Rescue Therapy for Acute Migraine, Part 1 - Triptans, Dihydroergotamine, and Magnesium - Headache 2012
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Rescue Therapy for Acute Migraine, Part 1 - Triptans, Dihydroergotamine, and Magnesium - Headache 2012

Rescue Therapy for Acute Migraine, Part 1 - Triptans, Dihydroergotamine, and Magnesium - Headache 2012

American Headache Society

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Rescue Therapy for Acute Migraine, Part 1 - Triptans, Dihydroergotamine, and Magnesium - Headache 2012 Document Transcript

  • 1. Review Article Rescue Therapy for Acute Migraine, Part 1: Triptans, Dihydroergotamine, and Magnesiumhead_2062 114..128 Nancy E. Kelley, MD, PhD; Deborah E. Tepper, MD Objective.—To review and analyze published reports on the acute treatment of migraine headache with triptans, dihydro- ergotamine (DHE), and magnesium in emergency department, urgent care, and headache clinic settings. Methods.—MEDLINE was searched using the terms “migraine” and “emergency,” and “therapy” or “treatment.” Reports from emergency department and urgent care settings that involved all routes of medication delivery were included. Reports from headache clinic settings were included only if medications were delivered by a parenteral route. Results.—Acute rescue treatment studies involving the triptans were available for injectable and nasal sumatriptan, as well as rizatriptan. Effectiveness varied widely, even when the pain-free and pain-relief statistics were evaluated separately. As these medications are known to work best early in the migraine, part of this variability may be attributed to the timing of triptan administration. Multiple studies compared triptans with anti-emetics, dopamine antagonists, and non-steroidal anti-inflammatory drugs. The overall percentage of patients with pain relief after taking sumatriptan was roughly equivalent to that recorded with droperidol and prochlorperazine. Sumatriptan was equivalent to DHE when only paired comparisons were performed. While the data extracted suggest that magnesium may be effective in treating all symptoms in patients experiencing migraine with aura across all migraine patients, its effectiveness seems to be limited to treating only photophobia and phonophobia. Conclusions.—Although there are relatively few studies involving health-care provider-administered triptans or DHE for acute rescue, they appear to be equivalent to the dopamine antagonists for migraine pain relief. The relatively rare inclusion of a placebo arm and the frequent use of combination medications in active treatment arms complicate the comparison of single agents with each other. Key words: migraine, emergency, treatment, dihydroergotamine, triptan, magnesium (Headache 2012;52:114-113) This review is the first installment of a 3-part series evaluating health-care provider—administered rescue therapy for acute migraine in the setting of an emergency department (ED), urgent care center, or headache clinic infusion center. Part 1 summarizes the results from published clinical studies involving triptans, dihydroergotamine (DHE), or magnesium. Pertinent information concerning migraine patho- physiology and the methodology commonly used for the assessment of migraine “rescue therapy” is also included. Part 2 will address the dopamine antago- nists, antihistamines, serotonin (5HT)3 antagonists, valproate and others (octreotide, lidocaine, nitrous oxide, propofol, and bupivacaine). Part 3 will address studies involving opioids, non-steroidal anti- inflammatory drugs (NSAIDs), steroids, and postdis- charge medications, as well as a general discussion of all therapies presented in the 3 articles. By the time he or she reaches 18 years of age, nearly every human has some personal experience From the Center for Headache and Pain, Neurological Insti- tute, Cleveland Clinic, Cleveland, Ohio, USA. Address all correspondence to D.Tepper, Center for Headache and Pain C-21, Cleveland Clinic Foundation, 9500 Euclid Avenue, Cleveland, OH 44195, USA, email: debtepper@ gmail.com Accepted for publication September 26, 2011. ISSN 0017-8748 doi: 10.1111/j.1526-4610.2011.02062.x Published by Wiley Periodicals, Inc. Headache © 2011 American Headache Society 114
  • 2. with headache. About half of the global adult popu- lation has an active headache disorder.1 Appro- ximately 10% of the global adult and pediatric popu- lation has migraine, with the highest prevalences in Europe and North America (15% and 13%, respec- tively) and the lowest in Africa (5%).1 Based on one recent survey, migraine prevalence in the USA is 12% overall (women 18%, men 6%).2 Headache is the fourth most common reason for adults in the USA to seek emergency care. Various studies have indicated that headache accounts for 1.4- 3.3 million ED visits annually in the US (1-3% of visits); at least two thirds of these visits involve a primary headache disorder.3-5 Patients who come to the ED for treatment of migraine generally have the following characteristics: symptoms unusually severe and/or prolonged; symp- toms