Ignite Creation Date:
2024-05-05 @ 11:45 AM
Last Modification Date:
2024-10-26 @ 9:12 AM
Study NCT ID:
NCT00122278
Status:
COMPLETED
Last Update Posted:
2018-11-13
First Post:
2005-07-20
Brief Title:
Headache in the Emergency Department ED - A Multi-Center Research Network to Optimize the ED Treatment of Migraines
Sponsor:
Montefiore Medical Center
Organization:
Montefiore Medical Center
Study Overview
Official Title:
Parenteral Corticosteroids as Adjuvant Therapy for Migraine Headaches
Status:
COMPLETED
Status Verified Date:
2018-04
Last Known Status:
None
Delayed Posting:
No
If Stopped, Why?:
Not Stopped
Has Expanded Access:
False
If Expanded Access, NCT#:
N/A
Has Expanded Access, NCT# Status:
N/A
Acronym:
None
Brief Summary:
Migraines are a specific type of headache that frequently recur and are very painful Although there are many medications that are effective against migraines none of these medications cure 100 of migraines Another problem with migraines is that although many times they get better after intravenous IV treatment in the emergency room ER about 13 of the time migraines recur the next day The purpose of this research project is to see if adding a medication called dexamethasone to standard ER therapy will help patients get better quicker and stay pain-free more often than if they receive placebo
Detailed Description:
Parenteral Corticosteroids as Adjuvant Therapy for Migraine Headaches
A OverviewAims Five million Americans present to emergency departments ED annually with headaches 1 The majority of these patients have migraine headaches 23 Parenteral medications of proven benefit for acute migraines include the triptans 4 dopamine-receptor antagonists 5-11 non-steroidals 12 and dihydroergotamine 13 Although these distinct classes of medication are often effective for the treatment of acute migraines their use is complicated by treatment failures 4914 recurrence of headache 1516 and side effects 17 all of which are of concern for patients with migraines 18 The ideal medication which would rapidly alleviate migraine pain without any recurrence of pain or side effects has not yet been identified
The role of corticosteroids in acute migraines is ill-defined Although used in patients with intractable migraines this class of medication is not widely used in typical migraine attacks However limited clinical data suggest that corticosteroids decrease the rate of recurrent headaches 19-21 and might decrease the pain of an acute attack 22 Further research is needed to define the role of corticosteroids in the ED treatment of acute migraine headaches
Specific Aim The specific aim of this study is to determine the efficacy of ten milligrams of parenteral dexamethasone as adjuvant therapy for the emergency department treatment of migraine headaches
Primary Hypothesis Twenty four hours after medication administration a greater percentage of migraine subjects who received dexamethasone will have
sustained pain-free headache relief and
no headache-related functional impairment when compared to subjects who receive placebo
Both groups will also receive the standard of care
Secondary Hypothesis Two hours after medication administration a greater percentage of migraine subjects who received dexamethasone will be headache pain-free when compared to subjects who receive placebo
B Background and Significance
Despite standard treatment a large percentage of emergency migraineurs continue to suffer from headaches after ED discharge Recurrent or persistent headaches rated as moderate or severe in intensity occurred in 14-43 of subjects 24 hours after discharge in ED-based migraine clinical trials 202324 In a Canadian population 45 of headache patients reported headache-related functional impairment within 24 hours of ED discharge 16
Some reports indicate that corticosteroids decrease the rate and intensity of recurrent migraine headaches 19-21 However the investigators could not find any corticosteroid clinical trials using recommended measures and outcomes 25 in a migraine population To the best of their knowledge no controlled clinical trial has tested the efficacy of corticosteroids as primary migraine-abortive therapy
Although the pathogenesis of migraine headaches is incompletely understood a sterile neurogenic inflammation is felt to be key to the pain generating pathway that occurs in acute migraines 15 Corticosteroids theoretically mitigate this inflammation and decrease the pain and duration of acute migraine attacks
One dose of intravenous dexamethasone has been well-tolerated in migraineurs 20 If this medication proves to have efficacy for migraines then this would represent a substantial contribution to headache medicine an effective tool in the armamentarium of emergency physicians and a cheap and safe method to decrease the pain and suffering of ED migraine patients
C Methods
C1 Overview This will be a randomized double-blind placebo-controlled clinical research trial testing the efficacy of intravenous dexamethasone sodium phosphate as adjuvant therapy for acute migraine headaches All subjects will receive standard-of-care migraine-abortive medication for their migraines In addition they will receive either ten milligrams of intravenous dexamethasone sodium phosphate or a comparable amount of placebo Subjects will be followed by telephone 24 hours after medication administration
C2 Study Sites Study sites will include the emergency departments of Montefiore Medical Center Jacobi Medical Center New York Presbyterian Hospital St Lukes Medical Center Bellevue Medical Center and Kings County Medical Center
C3 Selection of Participants The attending emergency physician will refer all adult patients who present with a chief complaint of headache during the regular hours of the data collectors Under the supervision of the site investigators the data collectors will inform patients about the study and ask for their consent to participate in this study as human subjects The data collectors will include in this study any patient who has a migraine headache as defined by the International Headache Society IHS-2003 11 migraine without aura 12 migraine with aura Patients will also be included if they have an IHS probable migraine IHS-2003 161 162 26 that has lasted between 72 and 168 hours In other words patients will also be included if their headache meets all IHS migraine criteria except that the duration of the headache has been between 73 and 168 hours These probable migraine patients will be included because they represent a substantial subset of ED primary headache patients Friedman et al unpublished data and because the majority of patients with a disabling probable migraine and a history of similar headaches will respond to migraine-specific medication 27
