motor fluctuations	24 weeks	200 mg entacapone or identical placebos concomitantly with each daily levodopa dose	‘ON’ and ‘OFF’ times. UPDRS	Long-term entacapone treatment prolonged the response to levodopa	Rinne et al., 1998 [8]
Tolcapone	Randomized, placebo controlled, double blind	59 (Treatment) vs. 58 (Placebo)	Wearing-off motor fluctuations	12 weeks	200 mg tolcapone t.i.d., in addition to levodopa/benserazide	Primary: efficacy of tolcapone in reducing ‘wearing off.’ Secondary: reduction in levodopa requirements	Tolcapone prolongs ‘on’ time. Reduction in daily levodopa dosage	Baas et al., 1997 [9]
	Randomized, placebo controlled, double blind	32 (Treatment) vs. 33 (Placebo)	Wearing-off motor fluctuations	6 weeks	Placebo or tolcapone 200 or 400 mg t.i.d.	Primary: effect of tolcapone on levodopa dosage	Tolcapone 200 mg t.i.d. may provide additional benefit	Dupont et al., 1997 [10]
	Randomized, placebo controlled, double blind	67 (Treatment) vs. 66 (Placebo)	Wearing-off motor fluctuations	12 weeks	100 and 200 mg, three times daily (t.i.d.) or placebo	Change in ‘OFF’ and ‘ON’ time	Tolcapone as an adjunct has efficacy in levodopa-treated patients	Rajput et al., 1998 [11]
	Randomized, placebo controlled, double blind	20 (Treatment) vs. 20 (Placebo)	Patients with advanced Parkinson’s disease	6 weeks	Placebo or tolcapone 100/200 mg t.i.d.	Instrumental gait analysis	The gait analysis confirmed that there is a substantial improvement independent from tolcapone	Shan et al., 2001 [12]
	Randomized, placebo controlled, double blind	98 (Treatment) vs. 102 (Placebo)	Without motor fluctuations	24 weeks	Placebo or tolcapone 100 or 200 mg t.i.d.	ADL and motor function	Tolcapone appears to be beneficial for patients with parkinsonism (without motor fluctuations)	Waters et al., 1997 [13]
Opicapone	Randomized, placebo controlled, double blind	147 (Treatment) vs. 135 (Placebo)	End-of-dose motor fluctuations	14–15 weeks	Placebo or 25/50 mg/day dosage of opicapone	Primary: change in absolute OFF-time	50 mg once daily resulted in a significant reduction in mean daily OFF-time	Lees et al., 2017 [16]
	Randomized, placebo controlled, double blind	145–145 (Treatment) vs. 147 (Placebo)	Motor fluctuations	14–15 weeks	Placebo or 25/50 mg/day dosage of opicapone	Primary: change in OFF-time. Secondary: OFF/ON-time responders (≥1 hour change from baseline), total ON-time, ON-time with and without troublesome dyskinesia. UPDRS	Both opicapone 25 and 50 mg were significantly more effective than placebo	Takeda et al., 2021 [17]
	Randomized, placebo controlled, double blind	122 (Entacapone) vs. 122 (Opicapone 5 mg) vs. 119 (Opicapone 25 mg) vs. 116 (Opicapone 50 mg) vs. 121 (Placebo)	Motor fluctuations	14–15 weeks	Opicapone (5 mg, 25 mg, or 50 mg once daily) or placebo or entacapone (200 mg with every levodopa intake)	Primary: change in absolute time in the OFF state	Opicapone 50 mg was superior to placebo and non-inferior to entacapone	Ferreira et al., 2016 [18]

Abbreviations: COMT – catechol-o-methyl transferase, EQ-5D – standardized measure of health-related quality of life developed by the EuroQol Group, PDQ-39 – Parkinson’s Disease Questionnaire-39, SF-36 – The Short Form (36) Health Survey, t.i.d. – three times a day, UPDRS – Unified Parkinson’s Disease Rating Scale.