not typical of their usual headache; and/or usual acute migraine treatment has been ineffective. Over half of migraineurs use over-the-counter “simple” analgesics to treat their headaches, and these are often ineffective.6 Few ED patients have used migraine-specific medications, such as triptans or ergotamine.7 Fiesseler et al8 reported that 14% of patients did not use any medications at all before presenting to the ED. This was significantly more likely to be the case in men than women (31% vs 9%, P = .003) and in those patients not previously seen by a neurologist (22% vs 5%, P = .004). By the definition provided by the International Classification of Headache Disorders (ICHD-2),9 migraine is a headache lasting 4-72 hours, with at least two characteristics of unilateral location, pulsating quality, moderate-to-severe intensity, aggravated by routine activity, and accompanied by photophobia and phonophobia or nausea and/or vomiting. The individual must have had at least 5 attacks, and the attacks must not be secondary. If headache has not occurred previously or is atypical, prolonged, and intractable, the individual may present for emergency evaluation and treatment. General management of migraines in the ED includes sufficient investigation for secondary causes of the acute headache and provision of effective treat- ment. Once the diagnosis of migraine has been estab- lished, the patient should be assessed for volume depletion, especially if there is a recent history of vomiting or reduced oral intake. Blood pressure should be managed and intrave- nous (IV) rehydration provided, in addition to a quiet, darkened, restful environment. Published reports suggest that medical treat- ment of migraine in the ED can be highly vari- able.10,11 For a variety of reasons, parenteral medications are used more often than oral medica- tions to treat acute migraine in ED and headache clinics. Many patients already have tried oral medi- cations at home, sometimes for several days, and these obviously have been ineffective. By the time patients arrive at the ED, they may have severe gas- troparesis, nausea, and vomiting, and therefore be less able to retain and absorb oral medications. In addition, ED physicians are motivated to use fast- acting therapies or cost-effective medications that give rapid relief of migraine with consequent discharge from the ED. Patients want rapid, complete relief of migraine pain and associated symptoms, with complete relief rated more important than rapid relief; also impor- tant to patients is that they are able to resume normal activities, that their migraine does not recur, and that any treatment-related side effects are mild and tran- sient.12,13 Migraine persists or recurs, however, in over 50% of patients after leaving the ED. Discharge plans seldom include measures to prevent recurrence or to re-treat if pain persists.14 Parenteral opiates/opioids (“narcotics”) and anti-emetics are commonly used as first-line migraine agents in US and Canadian EDs.15 There is, however, considerable variability in the frequency of narcotic use for migraine across treatment centers, ranging from 16% to 71%.11 Gupta et al7 reported that patients in their ED most often (67.5%) received dopamine antagonists, such as metoclopramide, prochlorperazine, and chlorpromazine, followed closely by opioids (64.1%), usually meperidine. About a third of their patients were treated with NSAIDs, and less than 10% received migraine “spe- cific” parenteral medications, such as sumatriptan or DHE. Patients in EDs outside of North America were most likely to be treated with parenteral NSAIDs.16,17 Headache 115
  • 3. PATHOPHYSIOLOGY OF MIGRAINE AND POTENTIAL TARGETS FOR TREATMENT Whatever the anatomical site of migraine biogen- esis, “migraine process” clearly involves meningeal mechanisms that activate nociceptive afferents that carry signals back to the brainstem.18 Migraine with aura is thought to involve cortical spreading depres- sion which progresses anteriorly from the visual cortex at a rate of 3-4 mm/minute and produces a consequent reduction in regional cerebral blood flow (oligemia).19 The perception of head pain involves trans- duction and transmission of pain signals from pain receptors and the interpretation of these pain signals by centrally located structures. Pain signals may arise from receptors located in the dura mater, the meningeal vessels, the intracranial segments of CN V, CN IX, and CN X, and the intracranial segments of the basilar, vertebral, and carotid arteries; all can transmit pain signals to the trigeminal nucleus cauda- lis (TNC) in the medulla and to the dorsal horn of the upper cervical spine.18 The activity of second order neurons in those two areas can be modified by inputs from the nucleus raphe magnus (serotonergic), peri- aqueductal gray area, locus ceruleus (noradrenergic), and rostral trigeminal nuclei, and by descending inhibitory transmissions from the cerebral cortex. These correspondingly modified signals are then relayed to the contralateral dorsomedial and ventro- posteromedial nuclei