Catechol-O-Methyltransferase (COMT) Inhibitors

See Parkinson's Disease Management for further details on drug choice and drug combinations.

The two licensed drugs in this class are tolcapone and entacapone. They reversibly inhibit the peripheral breakdown of L-dopa by the Catechol-O-Methyltransferase (COMT) enzyme, increasing the amount available for conversion to dopamine in the brain and reducing fluctuations in plasma levels.

Drugs in this class act by increasing the bioavailability in the brain and prolonging the action of dopamine.¹ NICE recommends that entacapone should be used as an adjunctive treatment in the later stages of Parkinson's Disease.² It is particulary useful in reducing the 'off-time' produced by levodopa, and can also reduce the dose of levodopa required.

Controlled trials also demonstrated an improvement in mobility and a reduction in disability. However, entacapone can have increased dopaminergic adverse effects such as nausea, vomiting, and dyskinesia.¹ NICE suggests therefore that because of poor concordance it should be given as triple therapy with levodopa and co-careldopa.

Tolcapone should be reserved for patients in whom triple therapy with entacapone is ineffective or who are unable to tolerate it.³ Tolcapone was suspended by the Committee on Safety of Medicines in November 1998 due to the risk of hepatotoxicity. However, following further evidence demonstrating its superior effectiveness to entacapone in controlling motor fluctuations, it was reinstated in April 2004 for specialist use only.¹

• Pregnancy - no human studies but maternal weight gain and reduced foetal development found in animal experiments
• Lactation - manufacturers advise avoidance as the drug is present in human milk
• Hepatic impairment:
  • Tolcapone - can raise liver enzymes, rare reports of fulminant hepatic failure
  • Entacapone - is metabolised by the liver, therefore, although no suggestions of hepatotoxicity per se, also contraindicated in patients with pre-existing liver disease.
• Phaeochromocytoma
• History of neuroleptic malignant syndrome
• Non-traumatic rhabdomyolisis

• COMT inhibitors increase available levels of levodopa so the dose of the latter may need to be lowered to reduce adverse effects.
• Tolcapone - warn patients regarding the risk of hepatotoxicity (see Monitoring), of the symptoms and signs of liver disorder, and to seek immediate medical attention if they occur.
• Warn patients that urine and other body fluids may be coloured orange.

(See individual drug Summaries of Product Characteristics for full list)

• Warfarin - small increase in INR values
• Antidepressants - interaction with MAOIs, tricyclics, paroxetine, venlafaxine and several others
• Dopaminergics - can enhance effect
• Iron - reduces absorption

• Gastro-intestinal
• Dry mouth
• Dyskinesias - reduced by lowering levodopa levels
• Dizziness
• Entacapone - reported to cause sudden sleep attacks with little or no warning⁵

Tolcapone - usually initiated by specialist as careful counselling required regarding risks vs benefits. Check liver function tests (LFTs) before prescribing. This does not apply to entacapone because there is no effect on liver function, although LFTs should be considered if there is any suggestion of pre-existing liver impairment.³

• Tolcapone - monitor LFTs every 2 weeks for first year of therapy, every 4 weeks for next six months, and every 8 weeks thereafter. Re-start monitoring schedule if the dose is increased. Stop the drug if abnormal LFTs or symptoms/signs of liver disease develop (LFTs are not always reliable).
• Entacapone - no similar monitoring required as there is no effect on liver function (however see contraindications regarding patients with hepatic impairment).