Rescue therapy for acute migraine, Part 3 - opioids, NSAIDs, steroids, and post-discharge medications - Headache 2012


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Rescue therapy for acute migraine, Part 3 - opioids, NSAIDs, steroids, and post-discharge medications - Headache 2012

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Rescue therapy for acute migraine, Part 3 - opioids, NSAIDs, steroids, and post-discharge medications - Headache 2012

  1. 1. Review Article Rescue Therapy for Acute Migraine, Part 3: Opioids, NSAIDs, Steroids, and Post-Discharge Medicationshead_2097 467..482 Nancy E. Kelley, MD, PhD; Deborah E. Tepper, MD Objective.—The final section of this 3-part review analyzes published reports involving the acute treatment of migraine with opioids, non-steroidal anti-inflammatory drugs (NSAIDs), and steroids in the emergency department (ED), urgent care, and headache clinic settings, as well as post-discharge medications. In the Conclusion, there is a general discussion of all the therapies presented in the 3 sections. Method.—Using the terms (“migraine” AND “emergency”) AND (“therapy” OR “treatment”), the author searched MEDLINE for reports from ED and urgent care settings that involved all routes of medication delivery. Reports from headache clinic settings were included only if medications were delivered by a parenteral route. Results.—Seventy-five reports were identified that compared the efficacy and safety of multiple acute migraine medica- tions for rescue. Of the medications reviewed in Part 3, opioids, NSAIDs, and steroids all demonstrated some effectiveness. When used alone, nalbuphine and metamizole were superior to placebo. NSAIDs were inferior to the combination of metoclopramide and diphenhydramine. Meperidine was arguably equivalent when compared with ketorolac and dihydroer- gotamine (DHE) but was inferior to chlorpromazine and equivalent to the other dopamine antagonists. Steroids afford some protection against headache recurrence after the patient leaves the treatment center. Conclusions.—All 3 opioids most frequently studied – meperidine, tramadol, and nalbuphine – were superior to placebo in relieving migraine pain, although meperidine combined with promethazine was not. Opioid side effects included dizziness, sedation, and nausea.With ketorolac being the most frequently studied drug in the class, NSAIDs were generally well tolerated, and they may provide benefit even when given late in the migraine attack. The rate of headache recurrence within 24-72 hours after discharge from the ED can be greater than 50%. Corticosteroids can be useful in reducing headache recurrence after discharge. As discussed in Parts 1, 2, and 3, there are effective medications for provider-administered “rescue” in all the classes discussed. Prochlorperazine and metoclopramide are the most frequently studied of the anti-migraine medications in the emergent setting, and their effectiveness is superior to placebo. Prochlorperazine is superior or equivalent to all other classes of medications in migraine pain relief. Although there are fewer studies involving sumatriptan and DHE, relatively “migraine- specific” medications, they appear to be equivalent to the dopamine antagonists for migraine pain relief. Lack of comparisons with placebo and the frequent use of combinations of medications in treatment arms complicate the comparison of single agents to one another.When used alone, prochlorperazine, promethazine, metoclopramide, nalbuphine, and metamizole were superior to placebo. Droperidol and prochlorperazine were superior or equal in efficacy to all other treatments, although they also are more likely to produce side effects that are difficult for a patient to tolerate (especially akathisia). Metoclopramide was equivalent to prochlorperazine, and, when combined with diphenhydramine, was superior in efficacy to triptans and NSAIDs. Meperidine was arguably equivalent when compared with ketorolac and DHE but was inferior to chlorpromazine and equivalent to the other neuroleptics. Sumatriptan was inferior or equivalent to the neuroleptics and equivalent to DHE when From the Center for Headache and Pain, Neurological Institute, Cleveland Clinic, Cleveland, OH, USA. Address all correspondence to D.E.Tepper, MD, Center for Headache and Pain, Neurological Institute, Cleveland Clinic C-21, 9500 Euclid Avenue, Cleveland, OH 44195, USA, email: To download a podcast featuring further discussion of this article, please visit Accepted for publication September 22, 2011. Conflict of Interest: None ISSN 0017-8748 doi: 10.1111/j.1526-4610.2012.02097.x Published by Wiley Periodicals, Inc. Headache © 2012 American Headache Society 467
