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

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.

References

Hurst

Stewart

. Gastric and duodenal ulcer, London: Oxford University Press, 1929.

Kaufman

Levine

. Acute gastric dilatation of stomach during attack of migraine. Radiology 1936; 27: 301–305.

Carsteirs

. Headache and gastric emptying time. Proc Roy Soc Med 1958; 51: 790–791.

Kreel

. The use of metoclopramide in radiology. Postgrad Med J 1973; 49(Suppl 4): 42–46.

Headache Classification Committee of the International Headache Society (IHS). The International Classification of Headache Disorders, 3rd edition (beta version). Cephalalgia 2013; 33: 629–808.

Volans

. Absorption of effervescent aspirin during migraine. Br Med J 1974; 4: 265–268.

Tokola

Neuvonen

. Effects of migraine attack and metoclopramide on the absorption of tolfenamic acid. Br J Clin Pharmacol 1984; 17: 667–675.

Tokola

Neuvonen

. Effect of migraine attacks on paracetamol absorption. Br J Clin Pharmacol 1984; 18: 867–871.

Thomsen

Dixon

Lassen

et al.

311C90 (zolmitriptan), a novel centrally and peripherally acting oral 5-hydroxytryptamine-1D agonist: A comparison of its absorption during a migraine attack in a migraine-free period. Cephalalgia 1996; 16: 270–275.

10.

Evers

Afra

Frese

et al.

EFNS guideline on drug treatment of migraine – revised report of an EFNS task force. Eur J Neurol 2009; 16: 968–981.

11.

Sramek

Hussey

Clements

et al.

Oral sumatriptan pharmacokinetics in the migraine state. Clin Drug Invest 1999; 17: 137–144.

12.

Cutler

Jhee

Majumdor

et al.

Pharmacokinetics of rizatriptan tablets during and between migraine attacks. Headache 1999; 39: 264–269.

13.

Aurora

Kori

Barrodale

et al.

Gastric stasis in migraine: More than just a paroxysmal abnormality during a migraine attack. Headache 2006; 46: 57–63.

14.

Volans

. Migraine and drug absorption. Clin Pharmacokinet 1978; 3: 313–318.

15.

Volans

. The effect of metoclopramide on the absorption of effervescent aspirin in migraine. Br J Clin Pharmacol 1975; 2: 27–63.

16.

Ross-Lee

Eadie

Heazlewood

et al.

Aspirin pharmacokinetics in migraine. The effect of metoclopramide. Eur J Clin Pharmacol 1983; 24: 777–785.

17.

Pini

Bertolotti

Trenti

et al.

Disposition of naproxen after oral administration during and between migraine attacks. Headache 1993; 33: 181–194.

18.

Haberer

Walls

Lener

et al.

Distinct pharmacokinetic profile and safety of a fixed-dose tablet of sumatriptan and naproxen sodium for the acute treatment of migraine. Headache 2010; 50: 357–373.

19.

Pini

Bertolotti

Bergonzani

et al.

Pharmacokinetics of tiaprofenic acid after oral administration in fasting patients during and between migraine attacks. Headache 1990; 30: 672–675.

20.

Wainscott

Kaspi

Volans

. The influence of effervescent aspirin in migraine. Br J Clin Pharmacol 1976; 3: 1015–1021.

21.

Aurora

Kori

Barrodale

et al.

Gastric stasis occurs in spontaneous, visually induced, and interictal migraine. Headache 2007; 47: 1443–1446.

22.

Yalcin

Okoyucu

Ucar

et al.

Changes in liquid emptying in migraine patients: Diagnosed with liquid phase gastric emptying scintigraphy. Intern Med J 2012; 42: 455–459.

23.

Boyle

Behan

Sutton

. A correlation between severity of migraine and delayed gastric emptying measured by an epigastric impedance method. Br J Clin Pharmacol 1990; 30: 405–409.

24.

Jung

Kim

et al.

Gastric emptying in migraine: A comparison with functional dyspepsia. J Neurogastroenterol Motil 2012; 18: 412–418.

25.