2. COMT inhibitors

2.1. Entacapone

Entacapone is the most used, specific, reversible, peripherally acting COMT inhibitor, which has been studied in five important, randomized clinical trials in the scientific literature [4–8]. Among the first Brooks et al. confirmed in a randomized, placebo-controlled, double-blind study (172 fluctuating, 128 non-fluctuating patients) that the addition of entacapone to levodopa treatment resulted in the increase of ON time in fluctuating patients [4]. Furthermore, entacapone treatment resulted in decreased levodopa requirements and significantly improved the quality of life in non-fluctuating patients as well. In line with this, another research group performed a randomized, double-blind, placebo-controlled, three-month-long study (162 PD patients, wearing-off motor fluctuations). They found that entacapone has additional antiparkinsonian effect, which was independent from the exact adjunct dopamine agonist therapy. Furthermore, they verified that the addition of entacapone to levodopa is safe [5]. In another randomized, double-blind study, the efficacy and safety of the addition of entacapone to levodopa (301 PD patients, motor fluctuations) was demonstrated through the Unified Parkinson’s Disease Rating Scale (UPDRS) activities of daily living (ADL) and motor scores, which improved obviously after entacapone addition [6]. The ON time significantly increased and at the same time, the OFF time decreased markedly in comparison with placebo [6]. Moreover, the daily levodopa requirement reduced unequivocally as well [6]. In a short duration (13 weeks, 270 PD patients) study, the authors concluded that entacapone has an overall positive effect on ADL, global functions, and motor performance [7]. Rinne et al. confirmed in a randomized, placebo-controlled, double-blind, parallel-group way (171 PD patients, wearing-off-type motor fluctuations, 6 months) that long-term entacapone treatment is able to reduce the symptoms of wearing-off by prolonging the effect of levodopa [8].

2.2. Tolcapone

Although tolcapone is used only when other COMT inhibitor was shown to be ineffective due to a known rare hepatotoxic side effect, five relevant clinical studies have been performed to prove the clinical efficacy of this drug [9–15]. Baas et al. confirmed in a multicentre, randomized, double-blind, placebo-controlled trial (119 PD patients with motor fluctuations) that tolcapone could prolong the ON time and simultaneously reduced the levodopa requirement, as well [9]. In agreement with these findings, another study group found in a short study that higher tolcapone dose (200 mg, t.i.d.) provides additional clinical benefit in PD patients with wearing-off phenomenon and results in a decrease in levodopa daily requirements [10]. Tolcapone significantly reduces the levodopa demand and has a great efficacy in the improvement of motor performance confirmed in a longer trial (3 months, 202 PD patients, wearing-off phenomenon) [11]. Furthermore, another researcher indirectly attempted to demonstrate the clinical effect of the addition of tolcapone to levodopa/benserazide combination, using gait analysis [12]. Interestingly, they found no improvement after tolcapone addition in gait performance of advanced PD patients [12]. In contrast, Waters et al. investigated in a 6 months double-blind, placebo-controlled trial (298 PD patients without motor fluctuations) the effect of tolcapone on ADL and motor function [13]. The results showed that tolcapone is beneficial in patients with parkinsonism even if motor fluctuations have not yet developed [13]. In recent years, an excellent systematic review was published focused on the safety and efficacy issues of tolcapone. During the systematic literature search, they found 32 relevant studies (4780 patients). They examined the most relevant safety aspect of tolcapone, namely hepatotoxicity. However, they found over 23 years only 7 cases of severe liver injury (3 were fatal). Important aspect of the three above mentioned fatal tolcapone liver toxicity that all these cases did not apply the tolcapone guideline accordingly. In contrast, there was an observable significant beneficial effect on the motor performance of PD patients. Furthermore, the Quality-of-Life measures and non-motor symptoms improved as well [14]. In 2004, a Cochrane systematic review was published, which focused on the efficacy and safety of entacapone and tolcapone. They detected 14 trials (2566 patients) for deeper assessment. The authors concluded that both tolcapone and entacapone are effective in reducing ‘OFF’ time. Furthermore, a tendency of reducing daily levodopa requirement was observed as well. However, they raised the concern that some patients on tolcapone had elevation in the liver enzymes. They suggested a close monitoring of liver enzymes in tolcapone treated PD patients [15].

2.3. Opicapone

Opicapone is a relatively new once-daily peripheral acting drug with a favorable side effect profile. There are currently three prominent clinical trials available with this COMT inhibitor [16–20]. Lees et al. evaluated the efficacy of 25 and 50 mg doses of opicapone in patients with end-dose motor fluctuations (286 PD patients) [16] and they found after 1 year that opicapone is a safe and well-tolerated drug [16]. Furthermore, the treatment with 50 mg dose resulted in a significant reduction of mean daily OFF-time [16]. In line with these results, another study group published a paper in which 25 and 50 mg opicapone was consistently effective in reducing OFF-time over 14–15 weeks (Japanese levodopa-treated PD patients, motor fluctuations) [17] and it has been proved that opicapone (50 mg) is superior to placebo in reducing OFF-time. Furthermore, opicapone (50 mg) was non-inferior to entacapone (200 mg) [18]. The post-hoc analysis of Bipark-1 and −2 studies focused on the potential difference of opicapone effectivity in different subgroups. They detected a more robust beneficial tendency of opicapone (50 mg) in the ‘earlier’ disease stage (< 6 years disease duration; < 4 levodopa intake/day). Opicapone treatment was effective in the ‘later’ group as well, but to a lesser extent [19]. The OPTIPARK study was a prospective, open-label trial [20]. The trial focused for 3 and 6 months on the opicapone treated patients (50 mg). The key findings further strengthened the previously published safety and efficacy results related to opicapone treatment. It was well tolerated during the observation period [20].

