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Abstract

Background

In most pharmacokinetic studies, the oral absorption of drugs is impaired during migraine attacks but exceptions occur. A study on gastric emptying using gastric scintigraphy indicated that gastric stasis also occurs interictally in migraine. These studies were reviewed critically.

Results

In seven studies, mainly investigating NSAIDs and analgesics, the early absorption of the drugs during 112 migraine attacks was delayed. The absorption of sumatriptan is usual in therapeutic doses, and rizatriptan was normal during 131 migraine attacks. The interictal gastric stasis observed using gastric emptying scintigraphy (GES) with solids (n = 13) could not be confirmed in a larger study (n = 27) using the same method. Also gastric emptying measured with GES with liquids (n = 7) and epigastric impedance (n = 64) was normal outside migraine attacks.

Conclusions and possible clinical implications

Drug absorption is not generally impaired during migraine attacks. Gastric emptying is most likely normal in the majority of migraine patients outside attacks. Prokinetic and antiemetic drugs such as metoclopramide and domperidone should not be routinely combined with oral analgesics or oral triptans. If, however, nausea is severe or vomiting occurs, treatment with an antiemetic with proven efficacy on the nausea of migraine can be indicated.

Keywords

Migraine attacks gastric stasis drug absorption aspirin triptans

Introduction

‘Several of our patients, in whom a diagnosis of organic pyloric obstruction has been made before admission and an operation advised on account of the large residue found in the stomach six hours after an opaque meal, were found on enquiry to have had a headache at the time of examination, and on giving another opaque meal the stomach was found to empty itself at the normal rate’, Briggs and Hurst, 1929 (1).

For 80 years it has been reported in case reports (see above vignette from 1929) that a barium meal examination of the stomach during a migraine attack could demonstrate gastric stasis and prolongation of the gastric emptying time, whilst repeated examination of the same patients when migraine free showed normal gastric function (1 –4).

Migraine patients with severe headache often suffer in addition from associated symptoms such as nausea/vomiting and phono- and photophobia (5). Nausea and/or vomiting are especially very frustrating symptoms for the patient and even if oral drugs are not actually vomited, this route of administration may not be optimal because delayed emptying of the stomach, as indicated by case reports (1 –4), could probably result in delayed absorption of drugs during migraine attacks.

Several pharmacokinetic studies during and outside migraine, from 1974 and further on, showed slow absorption of some analgesics during migraine attacks (6 –9), and these studies resulted in Europe in the introduction of combinations of prokinetic, antiemetic drugs and nonsteroidal anti-inflammatory drugs (NSAIDs) for acute migraine treatment (10). Two large studies have, however, failed to show this effect of migraine attacks on the absorption of the two triptans sumatriptan (11) and rizatriptan (12).

In addition, a study on gastric emptying using gastric scintigraphy from 2006 indicated that gastric paresis apparently occurs both between and during migraine attacks (13), indicating that gastric stasis is not only an ictal problem.

The aim of this review is to evaluate critically these pharmacokinetic and gastric emptying studies both during and outside migraine attacks and to discuss their possible clinical implications.

Methods

Search of the literature for studies for review

First Volans’ review from 1978 on drug absorption in migraine (14) was located in PubMed. Then the function ‘Similar articles’ was used and this resulted in 104 papers. From the abstracts of the 104 hits, 22 papers were selected as possibly relevant for the topic: drug absorption, gastric motility, and migraine. The full papers were retrieved and the reference lists were checked for relevant references. PubMed was searched with the search terms ‘gastroparesis’ and ‘migraine’. This resulted in 26 papers: Three were new, and these were retrieved, and the reference lists were checked for relevant references. In all new papers retrieved the reference lists were checked again for relevant references.

Results

Studies included

In total 12 studies (6 –9,11,12,15 –20) on drug absorption were included, as were five studies (13,21 –24) on gastric emptying during and outside migraine attacks. In addition, also included were three double-blind, cross-over clinical trials (25 –27) investigating the possible effects on headache and nausea of combining metoclopramide or domperidone with analgesics or an NSAID. Furthermore, five studies (28 –32) on the possible effect of sumatriptan on gastric emptying in humans were reviewed.

