Parenteral metoclopramide for acute migraine: meta-analysis of randomised controlled trials
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《英国医生杂志》
1 Department of Psychiatry, University of Cambridge, Cambridge CB2 2QQ, 2 Program in Emergency Medicine, Michigan State University, MI, 49503, USA, 3 Department of Emergency Medicine, Providence Health Care and St Paul's Hospital, Vancouver, BC, Canada, 4 Department of Medicine, University of Alberta, Edmonton, AB, Canada, 5 Division of Emergency Medicine, University of Alberta, 1G1.43 Walter Mackenzie Health Sciences Center, 8440-112 Street, Edmonton, AB, Canada T6G 2B7
Correspondence to: B H Rowe Brian.Rowe@ualberta.ca
Abstract
Migraine headache is a common problem in adult populations, with 6% of men and 15-17% of women experiencing around 36 episodes each a year.1 2 Migraine can be disabling; the average length of bed rest during an episode is 4.5 hours for men and 6.0 hours for women.2 This impairs quality of life, limits daily activities, and strains personal and professional relationships.3 Migraine headaches have important economic effects due to lost productivity and increased utilisation of healthcare services.2
The pathophysiology of migraine is poorly understood, and there is no clear consensus on the best treatment for acute attacks. Current clinical guidelines recommend agents such as sumatriptan, dihydroergotamine, ergotamine, chlorpromazine, and prochlorperazine.4 5 Metoclopramide has long been used for the treatment of nausea associated with acute migraine. In addition to its antiemetic properties, metoclopramide relieves gastric stasis and has the potential to enhance the absorption of other analgesics.6 In the late 1970s, anecdotal case reports suggested that patients with migraine who received metoclopramide for nausea experienced substantial pain relief before they had received an analgesic.7 Subsequent studies concluded that the dopamine antagonist properties of metoclopramide might make it effective as a single agent to treat acute migraine.8 Other dopamine antagonists such as prochlorperazine and chlorpromazine have also shown effectiveness in migraine.5
We assessed the evidence from controlled trials on the efficacy and tolerability of parenteral metoclopramide for acute migraine in adults.
Methods
We identified 596 abstracts, of which 36 were potentially relevant articles. Independent review of these 36 reports led to the inclusion of 13 studies (fig 1).12-24 As three of these studies had multiple arms (table and table on bmj.com), we were able to make 17 total comparisons. Study methods varied significantly, particularly for comparators and outcomes, and study quality was generally poor. Comparisons included metoclopramide with placebo, metoclopramide with other antiemetics, metoclopramide with non-antiemetics, and metoclopramide combinations with other antimigraine regimens (see table).
Fig 1 Identification of potentially relevant studies in review
Descriptive characteristics of studies included in systematic review
Metoclopramide versus placebo
Five studies (263 patients) compared metoclopramide with placebo.12-16 Metoclopramide was superior to placebo for all outcomes related to pain and nausea, although differences were not always statistically significant. Pooled data from three studies showed that metoclopramide more often led to significant reductions in headache pain (odds ratio 2.84, 95% confidence interval 1.05 to 7.68; fig 2), and in these studies, patients who received metoclopramide were significantly less likely to require rescue drugs (0.21, 0.05 to 0.85).12 13 15 Three studies suggested that metoclopramide produced larger improvements in pain scores on a visual analogue scale, but no standard deviations were reported, preventing statistical pooling.14-16 One study reported that metoclopramide was more likely than placebo to provide complete resolution of migraine; the difference, however, was not statistically significant (2.16, 0.36 to 12.84).16 Four studies found that metoclopramide was more effective than placebo in reducing nausea (4.20, 1.70 to 10.36),12 14-16 but only two studies15 16 reported relapse of migraine, and these found a statistically insignificant advantage favouring metoclopramide (0.30, 0.03 to 3.16).
Fig 2 Metoclopramide compared with placebo in reducing pain from acute migraine
Only two studies reported adverse events.13 16 One found a statistically insignificant increase in restlessness in the metoclopramide group (2.27, 0.19 to 26.81) whereas the other reported no restlessness, dystonic reactions, hypotension, or seizures in either treatment group.
Our sensitivity analyses failed to identify differences between studies of high and low quality.
