Curr Med Res Opin. 2001;17(1s) 

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Dopamine Antagonists

Metoclopramide also has 5-HT3-receptor antagonist and some 5-HT4-receptor agonist properties in addition to it antagonism of dopamine receptors. Its potential use in migraine became apparent when it was shown that, in addition to its anti-emetic properties, metoclopramide could reverse delayed aspirin absorption resulting from gastric stasis[1,2]. The oral absorption of tolfenamic acid during migraine can also be enhanced by rectal metoclopramide[3]. In contrast, rectal metoclopramide had little effect on the peak concentration or time to peak concentration when given with oral effervescent paracetamol compared with paracetamol alone[4]. It is also unclear whether the addition of metoclopramide to an analgesic confers any additional clinical benefit. A double-blind crossover study of effervescent aspirin 650 mg versus an effervescent preparation of aspirin 650 mg and metoclopramide 10 mg versus placebo showed that the active treatments were more effective than placebo but there was no significant difference between aspirin alone and aspirin plus metoclopramide with respect to analgesic efficacy or anti-nauseant effect[5]. Clinical trial data also do not support additional efficacy from oral metoclopramide combined with ergotamine over ergotamine alone[6].

Despite this apparent lack of clinical benefit, metoclopramide combined with analgesics is commonly recommended. A double-blind parallel study with oral sumatriptan 100 mg versus oral lysine aspirin 900 mg and metoclopramide 10 mg suggest that the combination is as effective as sumatriptan[7]. The combination has the advantage of being cheaper and better tolerated than sumatriptan and efficacy can be further improved by repeated dosing[8].

Metoclopramide has also been considered as monotherapy for migraine given by intravenous or intramuscular injection during an attack. Clinical trial data are too conflicting to make general recommendations[9,10,11,12].

The most common side-effect of metoclopramide is sedation, which can be an advantage for patients who have the opportunity to rest, as sleep can aid recovery[13]. Since metoclopramide readily crosses the blood-brain barrier, extrapyramidal side-effects such as akathisia, dystonic reactions and oculogyric crisis can occur. These are dose-related and more common in women and children. Galactorrhoea, mastalgia and menstrual dysfunction can result from hyperprolactinaemia, secondary to blockade of endogenous dopamine in the pituitary.

The usual recommended dose of metoclopramide given up to three times daily is: oral 10-20 mg; rectal 20 mg; intravenous or intramuscular 10 mg. Metoclopramide is available combined with paracetamol (Paramax®) and lysine aspirin (Migramax®).

Use of metoclopramide is not recommended in patients with phaeochromocytoma, pyloric stenosis, porphyria or Parkinson's disease. Special precautions include epilepsy, renal or hepatic impairment. Interactions include anticholinergics, phenothiazines and butyrophenones.

Domperidone mimics the anti-emetic and gastroprokinetic effects of metoclopramide without central side-effects as it does not cross the blood-brain barrier.

A double-blind crossover study of repeated doses of paracetamol 1 g alone versus paracetamol 1 g and either domperidone 20 mg or 30 mg showed that both combinations shortened the duration of an attack compared with paracetamol alone[14].

Domperidone 30 mg has also been given successfully in the prodromal stage of migraine to prevent attacks but data are limited[15].

Side-effects are fewer than those occurring after metoclopramide and include dry mouth and nervousness.

Hyperprolactinaemia from chronic use can result in galactorrhoea, mastalgia and menstrual irregularities. Intravenous domperidone has been associated with cardiac dysrhythmias.

The usual recommended dose given 4- to 8-hourly is: oral 20 mg; rectal 30-60 mg. It is available combined with paracetamol (Domperamol.). Domperidone should be used with caution in patients with Parkinson's disease and is not recommended for patients with pyloric stenosis.

Phenothiazines have antihistamine properties together with varying antagonist activity at Éø-adrenergic, cholinergic, dopaminergic and tryptaminergic receptors. The most commonly used phenothiazines in migraine are prochlorperazine and chlorpromazine.

Prochlorperazine has been used in combination with other antimigraine agents and as monotherapy. Although available as oral and buccal preparations, there are no published clinical trials using these formulations for migraine. A study of 37 patients given 5-10 mg of intravenous prochlorperazine to prevent nausea following subsequent 0.75 mg dihydroergotamine concluded that the combination was a safe and effective alternative to narcotics in the emergency room[16]. Intravenous prochlorperazine 3.5 mg has also been given prior to intravenous dexamethasone 20 mg for status migrainosus and was associated with a shortened response time and reduced insomnia and nausea compared to dexamethasone alone[17].

Results of trials of monotherapy with intravenous, intramuscular and rectal prochlorperazine are too inconclusive torecommendtheir use in migraine[11,12,18].

In contrast, trials of monotherapy with intravenous chlorpromazine have shown efficacy compared to sumatriptan[19], dihydroergotamine[20] and metoclopramide[10].

Side-effects of phenothiazines include sedation, postural hypotension, extrapyramidal reactions and ECG irregularities.

The usual adult doses of prochlorperazine are: oral 10 mg; rectal 25 mg; intramuscular 10 mg. The maximum daily oral dose is 30 mg. The usual adult doses of chlorpromazine given up to three times daily are: oral 25 mg; rectal 50-100 mg; intramuscular or intravenous 25-50 mg.

Contraindications to use include epilepsy, hypothyroidism, liver or renal dysfunction and phaeochromocytoma. Interactions include alcohol and other CNS depressants, antidepressants, antihypertensives and anticonvulsants.

Butyrophenones are antipsychotics, weak antihistamines and have dopamine-receptor antagonist activity. Although not commonly recommended for migraine, intravenous and intramuscular droperidol has been used in the emergency room as monotherapy for migraine[21,22,23].

Side-effects include extrapyramidal reactions but fewer autonomic symptoms than phenothiazines. The doses in clinical trials have been: intravenous 2.5-7.5 mg; intramuscular 2.5 mg. Contraindications and interactions are similar to those for phenothiazines.


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