Patients will be excluded if the emergency physician intends to perform a lumbar puncture in the ED because lumbar puncture has an independent association with 24 hour headache pain scores Patients will be excluded for persistent objective focal neurologic deficits as determined by the attending physician for fear of mistaking a stroke for a complicated migraine or for signs and symptoms concerning for other causes of malignant secondary headache such as meningitis subarachnoid hemorrhage carotid dissection or intracranial mass Patients will also be excluded for temperatures greater than 1003 degrees pregnancy or lactation or allergy or intolerance to any of the study medications Patients can only enroll once Patients over the age of 64 will be excluded for fear of increased risk of adverse reactions to study medications and increased risk of secondary headaches Patients who do not meet enrollment criteria will have basic demographic and headache variables recorded
C4 Randomization and Blinding Randomization is to be done by the research pharmacist at Montefiore Medical Center in blocks of six using computer generated random number tables available online The randomization will be stratified by study site In an order determined by the random number tables the pharmacist will insert medication into vials and place these vials into sequentially numbered brown paper research bags The research bags will be distributed by express courier in batches of six to the investigators at each site The research bags will be stored at each site in a locked location accessible to the data collectors When a subject has been identified the contents of each research bag will be administered by a clinical nurse Assignment will be known only by the research pharmacist However the assignment will accompany each research bag sealed in a small manila envelope in case a medical emergency mandates that the assignment be revealed
C5 Measures
C5a Categorical Scale As a primary measure this trial will use the four point descriptive scale recommended for use in migraine research 25 On this scale subjects are asked to characterize their migraine pain as none mild moderate or severe
C5b Disability Scale A descriptive categorical scale will be used to characterize the subjects headache-related disability On this scale subjects describe their disability as 1 none 2 mildly impaired having a little bit of difficulty doing what I usually do 3 moderately impaired having a great deal of difficulty doing what I usually do and can only do very minor activities or 4 severely impaired requiring bed rest 25
C5c Numerical Rating Scale for Pain An 11-point verbal numerical rating scale for pain will be a secondary measurement tool for this trial On this scale subjects are asked to describe their pain as a number between zero and ten with zero being no pain and ten being the worst pain imaginable This scale has been shown to perform comparably to a visual analog scale while being easier to administer 28
C6Outcomes The primary outcome will be the percentage of subjects who achieve and maintain a headache pain free state Persistent headache pain free is the recommended outcome for migraine clinical research 25 Subjects will be considered to have fulfilled the primary outcome if they achieve a pain free state in the ED and maintain this throughout the 24 hour period after receiving study medication The alternate primary outcome will be the number of subjects who report no headache-related disability for the period of time after ED discharge The major secondary outcome will be the percentage of subjects who report a headache pain-free status two hours after medication administration
Other secondary outcomes include rates of sustained headache relief moderate or severe pain becoming and maintaining a level of mild or none two-hour NRS change NRSbaseline-NRS2hours 24 hour NRS change NRSbaseline-NRS24hours need for rescue medication before two hours need for analgesic medication after discharge from the ED associated symptoms specifically weakness drowsiness dizziness unscheduled visits to a medical provider within 24 hours of medication administration and the percentage of patients who answer affirmatively to the question Do you want to receive the same medication the next time you come to the ED
C7 Data Collection Data Entry and Back-Up Data entry and follow-up of subjects will be accomplished by taking advantage of the research infrastructure in place at the Department of Emergency Medicine of the Albert Einstein College of Medicine Five full-time research assistants and one research clerk are funded by the department The research assistants are medical technician level full-time employees who have extensive clinical research experience and have passed required research ethics courses These research assistants staff the Montefiore ED during all operational hours
The initial data collection process will be performed by the data collectors at each individual site These data collectors will be different in each ED depending on the resources at the individual ED At Montefiore and Jacobi the data collectors are salaried trained technician level employees who have passed required research ethics courses The data collectors will be trained for this particular study by the principal investigator and site investigators Their training will include mock patient encounters The data collectors will use a standardized data collection instrument to collect baseline information pain scores and side effects in the ED After the ED data have been obtained the data collection instrument will be photocopied and faxed to a dedicated research clerk in the Department of Emergency Medicine at Albert Einstein College of Medicine The receiving fax machine is a private fax machine secured in an office behind two locked doors
The research clerk will be responsible for obtaining the 24 hour follow-up information At a time pre-arranged with the subject prior to the subjects discharge from the ED the research clerk will call the subject and obtain 24 hour follow-up information by reading questions off of the data collection instrument Twenty-four hour follow-up to be done during non-business hours will be performed by Montefiores research assistants who cover the ED 24 hours a day seven days every week These research assistants will retrieve the faxed data collection instruments obtain the follow-up information and then return the data collection instruments to the research clerk