Metoclopramide versus other antiemetics
Three studies (194 patients) compared metoclopramide with other antiemetics (chlorpromazine and prochlorperazine).15-17 These studies suggested that metoclopramide was less effective in relieving pain and nausea, although differences were not always statistically significant. Two studies16 17 found no difference in the rate of complete resolution of migraine (0.64, 0.23 to 1.76) whereas two15 17 found that metoclopramide was less likely to provide significant relief of headache (0.39, 0.18 to 0.87); however, in one study,17 reduction in pain scores on a visual analogue scale were not different between groups (weighted mean difference -0.53, 95% confidence interval -1.63 to 0.57). Pooled results from all three studies showed that patients who received metoclopramide were more likely to require rescue drugs (odds ratio 2.08, 1.04 to 4.17). Two studies found no significant differences in relapse of migraine (3.95, 0.88 to 17.66).15 17 Metoclopramide was less effective than other antiemetics in reducing nausea, but these differences were not statistically significant.
Two studies looked at adverse events.16 17 One reported no restlessness, dystonic reactions, hypotension, or seizures in either treatment group, whereas the other described several subgroups of adverse events (restlessness, drowsiness, nasal congestion, nausea, dizziness, dry mouth, significant falls in diastolic or systolic blood pressure) but found no statistically significant differences between groups.
No sensitivity analyses on study quality were possible because the studies were of high quality.
Metoclopramide versus non-antiemetics
Two studies (60 patients) compared metoclopramide with non-antiemetics.14 18 The first found no significant differences between metoclopramide and sumatriptan in the rate of complete resolution of migraine (2.27, 0.64 to 8.11), the likelihood of significant reduction of pain (18.38 to 0.96, 352.59), or the likelihood of significant reduction of nausea (19.74, 1.00 to 390.32).18 In the second study, metoclopramide was compared with ibuprofen on the basis of scores to measure pain and nausea on a visual analogue scale. Metoclopramide produced larger decreases in scores for both outcomes, but standard deviations were not reported, making analysis difficult. Patients in the metoclopramide group were significantly less likely to require rescue drugs (0.05, 0.00 to 0.56). Neither study reported adverse events, no common outcomes were reported, and no statistical pooling was possible. We did not perform sensitivity analyses because there were too few studies and no common outcomes.
Metoclopramide combinations versus other agents
Seven studies (211 patients) compared metoclopramide combinations (usually metoclopramide with dihydroergotamine) with other antimigraine regimens (hydroxyzinemeperidine, dihydroergotamine alone, valproate, ibuprofen, ketorolac, promethazine-meperidine).14 19-24 Owing to significant heterogeneity in study methods (see table), particularly for comparison treatments, studies were not pooled statistically.
One study19 showed that complete resolution of migraine was significantly more likely in patients who received metoclopramide (7.79, 1.79 to 33.86), and results from four studies suggested that patients who received metoclopramide were equally, or more, likely to have "significant reductions" in headache pain (fig 3). 20-23 Two studies showed that patients who received metoclopramide had equivalent, or larger, reductions in pain scores on the basis of a visual analogue scale (see fig A on bmj.com).14 19 We found no significant differences between groups for functional ability in two studies (see fig B on bmj.com)21 22 or nausea in two studies (see fig C on bmj.com).20 21 One study found no significant differences between groups in requirement for rescue drugs (0.22, 0.04 to 1.12).14 Three studies reported that patients who received metoclopramide were equally, or less, likely to have relapse of migraine (see fig D on bmj.com).20 22
Fig 3 Metoclopramide combined with other agents compared with other agents in reducing pain from acute migraine
Reporting for adverse events was inconsistent. Four studies found no significant differences for nausea between groups.19-21 24 One study found restlessness, dysphoria, and flushing more common among patients treated with metoclopramide and dihydroergotamine compared with those treated with hydroxyzine and meperidine or butorphanol, and no significant differences for dizziness.19 Another study found that drowsiness, dizziness, and an orthostatic blood pressure response were less common among patients treated with metoclopramide and dihydroergotamine compared with those treated with promethazine and meperidine.24
Because the study results were not pooled, we did not carry out sensitivity analyses.
Discussion
Stewart WF, Shechter A, Rasmussen BK. Migraine prevalence: a review of population-based studies. Neurology 1994;44(Suppl 4): S17-23.