  2. 2. only paired comparisons were considered. The overall percentage of patients with pain relief after taking sumatriptan was equivalent to that observed with droperidol or prochlorperazine. Key words: migraine, emergency, treatment, dihydroergotamine, triptan, magnesium (Headache 2012;52:467-482) In Part 1 of this review on physician-administered rescue therapy for acute migraine in the emergency department (ED), urgent care, and headache clinic infusion center settings, results of trials involving trip- tans, dihydroergotamine (DHE), and magnesium sulfate were presented. Information concerning migraine pathophysiology and the commonly used methodology for studies of migraine therapy in the ED also was included. Part 2 focused on studies involving dopamine antagonists, antihistamines, 5HT3 antagonists, valproate, and others (octreotide, lidocaine, nitrous oxide, propofol, and bupivacaine). The present paper, Part 3, includes studies involving opioids, non-steroidal anti-inflammatory drugs (NSAIDs), steroids, and post-discharge medications, as well as a general discussion of all therapies pre- sented in the 3 sections. OPIOIDS Opioids can modulate nociceptive input to the trigeminocervical complex and frequently are used to treat pain in the ED. Opioids do not, however, affect the inflammatory processes or the neurovascular changes that occur in migraine. Meperidine is the opioid most studied for ED headache treatment.1 Meperidine has poor oral bioavailability, and so, is usually given parenterally. Side effects include seda- tion, respiratory and cardiac depression, and increased risk of dependency. Nalbuphine is a semi- synthetic opioid with mixed agonist–antagonist analgesic properties. Its most frequent side effect is sedation. Nalbuphine can produce respiratory depression but is considered to have low abuse potential.2 Tramadol hydrogen chloride is an “atypical” opioid used for pain management.3 Tramadol weakly binds the mu opioid receptor and also inhibits sero- tonin and norepinephrine re-uptake. Tramadol is better tolerated than other opioids because of its low impact on the respiratory, cardiac, and gastrointesti- nal (GI) systems at therapeutic doses. There is evidence that all opioids can sensitize the central nervous system to pain (especially in migraineurs) and increase the risk of medication- overuse headache.4 Klapper and Stanton compared meperidine 75 mg plus hydroxyzine 75 mg intramuscular (IM) with DHE 1 mg plus metoclopramide 10 mg to treat patients whose abortives had failed.5 Pain reduction measured on a 4-point pain scale (PPS) (4-PPS) was greater with DHE/metoclopramide (-2.14 vs -0.86, P = .006), as was the percentage with headache relief (93% vs 21%, P < .001). Carleton et al compared meperidine 1.5 mg/kg plus hydroxyzine 0.7 mg/kg IM with DHE 1 mg plus hydroxyzine 0.7 mg/kg IM.6 There was similar efficacy in pain reduction mea- sured on a visual analog scale (VAS) (55.7% vs 53.5%, P = .81). Dizziness (DHE 2% vs meperidine 15%, P < .05) and drowsiness (DHE 21.5% vs mep- eridine 22.6%) were the most common side effects. Davis et al compared meperidine 75 mg plus promethazine 25 mg IM with ketorolac 60 mg IM, and rates of headache relief at 1 hour were not sig- nificantly different (63.3% vs 50%, respectively; P = .37).7 Duarte et al found that headache relief was similar between meperidine 100 mg plus hydroxyzine 50 mg IM and ketorolac 60 mg IM.8 Harden et al also found pain reduction (VAS) to be similar between meperidine 50 mg plus prometha- zine 25 mg IM, ketorolac 60 mg IM, and placebo/ normal saline (NS) IM (60% vs 44.4% vs 54.5%).9 Lane et al compared meperidine 0.4 mg/kg plus dimenhydrinate 25 mg intravenous (IV) with chlor- promazine 0.1 mg/kg IV (up to 3 doses); pain reduction (VAS) was significantly greater with prochlorperazine (-70.6 vs -44.5, P < .05).10 Larkin and Prescott compared meperidine 75 mg IM with ketorolac 30 mg IM, and headache relief at 468 March 2012