of the thalamus, a common des- tination for pain transmissions, and then on to the insular cortex, the anterior cingulate cortex, and the somatosensory cortex. Treatments for acute migraine, therefore, poten- tially may target the pain circuitry peripherally, cen- trally,or both.During the natural course of a migraine attack, both initial peripheral sensitization and, in most cases, subsequent central pain sensitization occurs. During peripheral sensitization, primary afferent neurons may become irritable and increase their spontaneous firing because of neurogenic inflamma- tion and dilation of meningeal blood vessels.With the onset of migraine, there is increased release of sub- stance P, inflammatory cytokines, and the vasodilator calcitonin gene-related peptide (CGRP), a potential vasodilator. There is also increased mast cell degra- nulation and release of histamine, sensitizing the individual to small changes in intracranial pressure, and causing the characteristic throbbing quality of migraine pain.20 Central sensitization is often marked by the development of cutaneous allodynia (the perception of pain in response to a normally non-painful sti- mulus), and this may involve the scalp, face, and even the arms. Cutaneous allodynia occurs in 79% of migraineurs.21 During central sensitization, the exci- tatory thresholds of second order neurons in the TNC and the dorsal horn of the cervical spine is reduced.22 THE STUDIES: METHODS Key words ([{migraine} AND emergency] AND [therapy OR treatment]) were searched in MEDLINE; hand searching of journals of emergency medicine and headache journals was performed, and reference lists from relevant studies also were searched. Studies included trials performed in EDs, urgent care clinics, and headache clinics. Most studies included were randomized and double-blind; if not, specific justification is provided for including the study in this review. If a study included patients with headaches other than migraine, that also has been noted. COMMON INCLUSION AND EXCLUSION CRITERIA Most studies included patients with moderate to severe head pain at baseline. A few studies also included patients with mild head pain; when this was the case, these patients were a small proportion of the total number randomized. Many studies, but not all, limited participation to patients who met ICHD cri- teria for migraine with aura or migraine without aura. Some studies based inclusion on the participant’s self- report of a prior diagnosis, while others utilized ED physicians or neurologists to diagnose the patients in the ED after informed consent was obtained but prior to randomization. Typical exclusion criteria included: (1) age <18 or >60/65 (although some studies included patients up to age 70); (2) no well-established history of migraine; (3) recent trauma; (4) suspected secondary headache 116 January 2012
  • 4. (thunderclap headache, fever, meningismus, altered mental status, focal neurological symptoms); (5) preg- nancy; (6) contra-indication to study drug(s); or (7) use of study drug(s) (or drug from same class) within the previous 24-48 hours. MEASURES TAKEN The International Headache Society’s Clinical Trial Subcommittee recommends that the primary endpoint in acute migraine treatment research should be the proportion of patients who are pain-free at 2-hour post-medication administration; but, this crite- rion is rarely used in studies conducted in the ED setting.23 Especially if they are headache-free or sat- isfied with treatment and the ED physician believes them ready for discharge, it is impractical to retain study patients in a busy ED for the full 2 hours required. Even so, the outcome measures of pain-free at 30 minutes to 2 hours was used in some studies, as was “sustained pain-free” (ie, the proportion of those who were pain-free at 1-2 hours and were still pain-free 24-48 hours after discharge). More typically reported were “headache relief”, which utilizes: (1) a 4-point pain scale (4-PPS) – 0 = none, 1 = mild, 2 = moderate, and 3 = severe; (2) an 11-PPS, where in “0” signifies no pain up to “10” that most often is used to signify the worst pain imag- inable or “the worst pain ever experienced”; or (3) a visual analog scale (VAS). A 10-cm horizontal non- hatched line marked from 0 on the left to 100 on the right and upon which patients rate the subjective intensity of these symptoms. Headache relief is defined as either a >50% decrease in VAS scores following administration of medication and/or a 4-PPS score of 0 or 1 compared with a score of 2 or 3 at baseline.