Hu XH, Markson LE, Lipton RB, Stewart WF, Berger ML. Burden of migraine in the United States: disability and economic costs. Arch Intern Med 1999;159: 813-8.
Edmeads J, Findlay H, Tugwell P, Pryse-Phillips W, Nelson RF, Murray TJ. Impact of migraine and tension-type headache on life-style, consulting behaviour, and medication use: a Canadian population survey. Can J Neurol Sci 1993;20: 131-7.
Silberstein SD. Practice parameter: evidence-based guidelines for migraine headache (an evidence-based review): report of the Quality Standards Subcommittee of the American Academy of Neurology. Neurology 2000;55: 754-62.
Pryse-Phillips WE, Dodick DW, Edmeads JG, Gawel MJ, Nelson RF, Purdy RA, et al. Guidelines for the diagnosis and management of migraine in clinical practice. Canadian Headache Society. CMAJ 1997;156: 1273-87.
Desmond PV, Watson KJR. Metoclopramide—a review. Med J Aust 1986;144: 366-9.
Hughes JB. Metoclopramide in migraine treatment. Med J Aust 1977;2: 580.
Schwarzberg MN. Application of metoclopramide specificity in migraine attacks therapy. Headache 1994;34: 439-41.
Colman I, Innes G, Brown MD, Roberts T, Grafstein E, Rowe BH. Parenteral metoclopramide for acute migraine. Cochrane Database Syst Rev 2003: CD003972.
Dickersin K, Scherer R, Lefebvre C. Identifying relevant studies for systematic reviews. BMJ 1994;309: 1286-91.
Jadad AR, Moore RA, Carroll D, Jenkinson C, Reynolds DJ, Gavaghan DJ, et al. Assessing the quality of reports of randomized clinical trials: is blinding necessary? Controlled Clin Trials 1996;17: 1-12.
Tfelt-Hansen P, Olesen J, Aebelholt-Krabbe A, Melgaard B, Veilis B. A double blind study of metoclopramide in the treatment of migraine attacks. J Neurol Neurosurg Psychiatry 1980;43: 369-71.
Tek DS, McClellan DS, Olshaker JS, Allen CL, Arthur DC. A prospective, double-blind study of metoclopramide hydrochloride for the control of migraine in the emergency department. Ann Emerg Med 1990;19: 1083-7.
Ellis GL, Delaney J, DeHart DA, Owens A. The efficacy of metoclopramide in the treatment of migraine headache. Ann Emerg Med 1993;22: 191-5.
Coppola M, Yealy DM, Leibold RA. Randomized, placebo-controlled evaluation of prochlorperazine versus metoclopramide for emergency department treatment of migraine headache. Ann Emerg Med 1995;26: 541-6.
Jones J, Pack S, Chun E. Intramuscular prochlorperazine versus metoclopramide as single-agent therapy for the treatment of acute migraine headache. Am J Emerg Med 1996;14: 262-4.
Cameron JD, Lane PL, Speechley M. Intravenous chlorpromazine vs intravenous metoclopramide in acute migraine headache. Acad Emerg Med 1995;2: 597-602.
Estaban-Morales A, Trujillo Chavez P, Rivera Martinez CG, Salazar Zuniga A. . Revista de la Sanidad Militar Argentina 1999;53(1): 36-40.
Belgrade MJ, Ling LJ, Schleevogt MB, Ettinger MG, Ruiz E. Comparison of single-dose meperidine, butorphanol, and dihydroergotamine in the treatment of vascular headache. Neurology 1989;39: 590-2.
Edwards KR, Norton J, Behnke M. Comparison of intravenous valproate versus intramuscular dihydroergotamine and metoclopramide for acute treatment of migraine headache. Headache 2001;41: 976-80.
Haugh MJ, Lavender L, Jensen LA, Giulano R. An office-based double-blind comparison of dihydroergotamine versus dihydroergotamine/metoclopramide in the treatment of acute migraine. Headache 1992;32: 251.
Klapper JA, Stanton JS. Ketorolac versus DHE and metoclopramide in the treatment of migraine headaches. Headache 1991;31: 523-4.
Klapper JA, Stanton JS. Current emergency treatment of severe migraine headaches. Headache 1993;33: 560-2.
Scherl ER, Wilson JF. Comparison of dihydroergotamine with metoclopramide versus meperidine with promethazine in the treatment of acute migraine. Headache 1995;35: 256-9.