  3. 3. 1 hour was greater with meperidine (44% vs 13%, P < .02).11 Richman et al compared meperidine 1.5 mg/kg IM with droperidol 2.5 mg; there was no difference in pain reduction (VAS) (-37 vs -47, P = .33).12 Belgrade et al compared meperidine 75 mg IM plus hydroxyzine 50 mg IM with DHE 1 mg plus metoclopramide 10 mg IV and to butorphanol 2 mg IM.13 Pain reduction (VAS) was greater with DHE plus metoclopramide (-59) and butorphanol (-54) vs meperidine/hydroxyzine (-37, P < .01). Patients experienced greater than 90% pain reduction more often in the DHE/metoclopramide group (38%) vs butorphanol (16%) or meperidine/hydroxyzine (0%, P < .01). The most common side effects with each were: meperidine/hydroxyzine = sedation (18%); DHE/metoclopramide = nausea (33%), dysphoria (43%), restlessness (19%), and flushing (29%); and butorphanol = dizziness (21%) and nausea (26%). Scherl and Wilson found that 1 hour headache relief was similar when comparing meperidine 75 mg plus promethazine 25 mg IM with DHE 0.5 mg plus meto- clopramide 10 mg IV (77.2% vs 86.2%, P = .37).14 Stiell et al compared meperidine 75 mg plus dimen- hydrinate 50 mg IM with methotrimeprazine (not available in the USA) 37.5 mg IM and found similar pain reduction (VAS) (-46.6 vs -40.3, P = .27).15 Alemdar et al compared tramadol 100 mg IV with placebo/NS IV.3 The percent pain free at 1 hour was not greater with tramadol (29.4% vs 11.8%, P = .40). Pain reduction (VAS) at 1 hour was greater in the tramadol group (70.6% vs 35.3%, P = .04). No side effects were observed at 1 hour. Engindeniz et al compared tramadol 100 mg IM with diclofenac sodium 75 mg IM, and headache relief was the same in both groups (80%).16 Tek and Mellon compared nalbuphine 10 mg IM with hydroxyzine 50 mg IM, with hydroxyzine plus nalbuphine IM, and with placebo/NS IM.2 For migraineurs without aura only, headache relief at 1 hour was greatest with nalbuphine alone compared with the other treatments (nalbuphine -2.16 vs nalbuphine/hydroxyzine -1.42 vs hydroxyzine -1.00 vs placebo -0.89, P < .01). Table 1 summarizes results from the studies involving meperidine, tramadol, and nalbuphine. NSAIDS Non-steroidal anti-inflammatory drugs (NSAIDs) can inhibit the neuroinflammatory cascade, prostaglandin synthesis, and platelet aggre- gation associated with the release of vasoactive substances, all processes that are involved in the ini- tiation and prolongation of migraine.The cyclooxyge- nase COX1/COX2 inhibitors such as ketorolac and indomethacin can inhibit the release of prostaglan- dins that activate nociceptive neurons in the spinal trigeminal nucleus, a process that leads to central sen- sitization in migraine.18 Seim et al found ketorolac 30 mg IV reduced headache less at 1 hour than prochlorperazine 10 mg IV (-40 vs -71, P = .04).19 Meredith et al found ketorolac 30 mg IV to be more effective than sumatriptan 20 mg nasal spray.20 Jakubowski et al21 compared ketorolac 15 mg IV bolused twice succes- sively (30 mg total) with sumatriptan 6 mg subcuta- neous (SQ) for the delayed treatment (4 hours) of migraine with cutaneous allodynia. No patient in the sumatriptan group was pain free after 2 hours, com- pared with 64% in the ketorolac group at 1 hour (P < .05). Patients in the sumatriptan group were then given ketorolac after the 2-hour assessment, and an hour later, 71% of these patients were pain free (P < .05). All patients who were pain free were also allodynia free (and vice versa). There were 9 patients who did not respond to ketorolac. All of these non- responders had a history of opioid use, as compared with only one of the 19 patients who did respond to ketorolac (P < .05). Three studies comparing ketorolac 60 mg IM with a combination of meperidine and promethazine or hydroxyzine yielded similar results. Davis et al compared ketorolac 60 mg IM with promethazine 25 mg IM plus meperidine 75 mg IM and found that there was no difference between the 2 groups in percentage pain free at 30 minutes (promethazine/ meperidine 20.8% vs ketorolac 22.3%).7 Harden et al found no difference in headache relief between ketorolac 60 mg IM (44.4%), meperidine 50 mg plus promethazine 25 mg IM (60%), or placebo/NS IM (54.5%).9 Duarte et al found no difference in pain reduction (VAS) for ketorolac 60 mg IM com- pared with meperidine 100 mg IM plus hydroxyzine Headache 469