The research clerk will enter all data into SPSS data entry V11 Completed data collection instruments will be sent to a second research clerk who will enter the data a second time into the same SPSS program After every ten subjects have been entered data will be backed up and stored on three different computers on two distinct campuses Prior to all analyses the two data sets will be compared Discrepancies will be corrected using the initial data collection instrument as the source The original version of each data collection instrument will be kept in a locked cabinet at its original site
C8 Medications In addition to study medication or placebo all subjects will receive standard migraine abortive therapy The optimal migraine-abortiveanalgesic medication for ED patients with acute migraine headaches has not yet been defined so the investigators have chosen intravenous metoclopramide an effective safe widely-available and economical dopamine receptor antagonist as the migraine treatment for this trial Parenteral dopamine-antagonists are recommended for use in the ED29 and are used more commonly than triptans in the ED setting 116 Metoclopramide has been shown to be at least as effective as subcutaneous sumatriptan at reducing pain 78 with comparable two hour activity limitations 30 The investigators will use 20 milligrams of intravenous metoclopramide a moderate dose when compared to their previous work 2330 In addition to metoclopramide each subject will also receive 25mg of diphenhydramine to prevent akathisia and other extra-pyramidal reactions to the metoclopramide 31 This combination of metoclopramide and diphenhydramine is commonly used in the ED setting and does not cause significant drowsiness or impairment of activities in migraineurs at two hours 30 The investigators view the potential anti-migraine effect of diphenhydramine 32 as added benefit for their subjects Metoclopramide diphenhydramine and the study medication will be placed into a 50cc bag of normal saline and administered as a slow intravenous drip over twenty minutes
Subjects who require rescue medication for persistent headache will receive another 20mg of intravenous metoclopramide This additional dose of metoclopramide is part of an ED-based protocol that has demonstrated a high rate of pain relief and patient satisfaction with a minimum of side effects 2330
Subjects who require more pain medication will receive a combination of ibuprofen and oral opiates at the discretion of the treating physician
All subjects will be discharged from the ED with two 400mg tablets of ibuprofen to be taken as needed for recurrence of headache Ibuprofen is an effective migraine treatment 9
C9 Interim Analysis Stopping Rules and Sample Size Calculation An interim analysis will be performed to detect an overwhelming superiority of the intervention A data monitoring committee will convene after 126 subjects have been enrolled The committee will look for a statistically significant difference in the primary outcome or a discrepancy in the rate of adverse effects measured by rate of hospitalization for presumed adverse reaction to medication The medications used in this study are well-known to the medical community and commonly used Neither the disease nor the medications cause mortality or significant permanent disability Therefore although the investigators will monitor the adverse effects that occur during this trial they do not anticipate that this will have a significant effect on the outcome
There are many different approaches to calculation of significance criteria that can be used in interim analyses and thus might be used to terminate a trial before the complete data are collected The investigators have chosen an intermediate approach based on the OBrien-Fleming procedure 33 and set the interim test criterion at 001 and the final test criterion at 004 Using a criterion for significance of 004 and a 2-tailed test this study will require 100 subjects in each group for a total of 200 subjects to have power of 80 to yield a statistically significant result This computation assumes that the difference in persistent headache pain-free proportions is 020 specifically 030 versus 050 the rate of persistent headache pain-free 24 hours after ED discharge in a previous similarly-dosed metoclopramide trial was 30 30 The clinical effect being sought is comparable to a number needed to treat of five the largest number needed to treat believed important to discover for this self-limited disease process The interim analysis will have adequate power 080 to discover a statistically significant difference alpha001 if the difference between the two groups is 30 60 versus 30
C10 Co-Variates The following variables will be assessed
C10a Cutaneous Allodynia Cutaneous allodynia is felt to be a marker of more intractable migraines 34 and can be tested for by lightly rubbing a 4 x 4 piece of gauze on the face of the subject 35 The data collectors will assess each subject for cutaneous allodynia prior to the administration of medication
C10b Duration of Headache Although likely to be collinear with allodynia this co-variate might be associated with intractable 24 hour headaches 20
C10c Pre-Medication In previous work although 25 of the investigators population took no analgesic medication prior to presentation to the ED this co-variate did not confound the association between study medication and persistent pain-free 30 Nevertheless the investigators will record all migraine-relevant medications used by their subjects prior to ED presentation group these by class and determine if this co-variate has a relationship with the primary outcomes
C11d Aura The investigators know of no documented association between aura and corticosteroids but this subject has been inadequately explored
C11e Prophylactic Medications In previous work 30 only a small minority of ED migraineurs were on prophylactic medication However these patients represent a sub-set of migraineurs with more severe disease
C11f Chronic Migraines Only a small minority of ED migraineurs can be classified as chronic Friedman unpublished data However these patients represent a sub-set of migraineurs at high risk of recurrent 24 hour headaches