Tfelt-Hansen P, Block G, Dahlof C, Diener HC, Ferrari MD, Goadsby PJ, et al. Guidelines for controlled trials of drugs in migraine: second edition. Cephalalgia 2000;20: 765-86.
((Ian Colman, postgraduate1)
Correspondence to: B H Rowe Brian.Rowe@ualberta.ca
Abstract
Migraine headache is a common problem in adult populations, with 6% of men and 15-17% of women experiencing around 36 episodes each a year.1 2 Migraine can be disabling; the average length of bed rest during an episode is 4.5 hours for men and 6.0 hours for women.2 This impairs quality of life, limits daily activities, and strains personal and professional relationships.3 Migraine headaches have important economic effects due to lost productivity and increased utilisation of healthcare services.2
The pathophysiology of migraine is poorly understood, and there is no clear consensus on the best treatment for acute attacks. Current clinical guidelines recommend agents such as sumatriptan, dihydroergotamine, ergotamine, chlorpromazine, and prochlorperazine.4 5 Metoclopramide has long been used for the treatment of nausea associated with acute migraine. In addition to its antiemetic properties, metoclopramide relieves gastric stasis and has the potential to enhance the absorption of other analgesics.6 In the late 1970s, anecdotal case reports suggested that patients with migraine who received metoclopramide for nausea experienced substantial pain relief before they had received an analgesic.7 Subsequent studies concluded that the dopamine antagonist properties of metoclopramide might make it effective as a single agent to treat acute migraine.8 Other dopamine antagonists such as prochlorperazine and chlorpromazine have also shown effectiveness in migraine.5
We assessed the evidence from controlled trials on the efficacy and tolerability of parenteral metoclopramide for acute migraine in adults.
Methods
We identified 596 abstracts, of which 36 were potentially relevant articles. Independent review of these 36 reports led to the inclusion of 13 studies (fig 1).12-24 As three of these studies had multiple arms (table and table on bmj.com), we were able to make 17 total comparisons. Study methods varied significantly, particularly for comparators and outcomes, and study quality was generally poor. Comparisons included metoclopramide with placebo, metoclopramide with other antiemetics, metoclopramide with non-antiemetics, and metoclopramide combinations with other antimigraine regimens (see table).
Fig 1 Identification of potentially relevant studies in review
Descriptive characteristics of studies included in systematic review
Metoclopramide versus placebo
Five studies (263 patients) compared metoclopramide with placebo.12-16 Metoclopramide was superior to placebo for all outcomes related to pain and nausea, although differences were not always statistically significant. Pooled data from three studies showed that metoclopramide more often led to significant reductions in headache pain (odds ratio 2.84, 95% confidence interval 1.05 to 7.68; fig 2), and in these studies, patients who received metoclopramide were significantly less likely to require rescue drugs (0.21, 0.05 to 0.85).12 13 15 Three studies suggested that metoclopramide produced larger improvements in pain scores on a visual analogue scale, but no standard deviations were reported, preventing statistical pooling.14-16 One study reported that metoclopramide was more likely than placebo to provide complete resolution of migraine; the difference, however, was not statistically significant (2.16, 0.36 to 12.84).16 Four studies found that metoclopramide was more effective than placebo in reducing nausea (4.20, 1.70 to 10.36),12 14-16 but only two studies15 16 reported relapse of migraine, and these found a statistically insignificant advantage favouring metoclopramide (0.30, 0.03 to 3.16).
Fig 2 Metoclopramide compared with placebo in reducing pain from acute migraine
Only two studies reported adverse events.13 16 One found a statistically insignificant increase in restlessness in the metoclopramide group (2.27, 0.19 to 26.81) whereas the other reported no restlessness, dystonic reactions, hypotension, or seizures in either treatment group.
Our sensitivity analyses failed to identify differences between studies of high and low quality.
