Clinical use in epilepsy

Pregabalin has recently been licensed in Europe, the USA and 40 additional countries, as adjunctive therapy in partial-onset epilepsy in adults, and its place in routine therapy has not yet been fully ascertained. However, the results from the clinical trials are encouraging, and prega-balin appears to be effective. The lack of interactions and its excellent pharmacokinetic properties make pregabalin an easy drug to use. It has no drug interactions and no interactions with the combined oral contraceptive pill. There is not enough experience to recommend use in preganancy, but in animal experimentation, no teratogenic effects were observed. Pregabalin has a reasonable side-effect profile, and the frequency of adverse effects may be reduced by slow titration. No life-threatening or serious idiosyncratic effects have been recorded. In addition to its effects in epilepsy, pregabalin shows a marked analgesic effect, especially against neuropathic pain and the drug is now widely licensed for this indication. Preliminary results also suggest that pregabalin has marked anxiolytic properties also. The usual starting dose in routine clinical practice is 150 mg/day given in two or three divided doses, and dose escalation up to 600 mg/day will depend on individual tolerability and response to the drug. The drug can be given either in a twice or three times daily regimen.

PRIMIDONE

Primary indications

Licensed for monotherapy/add-on therapy Usual preparations Usual dosage—adults

Usual dosage—children

Dosing intervals

Dose commonly affected by co-medication Dose affected by renal/hepatic disease Common drug interactions Serum level monitoring Target range

Common/important adverse events

Major mechanism of action Main advantages

Main disadvantages COMMENT

Partial and primary and secondarily generalized seizures. Adults and children

Both

Tablet: 250 mg

Initial: 62.5-125 mg/day Maintenance 250-1000 mg/day

Initial 1-2 mg/kg/day Maintenance 10-20 mg/kg/day

1-2 times/day

Severe hepatic and renal disease Extensive; see p. 172

Useful to measure the levels of derived phenobarbital

25-50 pmol/l (and derived phenobarbital 50-130 pmol/l)

As for phenobarbital. Also dizziness and nausea on initiation of therapy

Not a controlled drug; less risk of abuse than phenobarbital

Adverse event profile, as for phenobarbital

A prodrug of phenobarbital with probably some minor additional efficacy

Primidone was introduced into clinical practice in 1952. Although it has strong advocates, most clinicians feel that it functions simply as a prodrug of phenobarbital, with little clinical advantage (and significant disadvantages) compared with the parent drug. In most countries it is not, like phenobarbital, a drug of abuse and therefore it is not subject to special controls—a practical (and rather illogical!) benefit enjoyed by the drug.

Physical and chemical characteristics and mode of action

Primidone (molecular weight 218.25) is a crystalline powder with low solubility in water. The main action of primidone is due to the derived phenobarbital, and whether either primidone itself or a second active metabolite, phenylethylmalonamide, adds anything to its antiepileptic properties in controversial.

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