C11g Medication-Rebound Headaches This diagnosis has been inadequately explored in the ED setting and consists of complicated headache patients The investigators will not exclude these patients from this study because they are likely to benefit from this intervention 21
C11h Site To account for site-specific differences from influencing the results subjects from each site will be randomized in blocks of six to prevent unequal representation of a particular site in either arm This will prevent any one site from overly influencing the study
C11i RaceEthnicity This will be based on subjects report The significance of this co-variate for this study is unknown
C11j Age This will be recorded The significance of this co-variate for this study is unknown
C12kGender This will be recorded The significance of this co-variate for this study is unknown
C12 Analysis The data will be analyzed in an intention-to-treat manner Once a patient is randomized and receives the dexamethasone their pain scores will be included in the 24-hour analysis regardless of whether or not they received rescue medication or completed the protocol However lost-to-follow-up subjects will be excluded from the primary analysis a sensitivity analysis will be conducted in which lost-to-follow-up subjects are assumed to have a poor outcome Study enrollment will continue until the pre-determined number of subjects have completed the primary endpoint Chi-square analysis will be used to compare rates Students t-tests will be used to compare mean differences in pain scores Multivariate regression models will be used to analyze the influence of the co-variates discussed above particularly allodynia duration of headache and use of medication prior to ED presentation Briefly evidence of confounding will be sought by looking for an association between the heterogeneous variable and both the independent study medication and dependent pain status variables Between-group differences will be expressed as means or proportions bounded by 95 confidence intervals 95 CI
References
1 Vinson DR Treatment patterns of isolated benign headache in US emergency departments Ann Emerg Med 2002 39215-22
2 Bigal M Bordini CA Speciali JG Headache in an emergency room in Brazil Sao Paulo Med J 2000 11858-62
3 Luda E Comitangelo R Sicuro L The symptom of headache in emergency departments The experience of a neurology emergency department Ital J Neurol Sci 1995 16295-301
4 Akpunonu BE Mutgi AB Federman DJ et al Subcutaneous sumatriptan for treatment of acute migraine in patients admitted to the emergency department a multicenter study Ann Emerg Med 1995 25464-9
5 Bigal ME Bordini CA Speciali JG Intravenous chlorpromazine in the emergency department treatment of migraines a randomized controlled trial J Emerg Med 2002 23141-8
6 Kelly AM Ardagh M Curry C DAntonio J Zebic S Intravenous chlorpromazine versus intramuscular sumatriptan for acute migraine J Accid Emerg Med 1997 14209-11
7 Friedman B Corbo J Lipton R et al Metoclopramide Versus Sumatriptan for the ED Treatment of Migraines Neurology 2005
8 Esteban-Morales A Chavez PT Martinez CGR Zuniga AS Respuesta clinica de metoclopramida en comparacion con sumatriptan en el tratamiento de ataques agudos de migrana Revista de la Sanidad Militar Mexico 1999 5336-40
9 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 191083-7
10 Silberstein SD Young WB Mendizabal JE Rothrock JF Alam AS Acute migraine treatment with droperidol A randomized double-blind placebo-controlled trial Neurology 2003 60315-21
11 Seim MB March JA Dunn KA Intravenous ketorolac vs intravenous prochlorperazine for the treatment of migraine headaches Acad Emerg Med 1998 5573-6
12 Meredith JT Wait S Brewer KL A prospective double-blind study of nasal sumatriptan versus IV ketorolac in migraine Am J Emerg Med 2003 21173-5
13 Winner P Ricalde O Le Force B Saper J Margul B A double-blind study of subcutaneous dihydroergotamine vs subcutaneous sumatriptan in the treatment of acute migraine Arch Neurol 1996 53180-4
14 Ellis GL Delaney J DeHart DA Owens A The efficacy of metoclopramide in the treatment of migraine headache Ann Emerg Med 1993 22191-5
15 Goadsby PJ Lipton RB Ferrari MD Migraine--current understanding and treatment N Engl J Med 2002 346257-70
16 Ducharme J Beveridge RC Lee JS Beaulieu S Emergency management of migraine is the headache really over Acad Emerg Med 1998 5899-905
17 Hardman J Limbird L Goodman and Gilmans the pharmacological basis of therapeutics 9th ed New York McGraw-Hill Health Professions Division 1996
18 Lipton RB Hamelsky SW Dayno JM What do patients with migraine want from acute migraine treatment Headache 2002 42 Suppl 13-9
19 Krymchantowski AV Barbosa JS Dexamethasone decreases migraine recurrence observed after treatment with a triptan combined with a nonsteroidal anti-inflammatory drug Arq Neuropsiquiatr 2001 59708-11
20 Innes G Macphail I Dillon E Dexamethasone prevents relapse after emergency department treatment of acute migraine a randomized clinical trial Canadian Journal of Emergency Medicine 1999 1
21 Gallagher RM Emergency treatment of intractable migraine Headache 1986 2674-5
22 Monzillo P Nemoto P Costa A Sanvito W Tratamento Agudo Da Crise De Enxaqueca Refrataria Na Emergencia Arq Neuropsiquiatr 2004 62513-518
23 Corbo J Esses D Bijur PE Iannaccone R Gallagher EJ Randomized clinical trial of intravenous magnesium sulfate as an adjunctive medication for emergency department treatment of migraine headache Ann Emerg Med 2001 38621-7
24 Cameron JD Lane PL Speechley M Intravenous chlorpromazine vs intravenous metoclopramide in acute migraine headache Acad Emerg Med 1995 2597-602
25 Tfelt-Hansen P Block G Dahlof C et al Guidelines for controlled trials of drugs in migraine second edition Cephalalgia 2000 20765-86
26 Classification and diagnostic criteria for headache disorders cranial neuralgias and facial pain Headache Classification Committee of the International Headache Society Cephalalgia 1988 8 Suppl 71-96
27 Lipton RB Cady RK Stewart WF Wilks K Hall C Diagnostic lessons from the spectrum study Neurology 2002 58S27-31
28 Bijur PE Latimer CT Gallagher EJ Validation of a verbally administered numerical rating scale of acute pain for use in the emergency department Acad Emerg Med 2003 10390-2
29 Kelly AM Migraine pharmacotherapy in the emergency department J Accid Emerg Med 2000 17241-5
30 Friedman BW Corbo J Lipton RB et al A trial of metoclopramide vs sumatriptan for the emergency department treatment of migraines Neurology 2005 64463-8