Pharmacokinetic investigations of drugs during and outside migraine attacks

The early absorption during migraine attacks was investigated and found delayed in pharmacokinetic studies with effervescent aspirin 900 mg (n = 35)) (6), (n = 20) (15), and (n = 11) (16), tolfenamic acid 300 mg (n = 7) (7), paracetamol 1000 mg (n = 9) (8), and zolmitriptan 10 mg (n = 20) (9); for details see Table 1. With naproxen 500 mg (n = 10) there was a small but significant delay in T_max (2.9 hours (h) vs 1.9 h) but no effect on C_max or area under the curve (AUC) (17), Table 1. In contrast, this delayed absorption during migraine attacks was not shown in similar pharmacokinetic studies for the most frequently used triptan sumatriptan in doses of 50 mg (n = 47), 100 mg (n = 49) (11). Also when combined with naproxen 500 mg the absorption of sumatriptan 85 mg was unchanged during migraine attacks (n = 17) (18), as were the absorption of rizatriptan 5 mg (n = 18) (12) and the absorption of triaprofenic acid 300 mg (n = 10) (19); see Table 1. For oral sumatriptan 25 mg (n = 48) T_max was prolonged (2.4 h vs 1.8 h) but C_max was unchanged (11); see Table 1.

Table 1.

Drug absorption during and between migraine attacks as investigated in 11 pharmacokinetic studies (6 –9,11,12,15 –19). In all studies, except Ross-Lee (16), the analysis of the possible effect of migraine attacks on the absorption of drugs was based on analyses of drug levels in the same patients during and between attacks. In Ross-Lee (16) the absorption of aspirin in migraine patients was compared with the absorption in normal controls.

Study	Administration form and dose of drugs	Parameter evaluated	Controls	Migraine patients between attacks	Migraine patients during attacks
Volans 1974 (6)	Effervescent aspirin 900 mg	Concentrations of salicylate (ng/100 ml) after 30 and 60 min	(n = 20) Mean ± SEM 30 min: 7.88 ± 0.40 (N = 20) 60 min: 8.15 ± 0.29	(n = 14) Mean ± SEM 30 min: 7.11 ± 0.59 (N = 9) 60 min: 7.59 ± 0.53	(n = 35) Mean ± SEM 30 min: 4.97 ± 0.52^a (N = 18) 60 min: 6.63 ± 0.30^a
Volans 1975 (15)	Effervescent aspirin 900 mg	Concentrations of salicylate (ng/100 ml) after 30 and 60 min	(n = 20)^a Mean ± SEM 30 min: 7.88 ± 0.40 (N = 20) 60 min: 8.15 ± 0.29	(n = 13) Mean ± SEM 30 min: 7.04 ± 0.64 (N = 9) 60 min: 7.59 ± 0.92	(n = 20) Mean ± SEM 30 min: 4.77 ± 0.43^a (N = 18) 60 min: 6.62 ± 0.55
Ross-Lee et al. 1983 (16)	Soluble aspirin (ASA) 900 mg	C_max of ASA (mg/l) AUC_{0–2 h} (mg/l × h)	(n = 6) Mean ± SD C_max: 31 ± 12 AUC: 15 ± 5		(n = 11) Mean ± SD C_max: 13 ± 7^b AUC: 9 ± 4
Tokola and Neuvonen 1984 (8)	Effervescent paracetamol 1000 mg	Peak concentration of paracetamol (µmol/l)		(n = 9) Mean ± SEM 144 ± 16	(n = 9) Mean ± SEM 109 ± 14^a
Tokola and Neuvonen 1984 (7)	Capsules of tolfenamic acid, 300 mg	AUC 0–2 hours (mg/l × h)		(n = 7) Mean ± SEM 4.07 ± 0.61	(n = 7) Mean ± SEM 2.00 ± 0.66^a
Thomsen et al. 1996 (9)	Tablets of zolmitriptan, 10 mg	C_max within four hours (ng/ml)		(n = 18) Mean: 12.8 (range, 4 to 26)	(n = 20) Mean: 7.6 (range: 0 to 28)^a
Cutler et al. 1999 (12)	Tablets of rizatriptan 5 mg	C_max (ng/ml)		(n = 18) Geometric mean: 12.8	(n = 18) Geometric mean: 14.9
Sramek et al. 1999 (11)	Tablets of sumatriptan 25 mg^b	C_max (ng/ml) AUC_{0–4 h} (ng/ml × h)		(n = 48) Mean C_max: 16 Mean AUC: 38	(n = 48) Mean C_max: 13 Mean AUC: 29
Sramek et al. 1999 (11)	Tablets of sumatriptan 50 mg	C_max (ng/ml) AUC_{0–4 h} (ng/ml × h)		(n = 47) Mean C_max: 31 Mean AUC: 75	(n = 47) Mean C_max: 29 Mean AUC: 65
Tablets of sumatriptan 100 mg		(n = 49) Mean C_max: 54 Mean AUC: 128	(n = 49) Mean C_max: 51 Mean AUC: 113
Haberer et al. 2010 (18)	Fixed-dose tablet with naproxen 500 mg and sumatriptan 85 mg	Only results for sumatriptan. C_max (ng/ml), geometric mean (GM) AUC_0–∞ (h × ng/ml) (GM)		(N = 17) C_max: 42 (95% CI: 37–48) AUC₀–_∞: 211 (95% CI: 189–237)	(N = 17) C_max: 40 (95% CI: 36–44) AUC₀–_∞: 193 (95% CI: 167–223)
Pini et al. 1990 (19)	One tablet of tiaprofenic acid 300 mg	C_max (µg/ml)		(N = 10) Mean ± SD 40.1 ± 13.2	(N = 10) Mean ± SD 37.8 ± 9.8
Pini et al. 1993 (17)	Soluble naproxen 500 mg	C_max (µg/ml) T_max (h)		(N = 10) Mean ± SD: 71 ± 20 Mean ± SD 1.9 ± 1.2	(N = 10) Mean ± SD: 69 ± 27 Mean ± SD: 2.9 ± 2.2^a

