Antiemetic, Prokinetic, Neuroleptic, and Miscellaneous Drugs in the Acute Treatment of Migraines

Peer Tfelt-Hansen

William B. Young

Stephen D. Silberstein

Nausea and vomiting are common symptoms of migraine (48) and are often as distressing as the headache. Thus, in addition to analgesics or more specific antimigraine drugs, antinauseant agents are often used. For possible future use of antiemetics in migraine, the reader is referred to Dahlöf and Hargreaves (17).

During a migraine attack the absorption of orally administered drugs may be delayed (56,57,59,74,75,77, 79,80). This is most likely caused by gastric stasis, which contributes to the failure of some patients to respond to treatment (79). These pharmacokinetic observations led to the use of metoclopramide in migraine by virtue of its antiemetic property and its ability to promote gastric emptying, the so-called gastric prokinetic effect (10,53).

Neuroleptics have been used in the acute treatment of migraine, as analgesics and as antiemetics. Neuroleptics are also frequently used in the treatment of status migrainous (16). Probably their most important role today is as an alternative to opioids in emergency departments.

Several miscellaneous, alternative drugs for the treatment of migraine attacks deserve mention. These include drugs in common use despite limited evidence of efficacy in controlled double-blind trials (isometheptene combinations, dextropropoxyphene combinations, analgesic combination with antihistamines, morphinomimetics, lidocaine, and magnesium sulphate).

ANTIEMETIC AND PROKINETIC DRUGS

Metoclopramide

Pharmacologic Background

Metoclopramide is a benzamide derivative and, although related to the neuroleptics, has no significant antipsychotic or sedative properties. Metoclopramide is a dopamine and 5-hydroxytryptamine 3 (5-HT₃) receptor antagonist (29,53) and also possesses some 5-HT₄ agonist activity (11,53). The actions of metoclopramide include antagonism of emesis induced by apomorphine or ergotamine (10); it also induces hyperprolactinemia, a characteristic of dopaminergic blockade (10,36,55). It can cause serious extrapyramidal dysfunction, especially after high intravenous dosage (10,36,55).

In the gastrointestinal tract, metoclopramide enhances the motility of smooth muscle from the esophagus through to the proximal small bowel. It thereby accelerates gastric emptying and the transit of intestinal contents from the duodenum to the ileocecal valve (10,53). The mechanism of this prokinetic effect has not been fully elucidated, but an agonistic effect on 5-HT₄ receptors on the enteric nerve plexus has been postulated (11,53).

Pharmacokinetics

Metoclopramide is rapidly and completely absorbed after oral administration, but because of hepatic first-pass metabolism its bioavailability is reduced to about 75%. Metoclopramide is distributed rapidly to most tissues and readily crosses the blood-brain barrier and placenta. The half-life of the drug in plasma is 4 to 6 hours (10).

Pharmacokinetic Investigations of Oral Absorption During Migraine Attacks

In the first classical study by Volans on aspirin absorption during migraine attacks (79), it was shown that during established migraine attacks salicylate concentrations determined 30 and 60 minutes after administration of 900 mg effervescent aspirin were significantly lower than those in the control subjects, but between migraine attacks the
same patients demonstrated normal aspirin absorption. The impairment of aspirin absorption was ascribed to delayed gastric emptying because radiologic investigations had shown gastric stasis during migraine (43,45). In the next studies, two antinauseant agents, metoclopramide and thiethylperazine (the latter lacking the prokinetic activity), were tested for their possible effect on aspirin absorption during a migraine attack (80,82). Both drugs were given in a dose of 10 mg intramuscularly followed 10 minutes later by 900 mg effervescent aspirin. As was previously found, aspirin absorption was impaired during migraine, but metoclopramide normalized it. In those who had received thiethylperazine, aspirin absorption remained impaired. In a later study in which both aspirin and salicylate concentrations were measured following effervescent aspirin administration to patients during migraine attacks (60), the delay observed for aspirin reaching its absorption sites was not seen after 10 mg metoclopramide, given orally or intramuscularly. The oral absorption of the nonsteroidal anti-inflammatory drug (NSAID) tolfenamic acid was found to be impaired during migraine attacks, but the decreased absorption was reversed after 20 mg metoclopramide rectally (77). The absorption of paracetamol (75), naproxen (56), sumatriptan (57), and zolmitriptan (74) also was found to be slightly delayed during migraine attacks.