“Sustained headache relief” is defined as having headache relief while still in the ED and persisting for 24-48 hours. Many studies also evaluated functional disability, with pain assessments in the ED and then at postdis- charge follow-up.A 4-point disability scale is typically used: 0 = none (capable of normal daily activities), 1 = mild (some difficulty performing normal activi- ties), 2 = moderate (a great deal of difficulty perform- ing normal activities), 3 = severe (unable to get out of bed). When disability was reported for postdischarge follow-up, it was usually reported as the proportion of patients who achieved sustained disability-free (0 or none) status. Newer outcome measures attempt to incorporate the patients’ overall assessment of a medication’s efficacy in treating headache pain and accompany- ing symptoms, as well as treatment side effects and mode of administration. This assessment is typically reported as the proportion of patients that respond in the affirmative to “would take again” or “satisfied with current treatment.” TRIPTAN, DHE, AND MAGNESIUM When treatments from 2 different classes of medications were compared, a summary of results appears under both classes (for example, a study com- paring DHE to sumatriptan would appear under both DHE and triptans), but details of the results will only appear under one class.Where combinations of medi- cations were used, all members of the combination are represented within their own medication class. Triptans.—Two triptans (sumatriptan and rizatrip- tan) have been studied for treatment of acute migraine in the ED setting. These triptans act prima- rily as selective serotonin 1B/D (5HT1B/1D) agonists on extracerebral arteries. 5HT1B constricts blood vessels dilated by CGRP, and 5-HT1D further inhibits CGRP release from the activated peripheral nociceptive C-fibers.24 The triptans also inhibit the release of inflammatory peptides in the meninges and interfere with the transduction of pain signals to the TNC. The serum concentration of sumatriptan admin- istered subcutaneously (SQ) peaks between 10-12 minutes and is 97% bio-available.25 Rizatriptan reaches maximum concentration faster than other oral triptans.26 Triptans generally have been found to be safe and efficacious in the outpatient treatment of acute migraines. Their most common side effects are chest pressure, neck tightness, limb heaviness, tin- gling, dizziness, and flushing. Triptans are contraindi- cated for patients who have vascular disease, basilar/ hemiplegic migraine, or uncontrolled hypertension, are pregnant or at risk for pregnancy (Pregnancy Class C), or have used a different triptan or ergotamine/DHE within the previous 24 hours.27 Headache 117
  • 5. Because triptans do not affect the 5HT2A serotonin receptors, there is likely to be no risk of serotonin syndrome when used in monotherapy and no increased risk from combination with serotonin reuptake inhibitors.28 Seven randomized, double-blind studies com- pared sumatriptan 6 mg SQ with placebo or various other agents. One compared sumatriptan 20 mg nasal with ketorolac 30 mg IV. There was one study involv- ing rizatriptan 10 mg orally dissolvable tablets and one with sumatriptan 6 mg SQ, neither of which used a placebo or comparison group; these were included because they were carried out in an ED setting with a relatively large number of patients (98 and 147, respectively). Hay et al29 used rizatriptan orally dissolvable 10 mg tablets to treat 98 migraine patients in the ED and found that 73.5% were pain-free at 2 hours and 93% had headache relief. Miner et al30 determined the efficacy of sumatriptan 6 mg SC for patients with three headache diagnoses: migraine (M; n = 84), prob- able migraine (pM; n = 45), and tension-type head- aches (TTH; n = 18). Headache relief at 1 hour was similar across the groups (M 60% vs pM 56% vs TTH 67%,P = .61).Headache persisted at 48 hours in 66%. Common side effects included chest/neck tightness (8%), followed by drowsiness, increased head pain, and nausea (all 4%). Akpunonu31 found pain relief was greater with sumatriptan SQ 6 mg compared with placebo (70% vs 35%,P < .01).Side effects,most commonly“dizziness” or vertigo and tingling, were reported in 52% for sumatriptan SQ vs 27% for placebo.Five of 88 patients in the sumatriptan group reported benign chest tight- ness that resolved within 1 hour without treatment. Winner et al32 compared sumatriptan SQ 6 mg with DHE SQ. Each medication could be repeated once at 2 hours. More patients taking sumatriptan had pain relief at 2 hours (85.3% vs 73.1%, P = .002), but this advantage had dissipated at 3 hours (sumatriptan 86% vs DHE 90%).Common side effects included injection site discomfort (DHE 38.4% vs sumatriptan 17.7%), nausea (15.9% vs 5.9%),vomiting (6.5% vs 3.8%),and chest pain (0.9% vs 5.9%). Four studies compared sumatriptan with an anti- emetic. Kelly et al33 compared sumatriptan SQ 6 mg with chlorpromazine 12.5 mg IV (repeated up to 37.5 mg). All patients received IV metoclopramide 10 mg. At 2 hours, there was no difference in pain reduction as measured via VAS (sumatriptan -63.3 mm vs chlorpromazine -54.3 mm). No dystonia was reported. Friedman et al34 compared sumatriptan SQ 6 mg with IV metoclopramide 20 mg (repeated up to 80 mg) combined with IV diphenhydra- mine 25 mg. Pain reduction (11-PPS) at 2 hours was similar (sumatriptan -6.3 vs metoclopramide/ diphenhydramine -7.2), but the percentage pain-free was greater with metoclopramide/diphenhydramine (59% vs 35%, P = .04). Common side effects included weakness, drowsiness, and a feeling of