p < 0.05 for values during attacks vs values between attacks. ^bp < 0.05 for values during attacks vs normal controls. (a) The same control group as in Volans (6). (b) Only significant difference was T_max for 25 mg sumatriptan, 2.4 hours during migraine vs 1.8 hours pain free (p < 0.05) (11). ASA: acetylsalicylic acid; AUC: area under the curve; min: minutes; h: hours; CI: confidence interval.

In one study (15) intramuscular (i.m.) metoclopramide 10 mg could correct the impairment of the absorption of effervescent aspirin during a migraine attack, whereas this was not the case with i.m. antiemetic thiethylperazine 10 mg (20). Rectal metoclopramide 20 mg could correct the impaired absorption of oral tolfenamic acid (7), an NSAID with proven efficacy in migraine (33).

Clinical studies on the possible increase of antimigraine effect of an analgesic by adding a prokinetic antiemetic drug

In three double-blind, crossover, randomised trials the combinations of aspirin, paracetamol and the NSAID tolfenamic acid plus oral metoclopramide 10 mg or oral domperidone 20 mg and 30 mg were not consistently more effective than the drugs without an antiemetic; see Table 2 (25 –27). In two trials with oral metoclopramide plus aspirin or tolfenamic acid (25,26) the combinations were better anti-nauseants than placebo, whereas this was not the case for the combination of domperidone and paracetamol (27).

Table 2.

Possible effects on migraine headache and nausea by combining the two prokinetic antiemetic drugs, metoclopramide (10 mg) and domperidone (20 mg and 30 mg), with analgesics, aspirin (650 mg) (25) and paracetamol (1 g) (27), and an NSAID, tolfenamic acid (200 mg) (26) in three crossover trials.