Clinical Trials With Metoclopramide

For controlled clinical trials concerning the combination of NSAIDs plus metoclopramide, the reader is referred to Chapter 49.

Metoclopramide alone was not better than placebo in treating nausea (76), whereas the combinations of metoclopramide and tolfenamic acid (76), metoclopramide and paracetamol and diazepam (73), and metoclopramide and aspirin (72) were better than placebo. The possible enhancing effect of metoclopramide on the efficacy of analgesics in migraine has been difficult to demonstrate formally. Thus, metoclopramide just failed to enhance analgesia in one study (73) (P = .06), and increased the efficacy of tolfenamic acid only for some parameters, such as intensity of attack as a whole (76), whereas it failed to enhance the analgesic effect of effervescent aspirin (72). The efficacy of combinations of highly soluble aspirin salt and metoclopramide (see Chapter 50) indicate, however, that metoclopramide enhances the analgesic effect of analgesics. In controlled trials there was no convincing evidence for the usefulness of the combination of metoclopramide and ergotamine (33,66).

Metoclopramide (10 mg intravenously) was found to be better than placebo in patients with severe migraine presenting at an emergency department (71), indicating that metoclopramide per se might have an effect on the migraine attack, apparently confirming an earlier anecdotal observation (39). In contrast, intramuscular metoclopramide was without any effect on migraine pain (73). In one study, intravenous metoclopramide was as successful as intravenous chlorpromazine (12), but the lack of a placebo control precludes firm conclusions. In another trial in emergency departments, 10 mg metoclopramide intravenously was inferior to 10 mg prochlorperazine intravenously and not different from placebo (14). In controlled trials there is thus no convincing evidence for the effect of metoclopramide per se on migraine attacks.

Therapeutic Use

Metoclopramide is combined with orally administered drugs in the treatment of migraine attacks based on a two-fold rationale: it is an antiemetic and it can normalize the delayed absorption of orally administered drugs thereby optimizing their use. For the use of metoclopramide in combination with NSAIDs, the reader is referred to Chapter 49. Based on our clinical experience and one study (63) metoclopramide can probably also be used to increase the efficacy of triptans during migraine attacks.

The dose of metoclopramide is 10 to 20 mg orally, 20 mg by suppository, or 10 mg intramuscularly (see Table 52-1).

The side effect of metoclopramide 10 mg intravenously, akathisia, normally precludes its use in the treatment of migraine attacks. Metoclopramide (5 mg intravenously) is sometimes used as an antiemetic when intravenous dihydroergotamine is given (see Chapter 63).

Side effects include sedation and dystonic reactions such as torticollis, trismus, facial spasm, and oculogyric crisis (the extrapyramidal side effects are usually seen after single parenteral doses of metoclopramide).

Contraindications include pheochromocytoma, breastfeeding, and treatment with neuroleptics. Use in children under 12 years of age is also contraindicated.

Domperidone

Domperidone is a derivative of benzimidazole that possesses both antiemetic and prokinetic properties. It is a dopaminergic antagonist and produces marked hyperprolactinemia (9,10). The effects of domperidone on gastrointestinal motility closely resemble those of metoclopramide. Domperidone, however, crosses the blood-brain barrier poorly and, therefore, rarely causes extrapyramidal side effects.

Domperidone is rapidly absorbed after oral administration (time to peak plasma concentration [t_max] = 30 minutes]), whereas rectal absorption is slower (t_max = 60 minutes). Its oral and rectal bioavailability is only about 15%. The half-time for its elimination from plasma is about 7.5 hours (9).