31 Drug Consult St Louis Mosby Inc 2005
32 Swidan SZ Lake AE 3rd Saper JR Efficacy of intravenous diphenhydramine versus intravenous DHE-45 in the treatment of severe migraine headache Curr Pain Headache Rep 2005 965-70
33 OBrien PC Fleming TR A multiple testing procedure for clinical trials Biometrics 1979 35549-56
34 Burstein R Collins B Jakubowski M Defeating migraine pain with triptans a race against the development of cutaneous allodynia Ann Neurol 2004 5519-26
35 Ashkenazi A Sholtzow M Young WB Prevalence of Dynamic Mechanical Brush Allodynia in MIgraine Abstract Neurology 2004 62A83
A OverviewAims Five million Americans present to emergency departments ED annually with headaches 1 The majority of these patients have migraine headaches 23 Parenteral medications of proven benefit for acute migraines include the triptans 4 dopamine-receptor antagonists 5-11 non-steroidals 12 and dihydroergotamine 13 Although these distinct classes of medication are often effective for the treatment of acute migraines their use is complicated by treatment failures 4914 recurrence of headache 1516 and side effects 17 all of which are of concern for patients with migraines 18 The ideal medication which would rapidly alleviate migraine pain without any recurrence of pain or side effects has not yet been identified
The role of corticosteroids in acute migraines is ill-defined Although used in patients with intractable migraines this class of medication is not widely used in typical migraine attacks However limited clinical data suggest that corticosteroids decrease the rate of recurrent headaches 19-21 and might decrease the pain of an acute attack 22 Further research is needed to define the role of corticosteroids in the ED treatment of acute migraine headaches
Specific Aim The specific aim of this study is to determine the efficacy of ten milligrams of parenteral dexamethasone as adjuvant therapy for the emergency department treatment of migraine headaches
Primary Hypothesis Twenty four hours after medication administration a greater percentage of migraine subjects who received dexamethasone will have
sustained pain-free headache relief and
no headache-related functional impairment when compared to subjects who receive placebo
Both groups will also receive the standard of care
Secondary Hypothesis Two hours after medication administration a greater percentage of migraine subjects who received dexamethasone will be headache pain-free when compared to subjects who receive placebo
B Background and Significance
Despite standard treatment a large percentage of emergency migraineurs continue to suffer from headaches after ED discharge Recurrent or persistent headaches rated as moderate or severe in intensity occurred in 14-43 of subjects 24 hours after discharge in ED-based migraine clinical trials 202324 In a Canadian population 45 of headache patients reported headache-related functional impairment within 24 hours of ED discharge 16
Some reports indicate that corticosteroids decrease the rate and intensity of recurrent migraine headaches 19-21 However the investigators could not find any corticosteroid clinical trials using recommended measures and outcomes 25 in a migraine population To the best of their knowledge no controlled clinical trial has tested the efficacy of corticosteroids as primary migraine-abortive therapy
Although the pathogenesis of migraine headaches is incompletely understood a sterile neurogenic inflammation is felt to be key to the pain generating pathway that occurs in acute migraines 15 Corticosteroids theoretically mitigate this inflammation and decrease the pain and duration of acute migraine attacks
One dose of intravenous dexamethasone has been well-tolerated in migraineurs 20 If this medication proves to have efficacy for migraines then this would represent a substantial contribution to headache medicine an effective tool in the armamentarium of emergency physicians and a cheap and safe method to decrease the pain and suffering of ED migraine patients
C Methods
C1 Overview This will be a randomized double-blind placebo-controlled clinical research trial testing the efficacy of intravenous dexamethasone sodium phosphate as adjuvant therapy for acute migraine headaches All subjects will receive standard-of-care migraine-abortive medication for their migraines In addition they will receive either ten milligrams of intravenous dexamethasone sodium phosphate or a comparable amount of placebo Subjects will be followed by telephone 24 hours after medication administration
C2 Study Sites Study sites will include the emergency departments of Montefiore Medical Center Jacobi Medical Center New York Presbyterian Hospital St Lukes Medical Center Bellevue Medical Center and Kings County Medical Center
C3 Selection of Participants The attending emergency physician will refer all adult patients who present with a chief complaint of headache during the regular hours of the data collectors Under the supervision of the site investigators the data collectors will inform patients about the study and ask for their consent to participate in this study as human subjects The data collectors will include in this study any patient who has a migraine headache as defined by the International Headache Society IHS-2003 11 migraine without aura 12 migraine with aura Patients will also be included if they have an IHS probable migraine IHS-2003 161 162 26 that has lasted between 72 and 168 hours In other words patients will also be included if their headache meets all IHS migraine criteria except that the duration of the headache has been between 73 and 168 hours These probable migraine patients will be included because they represent a substantial subset of ED primary headache patients Friedman et al unpublished data and because the majority of patients with a disabling probable migraine and a history of similar headaches will respond to migraine-specific medication 27
Patients will be excluded if the emergency physician intends to perform a lumbar puncture in the ED because lumbar puncture has an independent association with 24 hour headache pain scores Patients will be excluded for persistent objective focal neurologic deficits as determined by the attending physician for fear of mistaking a stroke for a complicated migraine or for signs and symptoms concerning for other causes of malignant secondary headache such as meningitis subarachnoid hemorrhage carotid dissection or intracranial mass Patients will also be excluded for temperatures greater than 1003 degrees pregnancy or lactation or allergy or intolerance to any of the study medications Patients can only enroll once Patients over the age of 64 will be excluded for fear of increased risk of adverse reactions to study medications and increased risk of secondary headaches Patients who do not meet enrollment criteria will have basic demographic and headache variables recorded
