COMT Inhibitors

Catechol-O-methyltransferase inhibitors block peripheral breakdown of levodopa, extending its half life and smoothing plasma levels. They have no effect without levodopa and are used to treat wearing-off.

Pharmacokinetics. Entacapone acts peripherally with a short effect of about 2 hours, so it is taken with each levodopa dose. Opicapone binds tightly and is given once daily. Tolcapone also acts centrally.

• Entacapone 200 mg with each levodopa dose, up to 10 times daily; maximum 2,000 mg daily. Available as a fixed combination with levodopa and carbidopa.
• Opicapone 50 mg once daily at bedtime, at least 1 hour before or after levodopa.
• Tolcapone 100 mg three times daily; maximum 200 mg three times daily.

Differences. Opicapone is convenient and as effective as entacapone. Tolcapone is the most effective but can cause fatal liver failure, so it is a last resort.

• Wearing-off: add entacapone or opicapone to levodopa when doses wear off before the next is due; off time falls by 1 to 1.5 hours daily.
• Levodopa reduction: reduce levodopa by 10 to 30 percent if dyskinesia worsens.
• Tolcapone: only after other COMT inhibitors fail, under specialist care, with liver monitoring.

Selection. Not for early disease without fluctuations.

Contraindications. Phaeochromocytoma and paraganglioma. History of neuroleptic malignant syndrome or rhabdomyolysis. Non-selective MAO inhibitors. Tolcapone in liver disease or raised liver enzymes.

Adverse effects. Dyskinesia, nausea, diarrhoea (often after weeks or months), orange-brown urine, hallucinations, sleep disturbance. Tolcapone: severe hepatotoxicity.

Interactions. Catecholamines (adrenaline, noradrenaline, isoprenaline, dobutamine, methyldopa) and apomorphine have exaggerated effects. Entacapone reduces iron absorption. INR may change with warfarin.

Special groups.

• Pregnancy: avoid.
• Breastfeeding: avoid.
• Older adults: monitor for dyskinesia and diarrhoea.
• Liver impairment: opicapone 25 mg in moderate impairment, avoid in severe; use entacapone with caution.
• Kidney impairment: no adjustment.

Monitoring. Dyskinesia, weight, diarrhoea. Tolcapone: liver enzymes every 2 weeks for the first year, every 4 weeks for the next 6 months, then every 8 weeks; stop if ALT rises over the upper limit of normal or there is no benefit by 3 weeks.

Referral and escalation. Persistent diarrhoea with weight loss; jaundice or abdominal pain on tolcapone.