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

Figures & data

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.

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