C4 Randomization and Blinding Randomization is to be done by the research pharmacist at Montefiore Medical Center in blocks of six using computer generated random number tables available online The randomization will be stratified by study site In an order determined by the random number tables the pharmacist will insert medication into vials and place these vials into sequentially numbered brown paper research bags The research bags will be distributed by express courier in batches of six to the investigators at each site The research bags will be stored at each site in a locked location accessible to the data collectors When a subject has been identified the contents of each research bag will be administered by a clinical nurse Assignment will be known only by the research pharmacist However the assignment will accompany each research bag sealed in a small manila envelope in case a medical emergency mandates that the assignment be revealed
C5 Measures
C5a Categorical Scale As a primary measure this trial will use the four point descriptive scale recommended for use in migraine research 25 On this scale subjects are asked to characterize their migraine pain as none mild moderate or severe
C5b Disability Scale A descriptive categorical scale will be used to characterize the subjects headache-related disability On this scale subjects describe their disability as 1 none 2 mildly impaired having a little bit of difficulty doing what I usually do 3 moderately impaired having a great deal of difficulty doing what I usually do and can only do very minor activities or 4 severely impaired requiring bed rest 25
C5c Numerical Rating Scale for Pain An 11-point verbal numerical rating scale for pain will be a secondary measurement tool for this trial On this scale subjects are asked to describe their pain as a number between zero and ten with zero being no pain and ten being the worst pain imaginable This scale has been shown to perform comparably to a visual analog scale while being easier to administer 28
C6Outcomes The primary outcome will be the percentage of subjects who achieve and maintain a headache pain free state Persistent headache pain free is the recommended outcome for migraine clinical research 25 Subjects will be considered to have fulfilled the primary outcome if they achieve a pain free state in the ED and maintain this throughout the 24 hour period after receiving study medication The alternate primary outcome will be the number of subjects who report no headache-related disability for the period of time after ED discharge The major secondary outcome will be the percentage of subjects who report a headache pain-free status two hours after medication administration
Other secondary outcomes include rates of sustained headache relief moderate or severe pain becoming and maintaining a level of mild or none two-hour NRS change NRSbaseline-NRS2hours 24 hour NRS change NRSbaseline-NRS24hours need for rescue medication before two hours need for analgesic medication after discharge from the ED associated symptoms specifically weakness drowsiness dizziness unscheduled visits to a medical provider within 24 hours of medication administration and the percentage of patients who answer affirmatively to the question Do you want to receive the same medication the next time you come to the ED
C7 Data Collection Data Entry and Back-Up Data entry and follow-up of subjects will be accomplished by taking advantage of the research infrastructure in place at the Department of Emergency Medicine of the Albert Einstein College of Medicine Five full-time research assistants and one research clerk are funded by the department The research assistants are medical technician level full-time employees who have extensive clinical research experience and have passed required research ethics courses These research assistants staff the Montefiore ED during all operational hours
The initial data collection process will be performed by the data collectors at each individual site These data collectors will be different in each ED depending on the resources at the individual ED At Montefiore and Jacobi the data collectors are salaried trained technician level employees who have passed required research ethics courses The data collectors will be trained for this particular study by the principal investigator and site investigators Their training will include mock patient encounters The data collectors will use a standardized data collection instrument to collect baseline information pain scores and side effects in the ED After the ED data have been obtained the data collection instrument will be photocopied and faxed to a dedicated research clerk in the Department of Emergency Medicine at Albert Einstein College of Medicine The receiving fax machine is a private fax machine secured in an office behind two locked doors
The research clerk will be responsible for obtaining the 24 hour follow-up information At a time pre-arranged with the subject prior to the subjects discharge from the ED the research clerk will call the subject and obtain 24 hour follow-up information by reading questions off of the data collection instrument Twenty-four hour follow-up to be done during non-business hours will be performed by Montefiores research assistants who cover the ED 24 hours a day seven days every week These research assistants will retrieve the faxed data collection instruments obtain the follow-up information and then return the data collection instruments to the research clerk
The research clerk will enter all data into SPSS data entry V11 Completed data collection instruments will be sent to a second research clerk who will enter the data a second time into the same SPSS program After every ten subjects have been entered data will be backed up and stored on three different computers on two distinct campuses Prior to all analyses the two data sets will be compared Discrepancies will be corrected using the initial data collection instrument as the source The original version of each data collection instrument will be kept in a locked cabinet at its original site