Metoclopramide versus other antiemetics
Three studies (194 patients) compared metoclopramide with other antiemetics (chlorpromazine and prochlorperazine).15-17 These studies suggested that metoclopramide was less effective in relieving pain and nausea, although differences were not always statistically significant. Two studies16 17 found no difference in the rate of complete resolution of migraine (0.64, 0.23 to 1.76) whereas two15 17 found that metoclopramide was less likely to provide significant relief of headache (0.39, 0.18 to 0.87); however, in one study,17 reduction in pain scores on a visual analogue scale were not different between groups (weighted mean difference -0.53, 95% confidence interval -1.63 to 0.57). Pooled results from all three studies showed that patients who received metoclopramide were more likely to require rescue drugs (odds ratio 2.08, 1.04 to 4.17). Two studies found no significant differences in relapse of migraine (3.95, 0.88 to 17.66).15 17 Metoclopramide was less effective than other antiemetics in reducing nausea, but these differences were not statistically significant.
Two studies looked at adverse events.16 17 One reported no restlessness, dystonic reactions, hypotension, or seizures in either treatment group, whereas the other described several subgroups of adverse events (restlessness, drowsiness, nasal congestion, nausea, dizziness, dry mouth, significant falls in diastolic or systolic blood pressure) but found no statistically significant differences between groups.
No sensitivity analyses on study quality were possible because the studies were of high quality.
Metoclopramide versus non-antiemetics
Two studies (60 patients) compared metoclopramide with non-antiemetics.14 18 The first found no significant differences between metoclopramide and sumatriptan in the rate of complete resolution of migraine (2.27, 0.64 to 8.11), the likelihood of significant reduction of pain (18.38 to 0.96, 352.59), or the likelihood of significant reduction of nausea (19.74, 1.00 to 390.32).18 In the second study, metoclopramide was compared with ibuprofen on the basis of scores to measure pain and nausea on a visual analogue scale. Metoclopramide produced larger decreases in scores for both outcomes, but standard deviations were not reported, making analysis difficult. Patients in the metoclopramide group were significantly less likely to require rescue drugs (0.05, 0.00 to 0.56). Neither study reported adverse events, no common outcomes were reported, and no statistical pooling was possible. We did not perform sensitivity analyses because there were too few studies and no common outcomes.
Metoclopramide combinations versus other agents
Seven studies (211 patients) compared metoclopramide combinations (usually metoclopramide with dihydroergotamine) with other antimigraine regimens (hydroxyzinemeperidine, dihydroergotamine alone, valproate, ibuprofen, ketorolac, promethazine-meperidine).14 19-24 Owing to significant heterogeneity in study methods (see table), particularly for comparison treatments, studies were not pooled statistically.
One study19 showed that complete resolution of migraine was significantly more likely in patients who received metoclopramide (7.79, 1.79 to 33.86), and results from four studies suggested that patients who received metoclopramide were equally, or more, likely to have "significant reductions" in headache pain (fig 3). 20-23 Two studies showed that patients who received metoclopramide had equivalent, or larger, reductions in pain scores on the basis of a visual analogue scale (see fig A on bmj.com).14 19 We found no significant differences between groups for functional ability in two studies (see fig B on bmj.com)21 22 or nausea in two studies (see fig C on bmj.com).20 21 One study found no significant differences between groups in requirement for rescue drugs (0.22, 0.04 to 1.12).14 Three studies reported that patients who received metoclopramide were equally, or less, likely to have relapse of migraine (see fig D on bmj.com).20 22
Fig 3 Metoclopramide combined with other agents compared with other agents in reducing pain from acute migraine
Reporting for adverse events was inconsistent. Four studies found no significant differences for nausea between groups.19-21 24 One study found restlessness, dysphoria, and flushing more common among patients treated with metoclopramide and dihydroergotamine compared with those treated with hydroxyzine and meperidine or butorphanol, and no significant differences for dizziness.19 Another study found that drowsiness, dizziness, and an orthostatic blood pressure response were less common among patients treated with metoclopramide and dihydroergotamine compared with those treated with promethazine and meperidine.24
Because the study results were not pooled, we did not carry out sensitivity analyses.
Discussion
Stewart WF, Shechter A, Rasmussen BK. Migraine prevalence: a review of population-based studies. Neurology 1994;44(Suppl 4): S17-23.
Hu XH, Markson LE, Lipton RB, Stewart WF, Berger ML. Burden of migraine in the United States: disability and economic costs. Arch Intern Med 1999;159: 813-8.
Edmeads J, Findlay H, Tugwell P, Pryse-Phillips W, Nelson RF, Murray TJ. Impact of migraine and tension-type headache on life-style, consulting behaviour, and medication use: a Canadian population survey. Can J Neurol Sci 1993;20: 131-7.