Tfelt-Hansen and Olesen 1984 (25) (n = 85)	Placebo (P)	Aspirin (A)	Metoclopramide plus aspirin (MA)
Effect on pain
Worse or unchanged	77	61	59
Better or relieved	20	37^a	35^{a, N.S.}
Effect on nausea
Worse or unchanged	56	39	42
Better or relieved	22	24 ^N.S.(P)	28^a,N.S.
^ap < 0.05 for MA and A vs P; N.S.: non-significant difference between active drugs; N.S. (P): N.S. for A vs P.
Tokola et al. 1984 (26) (n = 49)	Placebo (P)	Tolfenamic acid (T)	Metoclopramide plus tolfenamic acid (MT)
Doses of drug used (one or two). Percentages taking two are indicated.
	81%	66%^a	56%^a,b(MT)
Severity at 1.5 hours (percentages of attacks with no or slight symptoms on a four-point rating scale)
	21%	46%^a	64%^a, N.S.
No nausea
	46%	62%^a,N.S.	60%^a
^ap < 0.05 for MA and A vs P; N.S.: non-significant difference between active drugs. ^b(MT): p < 0.5 for MT vs T. In this trial (Tokola et al. (26) 1984), seven efficacy parameters were used and for only two, dose of drugs used and rating of intensity of attack as a whole, was MT somewhat better than T (p < 0.05).
MacGregor et al. 1993 (27) (n = 46)	Placebo plus paracetamol 1 g (PP)	Domperidone 20 mg plus paracetamol 1 g (DP 20)	Domperidone 30 mg plus paracetamol 1 g (DP 30)
Median sum of intensity pain scores
	13.00	12.50^{N.S. (DP)}	11.00^{N.S. (DP)}
Duration (hours)
	17.5	12.00^a	12.00^a
Relief of nausea
	31%	44%^{N.S. (DP)}	52%^{N.S. (DP)}
N.S. (DP): no statistical significance differences between PP. DP 20 , and DP 30. ^ap < 0.05 for DP 20 and DP 30 vs P.

Investigations of gastric emptying during and outside migraine attacks

Gastric emptying rate (GER) during migraine attacks was found to be impaired with gastric emptying scintigraphy (GES) of solids in 13 patients (13,21), with GES with liquids in seven patients (22), and with epigastric impedance measurement in 14 patients (23); see Table 3. In two of these studies GER, measured with epigastric impedance (n = 46) and GES with liquids (n = 7), was normal between attacks compared with controls (n = 71) (22,23). GER measured with GES of solids was impaired between attacks in two studies (n = 10) (13) and (n = 3) (21) but normal in one larger study of 27 migraine patients without any dyspeptic symptoms during the interictal period (24); see Table 3.

The effect of sumatriptan on gastric emptying in normal individuals and absorption of paracetamol in migraineurs

In four studies in healthy volunteers parenteral sumatriptan delayed gastric emptying as measured with increased lag period or increased half-emptying time of liquids (28 –31). In a recent study, a clinically relevant oral sumatriptan 50 mg dose delayed gastric emptying of a gastric meal (32).

In one study in migraine patients outside attacks oral sumatriptan 100 mg delayed the absorption of paracetamol 1000 mg: T_max was 1. 4 hours without sumatriptan vs 2.8 hours with sumatriptan (34).

Discussion

This is not a traditional systematic review, but checking of a lot of reference lists in reviewed papers resulted in the retrieval of considerable more pharmacokinetic studies on drug absorption during migraine attacks, n = 11, in this review than in previous recent reviews of the subject, n = 4 (32), and n = 6 (33).

Possible delay of absorption of drugs during migraine attacks

The first hint that there could be gastric stasis during migraine attacks came from routine barium test meal X-ray examinations of the stomach already in 1929; see vignette (1). Several studies (2 –4,34) reported a considerable delay in gastric emptying of the barium test meal whereas the examination was normal when repeated between attacks. Most likely the most extreme examples, e.g. the large residue found in the stomach six hours after an opaque meal (34), and in the reports on gastric stasis during X-ray examination (2 –4,34), were published. Whether this was a more general problem during migraine attacks was unknown. Furthermore, it was not known whether this delay of gastric emptying of the solid barium meal, if present, would delay the gastric emptying of liquids, which probably correlates to the absorption of drugs as investigated extensively for the absorption of paracetamol. Thus measurement of early paracetamol absorption for evaluating gastric emptying correlates well with GES with liquids (35 –39).

Then in 1974 Volans, studying migraine patients attending the Princess Margaret Migraine Clinic in London, during acute migraine attacks showed that the absorption of effervescent aspirin is impaired during migraine attacks (6); see Table 1. He subsequently demonstrated that i.m. metoclopramide 10 mg could normalise the absorption of effervescent aspirin during migraine attacks (15). This effect of a prokinetic drug like metoclopramide strongly suggested that the delayed absorption of effervescent aspirin (6,15) ‘is related to impaired gastro-intestinal mobility with delayed gastric emptying’ (15). In contrast, a 10 mg i.m. dose of thiethylperazine, a phenothiazine antiemetic drug without prokinetic effect, could not normalise the absorption of effervescent aspirin (20).