C8 Medications In addition to study medication or placebo all subjects will receive standard migraine abortive therapy The optimal migraine-abortiveanalgesic medication for ED patients with acute migraine headaches has not yet been defined so the investigators have chosen intravenous metoclopramide an effective safe widely-available and economical dopamine receptor antagonist as the migraine treatment for this trial Parenteral dopamine-antagonists are recommended for use in the ED29 and are used more commonly than triptans in the ED setting 116 Metoclopramide has been shown to be at least as effective as subcutaneous sumatriptan at reducing pain 78 with comparable two hour activity limitations 30 The investigators will use 20 milligrams of intravenous metoclopramide a moderate dose when compared to their previous work 2330 In addition to metoclopramide each subject will also receive 25mg of diphenhydramine to prevent akathisia and other extra-pyramidal reactions to the metoclopramide 31 This combination of metoclopramide and diphenhydramine is commonly used in the ED setting and does not cause significant drowsiness or impairment of activities in migraineurs at two hours 30 The investigators view the potential anti-migraine effect of diphenhydramine 32 as added benefit for their subjects Metoclopramide diphenhydramine and the study medication will be placed into a 50cc bag of normal saline and administered as a slow intravenous drip over twenty minutes
Subjects who require rescue medication for persistent headache will receive another 20mg of intravenous metoclopramide This additional dose of metoclopramide is part of an ED-based protocol that has demonstrated a high rate of pain relief and patient satisfaction with a minimum of side effects 2330
Subjects who require more pain medication will receive a combination of ibuprofen and oral opiates at the discretion of the treating physician
All subjects will be discharged from the ED with two 400mg tablets of ibuprofen to be taken as needed for recurrence of headache Ibuprofen is an effective migraine treatment 9
C9 Interim Analysis Stopping Rules and Sample Size Calculation An interim analysis will be performed to detect an overwhelming superiority of the intervention A data monitoring committee will convene after 126 subjects have been enrolled The committee will look for a statistically significant difference in the primary outcome or a discrepancy in the rate of adverse effects measured by rate of hospitalization for presumed adverse reaction to medication The medications used in this study are well-known to the medical community and commonly used Neither the disease nor the medications cause mortality or significant permanent disability Therefore although the investigators will monitor the adverse effects that occur during this trial they do not anticipate that this will have a significant effect on the outcome
There are many different approaches to calculation of significance criteria that can be used in interim analyses and thus might be used to terminate a trial before the complete data are collected The investigators have chosen an intermediate approach based on the OBrien-Fleming procedure 33 and set the interim test criterion at 001 and the final test criterion at 004 Using a criterion for significance of 004 and a 2-tailed test this study will require 100 subjects in each group for a total of 200 subjects to have power of 80 to yield a statistically significant result This computation assumes that the difference in persistent headache pain-free proportions is 020 specifically 030 versus 050 the rate of persistent headache pain-free 24 hours after ED discharge in a previous similarly-dosed metoclopramide trial was 30 30 The clinical effect being sought is comparable to a number needed to treat of five the largest number needed to treat believed important to discover for this self-limited disease process The interim analysis will have adequate power 080 to discover a statistically significant difference alpha001 if the difference between the two groups is 30 60 versus 30
C10 Co-Variates The following variables will be assessed
C10a Cutaneous Allodynia Cutaneous allodynia is felt to be a marker of more intractable migraines 34 and can be tested for by lightly rubbing a 4 x 4 piece of gauze on the face of the subject 35 The data collectors will assess each subject for cutaneous allodynia prior to the administration of medication
C10b Duration of Headache Although likely to be collinear with allodynia this co-variate might be associated with intractable 24 hour headaches 20
C10c Pre-Medication In previous work although 25 of the investigators population took no analgesic medication prior to presentation to the ED this co-variate did not confound the association between study medication and persistent pain-free 30 Nevertheless the investigators will record all migraine-relevant medications used by their subjects prior to ED presentation group these by class and determine if this co-variate has a relationship with the primary outcomes
C11d Aura The investigators know of no documented association between aura and corticosteroids but this subject has been inadequately explored
C11e Prophylactic Medications In previous work 30 only a small minority of ED migraineurs were on prophylactic medication However these patients represent a sub-set of migraineurs with more severe disease
C11f Chronic Migraines Only a small minority of ED migraineurs can be classified as chronic Friedman unpublished data However these patients represent a sub-set of migraineurs at high risk of recurrent 24 hour headaches
C11g Medication-Rebound Headaches This diagnosis has been inadequately explored in the ED setting and consists of complicated headache patients The investigators will not exclude these patients from this study because they are likely to benefit from this intervention 21
C11h Site To account for site-specific differences from influencing the results subjects from each site will be randomized in blocks of six to prevent unequal representation of a particular site in either arm This will prevent any one site from overly influencing the study
C11i RaceEthnicity This will be based on subjects report The significance of this co-variate for this study is unknown
C11j Age This will be recorded The significance of this co-variate for this study is unknown
C12kGender This will be recorded The significance of this co-variate for this study is unknown