TABLE 52-1 Recommendation for the Use of Neuroleptics in the Treatment of Migraine^a

*Drug*		*Quality of Evidence*^b	*Scientific Effect*^c	*Clinical Impression of Effect*^d	*Adverse Effects*	*Comments (See Full Prescribing Information for Complete List of Adverse Events and Contraindications)*	*Role (by Consensus)*
Antiemetics
	Chlorpromazine IM	C	++	++	Mild to moderate	Extrapyramidal adverse events (e.g., dystonia), and sedation are associated with metoclopramide but rarely reported in the clinical trials reviewed. In some patients with migraine, sedation may be useful. Has role in pregnancy. Postural hypotension is an adverse event with chlorpromazine.	Adjunct therapy
	(0.1 mg/kg for 1-3 doses to 1 mg/kg)	B	++	++
	IV (12.5 to 37.5 mg)
	Metoclopramide
	IM (10 mg)	B	+	+	Infrequent to occasional		Adjunct therapy
	PR (20 mg)	B	++	?	Infrequent to occasional
	IV (0.1 mg/kg for 1-3 doses to 10 mg)	B	++	++
	Prochlorperazine					Consider IM or IV as adjunct first-line therapy in ED or office; consider PR as adjunct.
	PR (25 mg)	B	+++	+	Occasional
	IM (10 mg)	B	+++	++	Occasional
	IV (10 mg)	B	+++	+++	Frequent
Other Antiemetics
	Domperidone^e (30 to 120 mg)	B	?	?	?	?	Possible use for pre-emptive treatment of migraine (i.e., given during prodrome).
^aUnited States Headache Consortium Evidence Summary. ? = Not known. ^bQuality of the evidence: A, Multiple well-designed randomized clinical trials, directly relevant to the recommendation, yielded a consistent pattern of findings. B, Some evidence from randomized clinical trials supported the recommendation, but the scientific support was not optimal. For instance, either few randomized trials existed, the trials that did exist were somewhat inconsistent, or the trials were not directly relevant to the recommendation. An example of the last point would be the case where trials were conducted using a study group that differed from the target group of the recommendation. C, The US Headache Consortium achieved consensus on the recommendation in the absence of relevant randomized controlled trials. ^cScientific effect: 0, The drug is ineffective or harmful; +, The effect is either not statistically or not clinically significant (i.e., less than the minimal clinically significant benefit); ++, The effect is statistically significant and exceeds the minimally clinically significant benefit; +++, The effect is statistically significant and far exceeds the minimally clinically significant benefit. ^dClinical impression of effect: 0, Most patients do not get relief; +, Few people get complete relief; some get some relief; ++, Some people get complete relief; most get some relief; +++, Most people get complete or nearly complete relief. ^eCurrently not available in the U.S.

In one double-blind, crossover controlled trial, domperidone 20 mg and 30 mg orally plus 1 g paracetamol in repeated doses was found to decrease the duration of migraine attacks compared with placebo plus paracetamol, although there was no statistically significant effect on headache and nausea (50).

In addition, in two placebo-controlled trials, domperidone 30 mg given orally at the start of premonitory symptoms of migraine was better than placebo for the prevention of impending attacks of migraine (3,81).

Therapeutically, domperidone is an alternative for patients who have previously experienced side effects with metoclopramide. It also can be recommended for children under the age of 12, a group especially at risk of developing extrapyramidal side effects after metoclopramide use. The dose in children is 0.2 mg/kg. For adults the oral dose is 10 to 20 mg and 30 to 60 mg by suppository. Our personal experience with the use of domperidone during premonitory symptoms have been rather disappointing.

Side effects include sedation, acute dystonia (rarely), hyperprolactinemia, and galactorrhea. Contraindications include pheochromocytoma and concomitant treatment with neuroleptics.

Other Antiemetics

Neuroleptics such as chlorpromazine and prochlorperazine have, for many years, been given either by injection or suppository to combat the nausea of migraine, but there is little evidence from controlled clinical trials to substantiate their usefulness. In one small study (42), prochlorperazine 10 mg intravenously was superior to placebo in treating nausea and vomiting. In another trial, chlorpromazine 1 mg/kg intramuscularly was superior to placebo for relief of nausea (52).

Only gold members can continue reading. Log In or Register to continue