heaviness, the last greater for sumatriptan (11% vs 0%, P = .05). Friedman et al35 compared sumatriptan SQ 6 mg to trimethobenzamide 200 mg intramuscular (IM) plus diphenhydramine 25 mg IM. Pain reduction (11- PPS) at 2 hours was similar (trimethobenzamide/ diphenhydramine -4.4 vs sumatriptan -6.1). Kostic et al36 compared sumatriptan SQ 6 mg to prochlor- perazine 10 mg IV plus diphenhydramine 12.5 mg SQ. Pain reduction (VAS) at 80 minutes favored prochlorperazine/diphenhydramine (-73 vs -50, P < .05). Nine of 31 patients in the prochlorperazine/ diphenhydramine group reported restlessness, but none needed treatment. Meredith37 compared sumatriptan 20 mg nasal spray to ketorolac 30 mg IV. Mean pain reduction (VAS) at 1 hour favored ketorolac over sumatriptan (-71.5 vs -22.9, P < .05). Jakubowski et al38 com- pared sumatriptan SQ 6 mg to ketorolac 15 mg IV bolused twice successively (30 mg total) for the delayed treatment (4 hours) of migraine with cuta- neous allodynia. No patient in the sumatriptan group was pain-free after 2 hours compared with 64% in the ketorolac group at 1 hour (P < .05). Table 1 summarizes details of the studies involving sumatriptan and rizatriptan. DHE.—DHE is an ergot extract that activates 5HT1B and 5HT1D receptors, as do the triptans, but DHE can also activate 5HT1A, 5HT2A, 5HT1F, 5HT2C, 5HT3, and dopamine1- and dopamine2-receptor sub- types. DHE can block activation of the TNC by block- ing the release of prostaglandins from the glia39 and is associated with a low headache recurrence rate. 118 January 2012
  • 6. Table1.—StudiesComparingRizatriptan(RTP)andSumatriptan(STP)IndividuallyWithOtherAgentsforMigraineTherapy StudyAuthors(year) Group1(G1) Treatment mgor mg/kgRoute Group2(G2) Treatment mgor mg/kgRoute Venue–#If MultipleSites Research Design%Women Mean Age Group1 #pts Group2 #pts Hayetal(2003)29 RTP10PO–––ED3-/-/-884098– Akpunonuetal(1995)31 STP6SQPCB–SQED12R/DB/P88408848 Mineretal(2007)30 STP6SQ–––ED-/-/-742884– Winneretal(1996)32 STP6SQDHE1SQCL26R/DB/-8841150145 Kellyetal(1997)33 STP6SQCPZ12.5IVERDR/-/-67342023 Friedmanetal(2005)34 STP6SQMTC20IVERDR/DB/-86343840 plus–––DPH25IV–––––– Friedmanetal(2006)35 STP6SQTMB200IMEDR/DB/-92332020 plus–––DPH25IM–––––– Kosticetal(2010)36 STP6SQPCZ10IVEDR/DB/-64293531 plus–––DPH12.5IV–––––– Meredithetal(2003)37 STP20NLKET30IVEDR/DB/-86341613 StudyAuthors(year) %Pain-Free %Pain Relief %Sustained PainRelief%Disability-Free %Requiring Rescue %Patient Satisfaction G1G2G1G2G1G2G1G2G1G2G1G2 Hayetal(2003)29 74–93–74–85–––74– Akpunonuetal(1995)31 311370353387544–––– Mineretal(2007)30 ––60–64–––35––– Winneretal(1996)32 ––857377908568–––– Kellyetal(1997)33 42418572––––––9595 Friedmanetal(2005)34 355970832740––2657387 plus–––––––––––– Friedmanetal(2006)35 453080707585538430206070 plus–––––––––––– Kosticetal(2010)36 ––70963757–––––– plus–––––––––––– Meredithetal(2003)37 2777–––––––– Superiorperformanceisindicatedbybolding;iftreatment1superior,thenalsounderlined;iftreatment2superior,thenalsoitalicized. CL=clinic;CPZ=chlorpromazine;DB=doubleblind;DHEdihydroergotamine;DPH=diphenhydramine;ED=emergencydepartment;IM=intramuscular; IV=intravenous;KET=ketorolac;MTC=metoclopramide;P=placebo-controlled;PCB=placebo;PO=oral;R=randomized,SB=singleblind,SQ=subcutaneous; TMB=trimethobenzamide;–=notstudydatapoint. Headache 119
  • 7. While DHE has fewer side effects than ergota- mine tartrate, its predecessor, it can still cause nausea, vomiting, diarrhea, abdominal cramping, vasocon- striction, and leg pain.The appearance of nausea sug- gests that the patient has been given too high a dose of DHE, mediated by activation of the 5HT2 and 5HT3 receptors. DHE is generally non-sedating. It can be easily mixed with lidocaine to prevent injection site burning. As with the triptans, DHE is contraindi- cated for patients who have vascular disease, basilar/ hemiplegic migraine, or uncontrolled hypertension, are pregnant or at risk (Pregnancy Class X), or have used a triptan or ergotamine within the previous 24 hours.28 Because DHE, unlike the triptans, does affect the 5HT2A serotonin receptor, there may be a risk of serotonin syndrome when used in combination with serotonin reuptake inhibitors. Three studies compared DHE 1 mg IV or SQ as a single agent with other single agents or with combi- nations of DHE and an anti-emetic, and an additional seven studies compared a combination of DHE 0.5- 1.0 mg IV plus an anti-emetic (usually metoclopra- mide 5-10 mg IV) with another active agent. Bell et al40 compared DHE 1 mg IV (could be repeated once) with chlorpromazine 12.5 mg IV (repeated up to 37.5 mg) and to lidocaine 50 mg IV (repeated up to 150 mg). Although there was no difference in the pain-free rate, pain reduction (11-PPS) was greater for chlorpromazine than for lidocaine or DHE (-79.5% vs -50% vs -36.7%, P < .05). As stated pre- viously, Winner et al33 showed that DHE 1 mg SQ afforded less headache relief at 2 hours than sumatriptan 6 mg SQ (73.1% vs 8.3%, P = .002), but there was no difference at 4 hours.Saadah41 compared DHE 1 mg IV with DHE 0.5 mg plus prochlorpera- zine 5 mg, DHE 1 