C12 Analysis The data will be analyzed in an intention-to-treat manner Once a patient is randomized and receives the dexamethasone their pain scores will be included in the 24-hour analysis regardless of whether or not they received rescue medication or completed the protocol However lost-to-follow-up subjects will be excluded from the primary analysis a sensitivity analysis will be conducted in which lost-to-follow-up subjects are assumed to have a poor outcome Study enrollment will continue until the pre-determined number of subjects have completed the primary endpoint Chi-square analysis will be used to compare rates Students t-tests will be used to compare mean differences in pain scores Multivariate regression models will be used to analyze the influence of the co-variates discussed above particularly allodynia duration of headache and use of medication prior to ED presentation Briefly evidence of confounding will be sought by looking for an association between the heterogeneous variable and both the independent study medication and dependent pain status variables Between-group differences will be expressed as means or proportions bounded by 95 confidence intervals 95 CI
References
1 Vinson DR Treatment patterns of isolated benign headache in US emergency departments Ann Emerg Med 2002 39215-22
2 Bigal M Bordini CA Speciali JG Headache in an emergency room in Brazil Sao Paulo Med J 2000 11858-62
3 Luda E Comitangelo R Sicuro L The symptom of headache in emergency departments The experience of a neurology emergency department Ital J Neurol Sci 1995 16295-301
4 Akpunonu BE Mutgi AB Federman DJ et al Subcutaneous sumatriptan for treatment of acute migraine in patients admitted to the emergency department a multicenter study Ann Emerg Med 1995 25464-9
5 Bigal ME Bordini CA Speciali JG Intravenous chlorpromazine in the emergency department treatment of migraines a randomized controlled trial J Emerg Med 2002 23141-8
6 Kelly AM Ardagh M Curry C DAntonio J Zebic S Intravenous chlorpromazine versus intramuscular sumatriptan for acute migraine J Accid Emerg Med 1997 14209-11
7 Friedman B Corbo J Lipton R et al Metoclopramide Versus Sumatriptan for the ED Treatment of Migraines Neurology 2005
8 Esteban-Morales A Chavez PT Martinez CGR Zuniga AS Respuesta clinica de metoclopramida en comparacion con sumatriptan en el tratamiento de ataques agudos de migrana Revista de la Sanidad Militar Mexico 1999 5336-40
9 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 191083-7
10 Silberstein SD Young WB Mendizabal JE Rothrock JF Alam AS Acute migraine treatment with droperidol A randomized double-blind placebo-controlled trial Neurology 2003 60315-21
11 Seim MB March JA Dunn KA Intravenous ketorolac vs intravenous prochlorperazine for the treatment of migraine headaches Acad Emerg Med 1998 5573-6
12 Meredith JT Wait S Brewer KL A prospective double-blind study of nasal sumatriptan versus IV ketorolac in migraine Am J Emerg Med 2003 21173-5
13 Winner P Ricalde O Le Force B Saper J Margul B A double-blind study of subcutaneous dihydroergotamine vs subcutaneous sumatriptan in the treatment of acute migraine Arch Neurol 1996 53180-4
14 Ellis GL Delaney J DeHart DA Owens A The efficacy of metoclopramide in the treatment of migraine headache Ann Emerg Med 1993 22191-5
15 Goadsby PJ Lipton RB Ferrari MD Migraine--current understanding and treatment N Engl J Med 2002 346257-70
16 Ducharme J Beveridge RC Lee JS Beaulieu S Emergency management of migraine is the headache really over Acad Emerg Med 1998 5899-905
17 Hardman J Limbird L Goodman and Gilmans the pharmacological basis of therapeutics 9th ed New York McGraw-Hill Health Professions Division 1996
18 Lipton RB Hamelsky SW Dayno JM What do patients with migraine want from acute migraine treatment Headache 2002 42 Suppl 13-9
19 Krymchantowski AV Barbosa JS Dexamethasone decreases migraine recurrence observed after treatment with a triptan combined with a nonsteroidal anti-inflammatory drug Arq Neuropsiquiatr 2001 59708-11
20 Innes G Macphail I Dillon E Dexamethasone prevents relapse after emergency department treatment of acute migraine a randomized clinical trial Canadian Journal of Emergency Medicine 1999 1
21 Gallagher RM Emergency treatment of intractable migraine Headache 1986 2674-5
22 Monzillo P Nemoto P Costa A Sanvito W Tratamento Agudo Da Crise De Enxaqueca Refrataria Na Emergencia Arq Neuropsiquiatr 2004 62513-518
23 Corbo J Esses D Bijur PE Iannaccone R Gallagher EJ Randomized clinical trial of intravenous magnesium sulfate as an adjunctive medication for emergency department treatment of migraine headache Ann Emerg Med 2001 38621-7
24 Cameron JD Lane PL Speechley M Intravenous chlorpromazine vs intravenous metoclopramide in acute migraine headache Acad Emerg Med 1995 2597-602
25 Tfelt-Hansen P Block G Dahlof C et al Guidelines for controlled trials of drugs in migraine second edition Cephalalgia 2000 20765-86
26 Classification and diagnostic criteria for headache disorders cranial neuralgias and facial pain Headache Classification Committee of the International Headache Society Cephalalgia 1988 8 Suppl 71-96
27 Lipton RB Cady RK Stewart WF Wilks K Hall C Diagnostic lessons from the spectrum study Neurology 2002 58S27-31
28 Bijur PE Latimer CT Gallagher EJ Validation of a verbally administered numerical rating scale of acute pain for use in the emergency department Acad Emerg Med 2003 10390-2
29 Kelly AM Migraine pharmacotherapy in the emergency department J Accid Emerg Med 2000 17241-5
30 Friedman BW Corbo J Lipton RB et al A trial of metoclopramide vs sumatriptan for the emergency department treatment of migraines Neurology 2005 64463-8
31 Drug Consult St Louis Mosby Inc 2005
32 Swidan SZ Lake AE 3rd Saper JR Efficacy of intravenous diphenhydramine versus intravenous DHE-45 in the treatment of severe migraine headache Curr Pain Headache Rep 2005 965-70
33 OBrien PC Fleming TR A multiple testing procedure for clinical trials Biometrics 1979 35549-56
34 Burstein R Collins B Jakubowski M Defeating migraine pain with triptans a race against the development of cutaneous allodynia Ann Neurol 2004 5519-26
35 Ashkenazi A Sholtzow M Young WB Prevalence of Dynamic Mechanical Brush Allodynia in MIgraine Abstract Neurology 2004 62A83
Study Oversight
Has Oversight DMC:
None
Is a FDA Regulated Drug?:
True
Is a FDA Regulated Device?:
None
Is an Unapproved Device?:
None
Is a PPSD?:
None
Is a US Export?:
None
Is an FDA AA801 Violation?:
None