In seven studies investigating 112 migraine attacks (6 –9,15 –17), mainly on analgesics and NSAIDs used in acute migraine treatment, the early absorption of these drugs was decreased during migraine when compared to absorption between attacks in these patients. Also with the rather high dose of 10 mg zolmitriptan the early absorption was decreased during migraine (9). In contrast, in four studies (11,12,18,19), of triptans sumatriptan, 50 mg, 85 mg, and 100 mg, rizatriptan, 5 mg, or the NSAID tiaprofenic acid 300 mg, were given in 141 migraine attacks, and the early absorption during attacks was the same as when the drugs were given outside attacks. For oral sumatriptan 25 mg (n = 48), T_max was prolonged during migraine attacks but C_max was unchanged (11).

In conclusion, for some drugs, mainly NSAIDS, absorption is delayed to some extent during migraine attacks but this is not so for all acute antimigraine drugs. Thus two of the currently most used triptans, sumatriptan and rizatriptan, have normal absorption during migraine attacks.

Gastric motility measured during and outside migraine attacks

In four studies gastric emptying was impaired in 34 migraine attacks as measured with three different direct methods for evaluating gastric emptying (13,21,22,24). This finding supports the interpretation that the decreased absorption found for some drugs during migraine attacks (6 –9,15 –17) is caused by gastric stasis. Two studies found decreased gastric emptying outside attacks in 13 migraine patients (13,21) as measured with GES of solids, and this new finding was reported by Aurora et al. in 2006 as: ‘Gastric stasis in migraine: More than just a paroxysmal abnormality during a migraine attack’ (13). In contrast, investigations with GES with liquids in seven patients (22) and gastric impedance measurement in 46 patients (23) showed normal gastric emptying outside attacks. The delayed gastric emptying measured with GES of solids (n = 13) (13,21) was not confirmed in a recent study with GES of solids in 27 interictal migraine patients (24). In that study 32 patients with functional dyspepsia showed delayed gastric emptying compared with migraine patients and controls; see Table 3. Part of the reason for the discrepancy could be the selection of patients. Because migraine patients report a high incidence of unexplained upper abdominal pain (39) which could be a sign of functional dyspepsia (FD) (25), only patients without any dyspeptic symptoms during the interictal period were investigated in the larger study showing normal gastric emptying (24). As shown in Table 2 patients with FD had delayed gastric emptying compared with migraineurs and controls (24). In the two other studies (13,21), patients were excluded if they ‘had any condition known to effect gastric motility, i.e. diabetes, thyroid disease, gastric surgery, anorexia, psychiatric disorder, and head injury’ (13,22). If some of the migraine patients included in these two studies (13,21) had dyspeptic symptoms, this could theoretically result in some delay in gastric emptying in these patients. Another theoretical possible bias in the two studies showing interictal delay of gastric emptying is the investigation of a selective subgroup of patients who were sensitive to visual triggers of migraine attacks (13,21). Thus only a small minority, 7% of migraine patients, mentioned bright light as a migraine trigger in a clinic-based population (40).

Additional support for normal gastric emptying in migraine patients outside attacks comes from the observation of normal absorption of effervescent aspirin interictally in migraine patients compared with controls (6); see Table 2.

So far gastric emptying during and outside migraine attacks has not been investigated with newer methodology such as, for example, the 13 C-octanoic acid breath test (41,42). This methodology should be suitable for investigating migraine patients repeatedly because it involves radioactivity as does GES.

In my view it is most likely that gastric motility is generally normal outside attacks in migraine patients. This does not exclude that special subgroup, e.g. patients with both functional dyspepsia and migraine, who may have decreased gastric motility interictally.

The effect of sumatriptan on gastric emptying in humans

Despite the fact that both subcutaneous and oral sumatriptan in therapeutic doses delays gastric emptying in healthy volunteers (28 –31) or delays absorption of paracetamol in migraine patients (34), there was no delayed absorption of oral sumatriptan in doses of 50 mg, 85 mg and 100 mg during migraine attacks (11,18). This apparent lack of an effect of sumatriptan on its own absorption during migraine attacks remains unexplained.