mg plus prochlorperazine 10 mg, and DHE 1 mg plus prochlorperazine 3.5 mg. The percentage pain-free at 4 hours for DHE 1 mg alone was 83%, DHE 0.5 mg + prochlorperazine 5 mg 80%, DHE 1 mg + prochlorperazine 3.5 mg 89%,and DHE 1 mg + prochlorperazine 10 mg 95%. Side effects were reported in 100% of the patients receiving DHE alone, with the most common being sedation (30%), nausea (67%), and chest discomfort (75%). Haugh et al42 showed that DHE 1 mg IV plus metoclopramide 10 mg IV was not more effective than DHE 1 mg IV alone in the percentage of patients with headache relief at 1 hour (38%). Klapper and Stanton43 compared DHE 0.75-1 mg IV plus metoclopramide 5-10 mg IV with dexametha- sone 6 mg IV plus metoclopramide 5-10 mg IV and with placebo/normal saline IV. Headache relief at 30 minutes was equal for DHE/metoclopramide (82%) and dexamethasone/metoclopramide (78%) vs placebo (20%, P < .002). Edwards et al44 showed that DHE 1 mg IV plus metoclopramide 10 mg IV was similar in headache relief at 4 hours to valproate 500 mg IV (60%). Klapper and Stanton45 found that DHE 1 mg IV plus metoclopramide 5 mg IV pro- duced more headache relief at 1 hour than ketorolac 60 mg IM (78% vs 33%, P = .031). Belgrade et al46 compared DHE 1 mg plus metoclopramide 10 mg IV with meperidine 75 mg IM plus hydroxyzine 50 mg IM and with butorphanol 2 mg IM. Pain reduction (VAS) was greater with DHE/metoclopramide (-59) and butorphanol (-54) vs meperidine/hydroxyzine (-37, P < .01). There were more patients with >90% pain reduction with DHE/metoclopramide (38%) than butorphanol (16%) or meperidine/hydroxyzine (0%, P < .01). The most common side effect with meperidine/hydroxyzine was sedation (18%). With DHE/metoclopramide nausea (33%), dysphoria (43%), restlessness (19%), and flushing (29%) were the most common side effects; with butorphanol, it was dizziness (21%) and nausea (26%). Klapper and Stanton47 compared DHE 1 mg plus metoclopramide 10 mg IV with meperidine 75 mg plus hydroxyzine 75 mg IM. Pain reduction (4-PPS) was greater in the DHE plus metoclopramide group (-2.14 vs -0.86, P = .006). Scherl and Wilson48 showed that DHE 0.5 mg plus metoclopramide 10 mg IV was equally effective in providing 1 hour headache relief as meperidine 75 mg plus promethazine 25 mg IM (86.2% vs 77.2%); there were more lethargy and dizziness reported with promethazine/meperidine (7.2% vs 3.9%, P = .006). Carleton et al49 compared DHE 1 mg IV plus hydroxyzine 0.7 mg/kg (could repeat once) with mep- eridine 1.5 mg/kg plus hydroxyzine 0.7 mg/kg. Pain reduction (VAS) was similar in the two groups (DHE -41 vs meperidine -45, P = .81). Dizziness (DHE 2% vs meperidine 15%, P < .05) and drowsiness (DHE 120 January 2012
  • 8. 21.5% vs meperidine 22.6%) were the most common side effects. Callaham and Raskin50 pretreated all their study participants with prochlorperazine 5 mg IV, and after 30 minutes, average pain (11-PPS) dropped from 10.0 to 6.3 (NS). Three patients dropped out of the study at this point because of sufficient pain relief, and the remaining patients were randomized to receive either DHE 0.75 mg IV or NS placebo IV. Additional pain relief at 30 minutes was similar (5.2 vs 4.7). At this point, another seven patients left the study because of sufficient pain relief, four in DHE group and three in the placebo group. Then, the patients who had received DHE were given placebo and vice versa. A half hour later, those patients receiving DHE in the first round had more pain relief (2.5 vs 4.7, P = .05). Table 2 summarizes the DHE studies. Magnesium.—Magnesium can affect a number of neurochemical processes that are known to be involved in migraine pathophysiology. Magne- sium maintains calcium homeostasis by binding to N-methyl-D-aspartate glutamate receptors, modu- lates the release of substance P, and regulates the production of nitric oxide.51 Ionized magnesium can affect vascular tone52 and inhibits cortical spreading depression in rats.53 Mauskop et al54 found that 80% of patients treated with magnesium 1 g IV were pain-free 15 minutes postinfusion (P < .001). Of the 20% requir- ing rescue medications, the majority had chronic migraine (88%), and only 37.5% had low ionized magnesium (0.54 mmol/L or lower) compared with 89% who had sustained pain-freedom at 24 hours. Almost all patients experienced brief flushing with magnesium. Demirkaya et al55 compared magnesium 1 g IV with placebo/normal saline IV. Seventy percent of the patients had migraine with aura. A greater percentage receiving magnesium group was pain-free at 30 minutes (86.6% vs 6.6%; P < .0001). Mild side effects of flushing and face/neck burning were expe- rienced by 86.6% of the patients in both groups. Cete et al56 compared magnesium 2 g IV with metoclopramide 10 mg IV and with placebo/NS IV. Pain reduction (VAS) was similar for metoclopra- mide vs magnesium vs placebo (-38 vs -33 vs -24), but a smaller percentage in the metoclopramide and magnesium groups required rescue medications vs the placebo group (38% and 44% vs 65%; P = .04). Three percent of those taking metoclopramide com- plained