3. Expert opinion

Currently, there are three available COMT inhibitors in neurological clinical practice: entacapone, tolcapone, and opicapone. Randomized, controlled clinical trials were conducted for all three molecules, however to the best of our knowledge, no direct comparative study has been performed between individual COMT inhibitors to date (except the post-hoc analysis of BIPARK-1 and-2 studies [19]). In our view, conducting a prospective study for that would be important to facilitate clinical decision-making. However, all three drugs were found to be effective in treating motor fluctuations, reducing the need for levodopa, and improving quality of life. An important strength of COMT inhibitors is that they reduce the methylation of levodopa to 3-OMD. This leads to the normalization of potentially elevated homocysteine levels, known as a serious vascular risk factor. Furthermore, it does not reduce the methylation capacity to the detriment of other essential detoxification processes [21]. Nevertheless, each COMT inhibitor has some strengths and weaknesses. Entacapone is an easily available drug, mostly used in combination. Side effects are rare and mostly mild. However, multiple daily dosing is required and the enzyme inhibitory effect is primarily exerted on the periphery. Tolcapone is sufficient to be taken on average t.i.d. and has an inhibitory effect not only peripherally, but centrally, as well. Although it is the only centrally acting COMT inhibitor that can also regulate central nervous system dopaminergic fluctuations, interestingly, the effect of this drug is mediated primarily through peripheral COMT inhibition [22]. Importantly, tolcapone may have significant central side effects (e.g. nausea, drowsiness, insomnia, dizziness, hallucination) compared to the other two COMT inhibitors. Furthermore, rarely it causes very severe hepatotoxic side effects and requires close monitoring. Opicapone, although not easily available in all parts of the world, combines the positive properties of entacapone and tolcapone. Once daily dosing is sufficient and has no hepatotoxic effects. Each molecules have a significant beneficial effect in the treatment of patients with PD.

After describing the strengths and weaknesses of each COMT inhibitor, the purpose of the manuscript is to assist clinicians in decision-making in selection between them. From our point of view, opicapone can be given as a first choice. This drug is convenient for the patient as it should be taken once a day and lacks significant side effects. However, availability and price issues may considerably hamper its widespread use. The decision between the other two COMT inhibitors is difficult. Regarding safety approaches, entacapone is the most commonly used in daily clinical practice, but the gap-filling paper by Artusi et al. [14] tried to demystify the hepatotoxicity issue of tolcapone, which yields a major concern for clinicians. They found only 3 fatal hepatotoxic events, which may have developed because of an inappropriate monitoring scheme. Considering these data, we believe that tolcapone may be the second choice with close monitoring if it is acceptable for the patient. Interestingly to the best of our knowledge, in the absence of the effectiveness of not only entacapone but also that of opicapone, tolcapone can be chosen as a second-line treatment. However, there is an uncertainty in the scientific literature and in prescription rules related to this question. If the first two COMT inhibitors (opicapone, tolcapone) cannot be come into account, entacapone is the drug of choice, which is safe and easy to use, but has been shown to be less effective in previous studies.

As the disease progresses, wearing-off and other motor complications make PD very difficult to treat. Therefore, the exact time of starting COMT inhibitors may raise important questions as well. Currently, the COMT inhibitor treatments have an indication at the onset of motor fluctuations, however, previously published important work [4] has raised the possibility that it may reduce the need for levodopa in non-fluctuating patients as well. From a pathophysiological point of view, early initiation of these molecules discussed in this article may delay the development of motor complications by slowing the maladaptation process of dopamine receptors. Nevertheless, nowadays COMT inhibitors may have a special role in the management of wearing-off, so these molecules have become an important part of treatment protocols.

As a take home message, we conclude that not always entacapone is the first, nor the second choice. Our paper help to make better decision related to COMT inhibitors. However, the limited availability and the perhaps excessive fear from hepatotoxicity related specific COMT inhibitors, lead to unnecessary overuse of entacapone and inadequate symptom control.

Declaration of Interest

The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

Reviewer disclosures

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Additional information

Funding

This work was supported by Hungarian ‘Nemzet Fiatal Tehetségeiért Ösztöndíj’ (NTP-NFTÖ-21-B-0100 to A Salamon).