Silberstein SD. Practice parameter: evidence-based guidelines for migraine headache (an evidence-based review): report of the Quality Standards Subcommittee of the American Academy of Neurology. Neurology 2000;55: 754-62.
Pryse-Phillips WE, Dodick DW, Edmeads JG, Gawel MJ, Nelson RF, Purdy RA, et al. Guidelines for the diagnosis and management of migraine in clinical practice. Canadian Headache Society. CMAJ 1997;156: 1273-87.
Desmond PV, Watson KJR. Metoclopramide—a review. Med J Aust 1986;144: 366-9.
Hughes JB. Metoclopramide in migraine treatment. Med J Aust 1977;2: 580.
Schwarzberg MN. Application of metoclopramide specificity in migraine attacks therapy. Headache 1994;34: 439-41.
Colman I, Innes G, Brown MD, Roberts T, Grafstein E, Rowe BH. Parenteral metoclopramide for acute migraine. Cochrane Database Syst Rev 2003: CD003972.
Dickersin K, Scherer R, Lefebvre C. Identifying relevant studies for systematic reviews. BMJ 1994;309: 1286-91.
Jadad AR, Moore RA, Carroll D, Jenkinson C, Reynolds DJ, Gavaghan DJ, et al. Assessing the quality of reports of randomized clinical trials: is blinding necessary? Controlled Clin Trials 1996;17: 1-12.
Tfelt-Hansen P, Olesen J, Aebelholt-Krabbe A, Melgaard B, Veilis B. A double blind study of metoclopramide in the treatment of migraine attacks. J Neurol Neurosurg Psychiatry 1980;43: 369-71.
Tek DS, McClellan DS, Olshaker JS, Allen CL, Arthur DC. A prospective, double-blind study of metoclopramide hydrochloride for the control of migraine in the emergency department. Ann Emerg Med 1990;19: 1083-7.
Ellis GL, Delaney J, DeHart DA, Owens A. The efficacy of metoclopramide in the treatment of migraine headache. Ann Emerg Med 1993;22: 191-5.
Coppola M, Yealy DM, Leibold RA. Randomized, placebo-controlled evaluation of prochlorperazine versus metoclopramide for emergency department treatment of migraine headache. Ann Emerg Med 1995;26: 541-6.
Jones J, Pack S, Chun E. Intramuscular prochlorperazine versus metoclopramide as single-agent therapy for the treatment of acute migraine headache. Am J Emerg Med 1996;14: 262-4.
Cameron JD, Lane PL, Speechley M. Intravenous chlorpromazine vs intravenous metoclopramide in acute migraine headache. Acad Emerg Med 1995;2: 597-602.
Estaban-Morales A, Trujillo Chavez P, Rivera Martinez CG, Salazar Zuniga A. . Revista de la Sanidad Militar Argentina 1999;53(1): 36-40.
Belgrade MJ, Ling LJ, Schleevogt MB, Ettinger MG, Ruiz E. Comparison of single-dose meperidine, butorphanol, and dihydroergotamine in the treatment of vascular headache. Neurology 1989;39: 590-2.
Edwards KR, Norton J, Behnke M. Comparison of intravenous valproate versus intramuscular dihydroergotamine and metoclopramide for acute treatment of migraine headache. Headache 2001;41: 976-80.
Haugh MJ, Lavender L, Jensen LA, Giulano R. An office-based double-blind comparison of dihydroergotamine versus dihydroergotamine/metoclopramide in the treatment of acute migraine. Headache 1992;32: 251.
Klapper JA, Stanton JS. Ketorolac versus DHE and metoclopramide in the treatment of migraine headaches. Headache 1991;31: 523-4.
Klapper JA, Stanton JS. Current emergency treatment of severe migraine headaches. Headache 1993;33: 560-2.
Scherl ER, Wilson JF. Comparison of dihydroergotamine with metoclopramide versus meperidine with promethazine in the treatment of acute migraine. Headache 1995;35: 256-9.
Tfelt-Hansen P, Block G, Dahlof C, Diener HC, Ferrari MD, Goadsby PJ, et al. Guidelines for controlled trials of drugs in migraine: second edition. Cephalalgia 2000;20: 765-86.
((Ian Colman, postgraduate1)