Tfelt-Hansen

Olesen

. Effervescent metoclopramide and aspirin (Migravess) versus effervescent aspirin or placebo for migraine attacks: A double-blind study. Cephalalgia 1984; 4: 107–111.

26.

Tokola

Kangasniemi

Neuvonen

et al.

Tolfenamic acid, metoclopramide, caffeine and their combinations in the treatment of migraine attacks. Cephalalgia 1984; 4: 253–263.

27.

MacGregor

Wilkinson

Bancroft

. Domperidone plus paracetamol in the treatment of migraine. Cephalalgia 1993; 13: 124–127.

28.

Houghton

Fowler

Keene

et al.

Effect of sumatriptan, a new selective 5-HT1-like agonist, on liquid gastric emptying in man. Aliment Pharmacol Ther 1992; 6: 685–691.

29.

Coulie

Tack

Maes

et al.

Sumatriptan, a selective 5-HT1 receptor agonist, induces a lag phase for gastric emptying of liquid in humans. Am J Physiol 1997; 272(Pt 1): 6902–6908.

30.

Vingerhagen

Hausken

Gilja

et al.

Influence of a 5HT1 receptor agonist on gastric accommodation and initial transpyloric flow in healthy subjects. Neurogastroenterol Motil 2000; 12: 95–101.

31.

Kwiatek

Fox

Steingoetter

et al.

Effects of clonidine and sumatriptan on postprandial gastric volume response, antral contractions waves and emptying: An MRI study. Neurogastroenterol Motil 2009; 21: 928–e71.

32.

Sakamoto

Sekino

Yamado

et al.

Effect of sumatriptan on gastric emptying: A crossover study using the BreathID system. World J Gastroenterol 2012; 18: 3415–3419.

33.

Tfelt-Hansen

Rolan

Nonsteroidal anti-inflammatory drugs in the acute treatment of migraine. In: Olesen

Goadsby

Ramadan

et al. (eds). The headaches, 3rd edn. Philadelphia: Lippincott Williams & Wilkins, 2006, pp. 449–457.

34.

Usha Rani

Naidu

Ramesh Kumar Rao

et al.

Sumatriptan delays paracetamol absorption in migraine patients. Clin Drug Invest 1996; 11: 300–304.

35.

Aurora

Papapetropoulos

Kori

et al.

Gastric stasis in migraineurs: Etiology, characteristics, and clinical and therapeutic implications. Cephalalgia 2013; 33: 408–415.

36.

Parkman

. Migraine and gastroparesis from a gastroenterologist’s perspective. Headache 2013; 53(Suppl 1): 4–10.

37.

Glerup

Bluhme

Villadsen

et al.

Gastric emptying: A comparison of three methods. Scand J Gastroenterol 2007; 42: 1182–1186.

38.

Sanaka

Koike

Yamamoto

et al.

A reliable and convenient parameter of the rate of paracetamol absorption to measure gastric emptying of liquids. Int J Clin Pharmacol Ther 1997; 35: 509–513.

39.

Kurth

Holtmann

Neufang-Huber

et al.

Prevalence of unexplained upper abdominal symptoms in patients with migraine. Cephalalgia 2006; 26: 506–510.

40.

Andress-Rothrock

King

Rothrock

. An analysis of migraine triggers in a clinic-based population. Headache 2010; 50: 1366–1370.

41.

Bonfrate

Grattagliano

Palasciano

et al.

Dynamic carbon 13 breath test for the study of liver function and gastric emptying. Gastroenterol Rep (Oxf) 2015; 3: 12–21.

42.

Shin

Camillari

. Diagnostic assessment of diabetic gastroparesis. Diabetes 2013; 62: 2667–2673.

43.

A study to compare oral sumatriptan with oral aspirin plus oral metoclopramide in the acute treatment of migraine. Oral Sumatriptan and Aspirin plus Metoclopramide Comparative Study Group. Eur Neurol 1992; 32: 177–186.

44.

Chabriat

Joire

Danchot

et al.

Combined oral lysine acetylsalicylate and metoclopramide in the acute treatment of migraine: A multicenter double-blind placebo-controlled study. Cephalalgia 1994; 14: 297–300.