Possible clinical implications

The lack of evidence of increased antimigraine effect of analgesics plus metoclopramide

In the early pharmacokinetic studies (6 –8,15) the early absorption of effervescent aspirin, effervescent paracetamol and the NSAID tolfenamic acid seemed to be impaired during migraine attacks. Metoclopramide could normalise the absorption of aspirin when given in an i.m. dose of 10 mg (15) and the absorption of tolfenamic acid when given in a rectal dose of 20 mg (7). These pharmacokinetic studies led to the introduction of the drug combination of metoclopramide plus an analgesic (25,43 –52). The combinations of aspirin or paracetamol with metoclopramide were in several randomised controlled trials (RCTs) comparable to oral sumatriptan 50 mg to 100 mg and zolmitriptan 2.5 mg (45,48,51,52), and in one study superior to oral ergotamine 1 mg plus caffeine 100 mg (48).

It is, however, noteworthy that combining metoclopramide or domperidone with aspirin, tolfenamic acid, or paracetamol, did not result in a consistent increase in antimigraine effect for the combinations vs the analgesics per se (25 –27); see Table 2.

In a meta-analysis of three RCTs a high-buffered formulation of 1000 mg, effervescent aspirin had a headache response (HR) of 52% and pain free (PF) 27%, which was quite comparable to encapsulated sumatriptan 50 mg (HR: 47% and PF: 29%), and both drugs were superior to placebo (HR: 34% and PF: 15%) (53). These results, indicating comparability of buffered effervescent aspirin with a reasonable dose of oral sumatriptan, suggest that for this formulation of aspirin there is probably no general need to combine the drug with metoclopramide.

The lack of clinical effect of combinations on migraine pain could be due to the oral administration of metoclopramide in these combinations. This route of administration of metoclopramide could be less optimal during migraine attacks than the intramuscular and rectal routes of the drug used during the pharmacokinetic studies (8,15). That a prokinetic drug can increase the efficacy of an antimigraine drug has, however, been demonstrated for the combination of trimebutine and rizatriptan in one trial (54). Trimebutine acts locally on the stomach without any systemic absorption (54).

As shown in Table 4, which summarises the opinion of four national or international societies, the European Federation of Neurological Societies generally recommends the intake of oral metoclopramide or domperidone before intake of NSAID and triptans (10). The Canadian (55) and French (56) Headache Societies recommend metoclopramide as an antiemetic, and the American guidelines (57) do not even recommend metoclopramide as an antiemetic.

Table 3.

Methods used for evaluating gastric emptying in migraine patients. For absorption of drugs in migraine, see text and Table 1.

Method	Normal values in controls	Examples of results in migraine patients
GES of solids	Gastric retention of radioactivity: Two hours: < 60% Four hours: <10% (36)	Mean gastric retention of radioactivity at two hours.
GES of solids	Mean 44% (range, 17%–65% (n = 10) (13)	Migraineurs, interictal: 61% (n = 10) (13) Migraineurs, ictal: 56% (n = 9) (13)
T½ for emptying of stomach: Mean = 112 min (range: 57–182 min) 24 (n = 10) (13)	Mean T½ for emptying of stomach: Migraineurs, interictal: 189 min (range: 79–426 min) (n = 10) (13) Migraineurs, ictal: 150 min (range: 85 – 265 min). (N = 9) (13)
	Mean = 95 ± 23 min (n = 12) (24) (Patients with functional dyspepsia: mean = 126 ± 53 nmin (n = 32) (24)	Interictal: 101 ± 24 min (n = 27) (24)
	Mean = 68 min (10th percentiles: 52–86) (n = 38) (61)
GES of liquids	Mean T½: 26 min (17–34 min) (n = 7) (22) 12 min (range: 4 to 22 min) (n = 8) (62) Range : 20– > 30 min (n = 6) (63)	Mean T½: Migraineurs, interictal: 26 min (range: 17–34 min) (n = 7) (22) Migraineurs, ictal: 48 min (24–73 min) (n = 7) (22)
Epigastric impedance	Mean T½: 9 ± 5 min (n = 64) (24) Range: 13–30 min (n = 6) (63)	Mean T½: Migraineurs, interictal: 10 ± min (n = 46) (23). Migraine, moderate to severe attacks (n = 11): 29 to > 60 min (24)

GES: gastric emptying scintigraphy; min: minutes.