of dystonia, and 8% taking magnesium complained of flushing. Corbo et al57 compared magnesium 2 g IV with placebo/NS IV. All patients received metoclopramide 20 mg IV (repeated up to 60 mg). Pain reduction (VAS) was not different between the groups (magnesium -55 vs placebo -71), but return to normal functioning on a 4-point disabil- ity scale was greater for the placebo group (magne- sium 8% vs placebo 17%; P < .05).The most common side effect noted was flushing (magnesium 48% vs placebo 22%, not significant). Bigal et al58 compared magnesium 1 g IV with placebo/NS IV.Although they did have significantly less photophobia and phono- phobia, for patients without aura, headache relief at 1 hour was not greater with magnesium compared with placebo (33.3% vs 16.6%). Patients with aura had greater headache relief at 1 hour with magnesium (50% vs 13.3%; P < .05). Ginder et al59 compared magnesium 2 g IV with prochlorperazine 10 mg IV for undifferentiated acute headache. At 30 minutes postinfusion, prochlorperazine provided greater headache relief (90% vs 56%; P = .04). One patient (5%) reported dysphoria with prochlorperazine, and four patients (25%) reported IV burning pain with magnesium. Frank et al60 compared magnesium 2 g IV with placebo/normal saline IV. There was no dif- ference in pain reduction (VAS) at 30 minutes (mag- nesium -16 vs placebo -15; P = .85).There were more side effects for magnesium (62% vs 29%, P = .03), most commonly flushing. Table 3 summarizes studies involving magnesium. CONCLUSIONS: TRIPTANS, DHE, AND MAGNESIUM Triptans.—In the only study to use an oral triptan in the ED, 73.5% of migraineurs were pain-free at 2 hours using rizatriptan 10 mg orally dissol- vable tablets. This was, however, not a randomized, controlled trial. In terms of “percent pain-free at two hours,” sumatriptan was similar to prochlorperazine (both ~40%) but inferior to metoclopramide plus diphen- hydramine (59% vs 35%); this percent pain-free in Headache 121
  • 9. Table2.—StudiesComparingDihydroergotamine(DHE)WithOtherAgentsforMigraineTherapy StudyAuthors(year) Group1(G1) Treatment mgor mg/kgRoute Group2(G2) Treatment mgor mg/kgRoute Venue–#If MultipleSites Research Design%Women Mean Age Group1 #pts Group2 #pts KlapperandStanton(1991)43 DHE1IVPCB–IVCLR/DB/P––910 plusMTC10IV––––––––– Saadah(1992)41 DHE1IVDHE1IVCL-/-/-80411028 plus–––PCZ10IV–––––– Haughetal(1992)42 DHE1IMDHE1IMCLR/DB/-943688 plus–––MTC10IM–––––– KlapperandStanton(1991)45 DHE1IVKET60IMCLR/DB/-––99 plusMTC10IV––––––––– ScherlandWilson(1995)48 DHE0.5IVMEP75IMEDR/-/-70311413 plusMTC10IVPMZ25IM–––––– Edwardsetal(2001)44 DHE1IVVPT500IVEDR/-/-88422020 plusMTC10IV––––––––– Belgradeetal(1989)46 DHE1IVMEP75IMEDR/-/-63302122 plusMTC10IVHDX50IM–––––– KlapperandStanton(1993)47 DHE1IVMEP75IMEDR/DB/-––1414 plusMTC10IVHDX75IM–––––– Belletal(1990)40 DHE1IVCPZ12.5IVED2R/SB/-79–2624 Winneretal(1996)32 DHE1SQSTP6SQCL26R/DB/-8841145150 Carletonetal(1998)49 DHE1IVMEP1.5IVED11R/DB/-82327878 plusHDX0.7IVHDX0.7IV–––––– 122 January 2012
  • 10. Table2.—Continued StudyAuthors(year) %Pain-Free %Pain Relief %Sustained PainRelief%Disability-Free %Requiring Rescue %Patient Satisfaction G1G2G1G2G1G2G1G2G1G2G1G2 KlapperandStanton(1991)43 ––7820––440–––– plus–––––––––––– Saadah(1992)41 8395 plus–––––––––––– Haughetal(1992)42 1325383886875787–––– plus–––––––––––– KlapperandStanton(1991)45 7833100891167 plus–––––––––––– ScherlandWilson(1995)48 86775433 plus–––––––––––– Edwardsetal(2001)44 45509060 plus–––––––––––– Belgradeetal(1989)46 ––380>90painreduction–––– plus–––––––––––– KlapperandStanton(1993)47 ––9321–––––––– plus–––––––––––– Belletal(1990)40 233337805389––50212667 Winneretal(1996)32 ––738590776885–––– Carletonetal(1998)49 ––5456362932142118–– plus–––––––––––– Superiorperformanceisindicatedbybolding;iftreatment1superior,thenalsounderlined;iftreatment2superior,thenalsoitalicized. CL=clinic;CPZ=chlorpromazine;DB=doubleblind;DPH=diphenhydramine;ED=emergencydepartment;HDX=hydroxyzine;IM=intramuscular;IV=intravenous; KET=ketorolac;MEP=meperidine;MTC=metoclopramide;P=placebo-controlled;PCB=placebo;PCZ=prochlorperazine;PMZ=promethazine;R=randomized, SB=singleblind,SQ=subcutaneous;STP=sumatriptan;VPT=valproate;–=notstudydatapoint. Headache 123
  • 11. Table3.—StudiesComparingMagnesium(MAG)WithOtherAgentsforMigraineTherapy StudyAuthors(year) Group1(G1) Treatment mgor mg/kgRoute Group2(G2) Treatment mgor mg/kgRoute Venue–#If MultipleSites Research Design%Women Mean Age Group1 #pts Group2 #pts Demirkayaetal(2001)55 MAG1000IVPLB–IVCLR/SB/P80351515 Corboetal(2001)57 MAG2000IVPLB–IVED2R/DB/P95382123 Franketal(2004)60 MAG2000IVPLB–IVED2R/DB/P76332121 Bigaletal(2002)58 MAG1000IVPLB–IVCL2R/DB/P65293030 –––––––withaura78283030 Ceteetal(2004)56 MAG1000IVPLB–IVED2R/DB/P84403640 Alsoversus–––MTC10IV––––37– Ginderetal(2000)59 MAG2000IVCPZ10IVEDR/DB/P69–1620 Mauskopetal(1996)54 MAG1000IV–––CL-/-/-733840– StudyAuthors(year) %Pain-Free %Pain Relief %Sustained PainRelief%Disability-Free %Requiring Rescue %Patient Satisfaction G1G2G1G2G1G2G1G2G1G2G1G2 Demirkayaetal(2001)55 8701007–––––––– Corboetal(2001)57 ––1522––817–––– Franketal(2004)60 ––1924––––8186–– Bigaletal(2002)58 231033176747–––––– 37750138373–––––– Ceteetal(2004)56 ––47354848––4465–– Alsoversus––5257–––38––– Ginderetal(2000)59 12405690–––5050–– Mauskopetal(1996)54 80–––56–––20––– Superiorperformanceisindicatedbybolding;iftreatment1superior,thenalsounderlined;iftreatment2superior,thenalsoitalicized. CL=clinic;CPZ=chlorpromazine;DB=doubleblind;ED=emergencydepartment;IV=intravenous;MTC=metoclopramide;P=placebo-controlled;PCB=placebo; R=randomized;SB=singleblind;–=notstudydatapoint. 124 January 2012