45.

Pradalier

Guérard des Laurcens

Peraudeau

et al.

Calcium carbasalate-metoclopramide combination versus dihydroergotamine in the treatment of migraine attacks [article in French]. Path Biol (Paris) 1995; 43: 806–813.

46.

Tfelt-Hansen

Henry

Mulder

et al.

The effectiveness of combined oral lysine acetylsalicylate and metoclopramide compared with oral sumatriptan for migraine. Lancet 1995; 346: 923–926.

47.

Henry

Hlesse-Provost

Dillenschneider

et al.

Efficacité et tolérance de l’association effervescente aspirine-métoclopramide dans le traitment de la crise de migraine sans aura. Essai randomisé en double-aveugle contre placebo. Presse Med 1995; 24: 254–258.

48.

Le Jeunne

Gómez

Pradalier

et al.

Comparative efficacy and safety of calcium carbasalate plus metoclopramide versus ergotamine plus caffeine in the treatment of acute migraine attacks. Eur Neurol 1999; 41: 37–43.

49.

Geraud

Compagnon

Rossi

et al.

Zolmitriptan versus a combination of acetylsalicylic acid and metoclopramide in the acute oral treatment of migraine: A double-blind, randomized, three-attack study. Eur Neurol 2002; 47: 88–98.

50.

Tfelt-Hansen

. Unpublished clinical trials with sumatriptan. Lancet 2009; 374: 1501–1502.

51.

Kirth

Derry

Moore

. Aspirin with and without an antiemetic for acute migraine treatment in adults. Cochrane Database Syst Rev 2013; 4: CD008041–CD008041.

52.

Derry

Moore

. Paracetamol (acetaminophen) with and without an antiemetic for acute migraine headache in adults. Cochrane Database Syst Rev 2013; 4: CD008040–CD008040.

53.

Lampl

Voelker

Diener

. Efficacy and safety of 1,000 mg effervescent aspirin: Individual patient data meta-analysis of three trials in migraine headache and migraine accompanying symptoms. J Neurol 2007; 254: 705–712.

54.

Krymchantowski

Filho

Bigal

. Rizatriptan vs. rizatriptan plus trimebutine for the acute treatment of migraine: A double-blind, randomized, cross-over, placebo-controlled study. Cephalalgia 2006; 26: 871–874.

55.

Worthington

Pringsheim

Gawel

et al.

Canadian Headache Society Guideline: Acute drug therapy for migraine headache. Can J Neurol Sci 2013; 40(5 Suppl 3): S1–S80.

56.

Lanteri-Minet

Valade

Geraud

et al.

Revised French guidelines for the diagnosis and management of migraine in adults and children. J Headache Pain 2014; 15: 2–2.

57.

Marmura

Silberstein

Schwedt

. The acute treatment of migraine in adults: The American Headache Society evidence assessment of migraine pharmacotherapies. Headache 2015; 55: 3–20.

58.

Sumano Schellenberg E, Dryden DM, Pasichnyk D, et al. Acute migraine treatment in emergency settings. Rockville, MD: Agency for Healthcare Research and Quality (US), 2012 Nov. Report No.: 12 (13): EHC142-EF. AHRQ Comparative Effectiveness Reviews.

59.

Eken

. Reappraisal of intravenous metoclopramide in migraine attack: A systematic review and meta-analysis. Am J Emerg Med 2015; 33: 331–337.

60.

Becker

. Acute migraine treatment in adults. Headache 2015; 55: 778–793.

61.

Szarka

Camilleri

Vella

et al.

A stable isotope breath test with a standard meal for abnormal gastric emptying of solids in the clinic and in research. Clin Gastroenterol Hepatol 2008; 6: 635–648.

62.

Nimmo

Heading

Wilson

et al.

Inhibition of gastric emptying and drug absorption by narcotic analgesics. Br J Clin Pharm 1975; 2: 509–513.

63.

Sutton

Thompson

Sobnack

. Measurement of gastric emptying rates by radioactive isotope scanning and epigastric impedance. Lancet 1985; 1: 898–900.