Table 4.

Recommendations or statements in official guidelines concerning use of oral metoclopramide as an adjunctive drug, supposedly for antiemetic or prokinetic effect, in the acute treatment of migraine.

European Federation of Neurological Society 2009 (10)	‘Before intake of NSAID and triptans, oral metoclopramide or domperidone is recommended’
Canadian Headache Society 2013 (57)	‘Metoclopramide (10 mg orally) is recommended for use with acute migraine medications for migraine attacks to improve relief of nausea.’
French Society for the Study of Migraine Headache 2014 (58)	‘The association of metoclopramide with acetylsalicylic acid improves digestive symptoms, but does not increase the analgesic effect.’
American Headache Society 2015 (59)	(Only IV metoclopramide as acute treatment of migraine is briefly mentioned.)

NSAID: nonsteroidal anti-inflammatory drug; IV: intravenous.

Finally, intravenous metoclopramide probably has some antimigraine effect per se (58,59), but there is no evidence for an effect of 10 mg oral metoclopramide. Thus in one cross-over trial with 49 migraine patients, oral metoclopramide 10 mg was not better than placebo for any of the seven efficacy parameters (26).

My clinical recommendations on the use of antiemetic and prokinetic drugs in the treatment of migraine attacks

In a recent review from 2015 on acute migraine treatment in adults, metoclopramide is recommended as an antiemetic because it is the drug with the greatest evidence for antiemetic effect in migraine (60).

It should be noted that because of the risk of neurological side effects the European Medicines Agency (EMA) has from 2013 restricted the use of metoclopramide to only short-term use (up to five days), which should not cause problems in acute migraine treatment. According to the EMA metoclopramide remains indicated in adults ‘for symptomatic treatment of nausea and vomiting including that associated with acute migraine (where it may also be used to improve absorption of oral analgesics)’.

In my view, prokinetic and antiemetic drugs such as metoclopramide and domperidone should not be combined routinely with oral analgesics or oral triptans. If, however, nausea is severe or vomiting occurs, treatment with an antiemetic with proven efficacy on the nausea of migraine can be indicated. In this case, despite the lack of evidence for an additional effect on migraine of a prokinetic drug and analgesics (10), an antiemetic with a prokinetic effect like metoclopramide should be preferred to thiethylperazine, for example, a phenothiazine antiemetic without prokinetic effect which could not normalise the absorption of effervescent aspirin (20).

So in adults I would suggest treatment with metoclopramide for severe nausea/vomiting associated with migraine. In children domperidone, which does not cross the blood-brain barrier, should be used instead.

Article highlights

Delayed absorption of drugs during migraine occurs with some but not all drugs.

Prokinetic and antiemetic drugs should not be routinely combined with oral analgesics or oral triptans.

If nausea is severe or vomiting occurs, treatment with an antiemetic, e.g. metoclopramide, with proven efficacy on the nausea of migraine can be used.

Gastric emptying is most likely normal in the majority of migraine patients outside attacks.

Footnotes

Declaration of conflicting interests

The author declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Funding

The author received no financial support for the research, authorship, and/or publication of this article.

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Delayed absorption of many (paracetamol,aspirin,other NSAIDs and zolmitriptan) but not all (sumatriptan,rizatriptan) drugs during migraine attacks and most likely normal gastric emptying outside attacks. A review

Abstract

Background

Results

Conclusions and possible clinical implications

Keywords

Introduction

Methods

Search of the literature for studies for review

Results

Studies included

Pharmacokinetic investigations of drugs during and outside migraine attacks

Clinical studies on the possible increase of antimigraine effect of an analgesic by adding a prokinetic antiemetic drug

Investigations of gastric emptying during and outside migraine attacks

The effect of sumatriptan on gastric emptying in normal individuals and absorption of paracetamol in migraineurs

Discussion

Possible delay of absorption of drugs during migraine attacks

Gastric motility measured during and outside migraine attacks

The effect of sumatriptan on gastric emptying in humans

Possible clinical implications

The lack of evidence of increased antimigraine effect of analgesics plus metoclopramide

My clinical recommendations on the use of antiemetic and prokinetic drugs in the treatment of migraine attacks

Article highlights

Footnotes

Declaration of conflicting interests

Funding

References