  • 12. the metoclopramide group (59%) was, however, sub- stantially higher than that recorded in a separate study that compared percent pain-free at 2 hours for three doses of metoclopramide (10, 20, and 40 mg).61 In terms of pain relief, diphenhydramine plus prochlorperazine surpassed sumatriptan; this was not the case, however, for trimethobenzamide plus diphenhydramine. Sumatriptan was faster than DHE in providing pain relief, but the advantage was not sustained over time, with headache recurrence at 24 hours being less in the DHE group. In addition, sumatriptan nasal spray was not as effective as ketorolac IV in relieving pain. Of special note, sumatriptan was not at all effec- tive (zero patients pain-free at 2 hours) when admin- istration was delayed until after the development of central sensitization, as determined by the presence of cutaneous allodynia in the scalp and/or face of the patient. Sumatriptan SQ 6 mg as a single agent was supe- rior to placebo, with 70% having pain relief and about one third being pain-free before discharge from the ED and remaining pain-free for 24 hours. These per- centages appear modest compared with phenothia- zines (to be reviewed in a subsequent paper in this series), but with the minimal side effects resolving on their own before patients even leave the ED, sumatriptan certainly can be recommended as first- line therapy for migraine patients who have not developed cutaneous allodynia. These emergent and urgent care results are similar to those of studies using triptans for outpa- tient treatment of their migraines in which up to 40% of individual headaches were not relieved by triptans and up to 25% of patients did not respond to triptans for any of their headaches.62 Of some interest, in studies that looked at ED physician medication choices rather than efficacy of medications, patients treated with triptans tended to spend less time in the ED than those treated with other medications (112 minutes vs 265 minutes).63 DHE.—As a single agent, DHE 1 mg IV or SQ has not been as effective as prochlorperazine IV, but DHE did appear to enhance the pain relief of prochlorperazine when administered 30 minutes after, as opposed to 60 minutes after, the initial dose of prochlorperazine. Relief with DHE was slower than with sumatriptan SQ; but ultimately, DHE pro- vided similar pain relief prior to ED discharge and greater sustained pain relief at 24 hours. Five additional studies compared the commonly used combination of DHE and metoclopramide with other active agents. This combination was superior in pain relief to ketorolac and to meperidine plus hydroxyzine (2 studies) but similar to butorpha- nol, valproate, and meperidine plus a neuroleptic (promethazine or metoclopramide). The question arises as to the relative contributions of DHE and metoclopramide to pain relief. One study suggested that any additional pain relief afforded by the meto- clopramide may be minimal, given that the combina- tion of DHE plus metoclopramide was no more effective for pain relief than DHE alone. When IV DHE is used as a single agent, nausea is a common adverse event (33-67%). Pretreatment with an anti-emetic is recommended to anticipate IV DHE-induced nausea. Other side effects include sedation (22-30%), dysphoria (43%), flushing (29%), and chest discomfort (as high as 75% in one study), which usually resolve without intervention. Magnesium.—Magnesium can be effective in treat- ing all symptoms of patients who have migraine with aura, although it appears effective in treating only associated symptoms of photophobia and phonopho- bia across all migraine patients. Using magnesium in conjunction with metoclopramide, however, may worsen the therapeutic outcome perhaps through magnesium causing cerebral vasodilation. Mag- nesium has minimal side effects, chief among them being loose stools. Magnesium also can lower blood pressure temporarily. When used in combination with DHE, magnesium can help mitigate the blood pressure increase at times associated with DHE. Magnesium is safe to use in pregnancy. As noted in the introduction, Part 2 of this series will address the neuroleptics, antihistamines, serotonin (5HT)3 antagonists, valproate, and others (octreotide, lidocaine, nitrous oxide, propofol, and bupivacaine). Part 3 will address the opiates/opioids, NSAIDs, steroids, and postdischarge medications, including as well, a general discussion of all therapies presented in the 3 articles. Headache 125
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