  4. 4. Table1.—StudiesComparingMeperidine(MEP),Tramadol(TMD),andNalbuphine(NLB)IndividuallytoOtherAgentsforMigraineTherapy.SuperiorPerformanceis IndicatedbyBoldfacedCharacters;ifTreatment1Superior,ThenAlsoUnderlined;ifTreatment2Superior,ThenAlsoItalicized StudyFirst Author (year) Group1 (G1) Treatment mgor mg/kgRoute Group2 (G2) Treatment mgor mg/kgRoute Venue– #IfMultiple Sites Research Design%Women Mean Age Group1# Pts Group2# Pts Cicek(2004)17 MEP50IMPCBNAIMEDR/DB/P88394948 Larkin(1992)11 MEP75IMKET30IMEDR/DB77331615 Richman(2002)12 MEP1.5IMDPD2.5IMEDR/DB73321415 Harden(1996)9 MEP50IMPCBNAIMEDR/DB/P80331010 PlusPMZ25IM—NA—————— Scherl(1995)14 MEP75IMDHE0.5IVEDR70311314 PlusPMZ25IMMTC10IV————— Davis(1995)7 MEP75IMKET60IMEDR/DB81352220 PlusPMZ25IM—NA—————— Stiell(1991)15 MEP75IMMTM37.5IMEDR/DB76323737 PlusDMH50IM—NA—————— Lane(1989)10 MEP0.4IMCPZ0.1IMEDR/DB85312224 PlusDMH50IM—NA—————— Duarte(1992)8 MEP100IMKET60IMEDR/DB80352525 PlusHDX50IM—NA—————— Carleton(1998)6 MEP1.5IVDHE0.5IVED11R/DB82327878 PlusHDX0.7IVHDX0.7IV————— Belgrade(1989)13 MEP75IMDHE1IVEDR63302122 PlusHDX50IMMTC10IV————— Klapper(1993)5 MEP75IMDHE1IVCLR/DB——1414 PlusHDX75IMMTC10IV————— Engindeniz(2005)16 TMD100IMDCF75IMEDR/SB——2020 Alemdar(2007)3 TMD100IVPCBNAIVEDR/SB/P82401717 Tek(1987)2 NLB1.5IMPCBNAIMEDR/DB/P75301818 470 March 2012
  5. 5. Table1.—Continued StudyFirst Author (year) %PainFree%PainRelief%SustainedPainRelief%DisabilityFree%RequiringRescue%PatientSatisfaction G1G2G1G2G1G2G1G2G1G2G1G2 Cicek(2004)17 ——6556————4157—— Larkin(1992)11 3064413————3873—— Richman(2002)12 ——4953————4333—— Harden(1996)9 ——6055———————— Plus———————————— Scherl(1995)14 71863354—————— Plus———————————— Davis(1995)7 212255506450—————— Plus———————————— Stiell(1991)15 59517782——2730—— Plus———————————— Lane(1989)10 5685————508—— Plus———————————— Duarte(1992)8 2024———————— Plus———————————— Carleton(1998)6 5654293614321821—— Plus———————————— Belgrade(1989)13 038>90painreduction———— Plus———————————— Klapper(1993)5 2193—————— Plus———————————— Engindeniz(2005)16 35458080656070652020—— Alemdar(2007)3 291271355929—————— Tek(1987)2 5523———————— —=nodataobtained.Researchdesign–DB=doubleblind;P=placebocontrolled;R=randomized;SB=singleblind. Route–IMintramuscular;IV=intravenous.Treatments–CPZ=chlorpromazine;DCF=diclofenac;DHE=dihydroergotamine;DMH=dimenhydrinate;DPD=droperidol; HDX=hydroxyzine;KET=ketorolac;MTC=metoclopramide;MTM=methotrimeprazine;PCBplacebo;PMZ=promethazine.Venue–CL=clinic;ED=emergency department;NA=notapplicable. Headache 471
  6. 6. 50 mg IM (-33.5 vs -33.7, P = .76); the percentage complaining of nausea and drowsiness was not significantly less for ketorolac (28% vs 48%, P = .15).8 Larkin and Prescott compared ketorolac 30 mg IM with meperidine 75 mg IM; the percentage pain free at 1 hour was greater for meperidine (30% vs 6%, P < .05), as was sustained pain freedom at 24 hours (44% vs 13%, P < .02), and no adverse events were reported in either group.11 Klapper and Stanton found that ketorolac 60 mg IM was less effective in treating migraine than DHE 1 mg IV plus metoclo- pramide 5 mg IV; headache relief (4-PPS) at 1 hour was greater for DHE/metoclopramide (78% vs 33%, P = .031).22 Bigal et al compared metamizole (MMZ, also called dipyrone and not available in the USA) 1000 mg IV with placebo/NS IV.23 For migraineurs without aura, pain reduction (11-PPS) with MMZ was more effective than placebo at 30 and 60 minutes (-4.0 vs -1.2, P < .01 and -6.0 vs -3.0, P < .01). For patients with aura, the reduction was also significantly greater with MMZ at 30 and 60 minutes (-4.9 vs -0.9, P < 0.01 and -6.4 vs -1.9, P < .01). Krymchantowski et al then compared MMZ 1000 mg IV with lysine clonixinate (LC, an NSAID not available in the USA) 200 mg IV, deliv- ered as a 25 mL infusion over 5 minutes.24 The per- centage pain free at 60 and 90 minutes was greater with LC (60 minutes: 33% vs 13%, P < .001; 90 minutes: 86.7% vs 73%, P < .001). There was no follow-up post-discharge. Patients receiving LC had more injection-site pain than those receiving MMZ (13/15 vs 3/15, P < .0001). Engindeniz et al compared diclofenac sodium 75 mg IM with tramadol 100 mg IM. Headache relief at 2 hours was the same for both groups (80%).16 Ellis et al compared ibuprofen 600 mg oral (PO) with metoclopramide 10 mg IV and placebo; pain reduction (VAS) was similar for metoclopramide and metoclopramide/ibuprofen (-75 vs -50) but was greater in both these groups (P < .01) than in the ibuprofen or placebo groups, which were the same (-25).25 Table 2 summarizes the studies involving ketoro- lac, diclofenac, ibuprofen, LC, and MMZ (the last not an NSAID). STEROIDS The rate of headache recurrence within 24-72 hours following discharge from the ED can exceed 50%, and corticosteroids typically are used in the ED in an attempt to reduce the frequency of such recur- rence.26,27 The steroids can act to suppress the sterile inflammation underlying migraine and may reduce the likelihood of headache recurrence and ED “recidivism.” Klapper and Stanton compared dexamethasone 6 mg IV plus metoclopramide 5-10 mg IV with DHE 0.75-1 mg IV plus metoclopramide 5-10 mg IV and to placebo/NS IV; both DHE/metoclopramide (82%) and dexamethasone/metoclopramide (78%) pro- vided a greater percentage of patients with headache relief at 30 minutes than placebo (20%, P < .002) but were not significantly different from one.28 Baden and Hunter compared dexamethasone 10 mg IV with placebo/NS IV as adjuvant treatment to prevent recurrence 48-72 hours post-ED discharge; headache recurrence was lower with dexamethasone (12.9% vs 58.3%, P < .001), and there was an equal incidence of side effects (19.4% vs 20.8%, P = 1.0), none serious.29 Friedman et al compared dexamethasone 10 mg IV with placebo/NS IV for prevention of headache recurrence within 24 hours.30 Both groups received metoclopramide 20 mg plus diphenhydramine 25 mg IV (which could be repeated twice) for initial treat- ment.The percentage headache free at discharge who remained so at 24 hours was similar (dexamethasone 25% vs placebo 19%, P = .34). When the subgroup of patients whose headache duration was more than 72 hours at ED presentation was analyzed separately, the difference in sustained pain freedom almost met the criterion for statistical significance (dexametha- sone 38% vs placebo 13%, P = -.06). In the dexa- methasone group, 6% reported a “burning sensation” at the injection site. Rowe et al compared dexametha- sone 15 mg IV with placebo/NS IV in preventing migraine recurrence 48-72 hours and 7 days post- discharge.31 The percentage reporting severe head- ache recurrence was similar for both dexamethasone and placebo at 48-72 hours (22% vs 32%) and at 7 days (28% vs 40%). Of note, headache recurrence was more likely to occur if the pain rating on the VAS at discharge was >20 mm (P < .05). Innes et al 472 March 2012
  7. 7. Table2.—StudiesComparingKetorolac(KET),Diclofenac(DCF),Ibuprofen(IBU),Metamizole(MMZ),andLysineClonixinate(LYC)IndividuallytoOtherAgentsfor MigraineTherapy.SuperiorPerformanceisIndicatedbyBoldfacedCharacters;ifTreatment1Superior,ThenAlsoUnderlined;ifTreatment2Superior,ThenAlsoItalicized StudyFirstAuthor(year) Group1(G1) Treatment mgor mg/kgRoute Group2 (G2)Treatment mgor mg/kgRoute Venue–# IfMultipleSites Research Design%Women Mean Age Group1 #Pts Group2 #Pts Seim(1998)19 KET30IVPCZ10IVEDR/DB92333529 Jakubowski(2005)21 KET30IVSTP6SQEDR/DB——1414 Meredith(2003)20 KET30IVSTP20NSEDR/DB86341316 Larkin(1992)11 KET30IMMEP75IMEDR/DB77331516 Harden(1996)9 KET60IMMEP50IMEDR/DB/P80331010 Plus———PMZ25IM————— alsovs———PCBNAIM————10 Duarte(1992)8 KET60IMMEP100IMEDR/DB80352525 Plus———HDX50IM————— Klapper(1991b)22 KET60IMDHE1IVCLR/DB——99 Plus———MTC5IV————— Davis(1995)7 KET60IMMEP75IMEDR/DB81352022 Plus———PMZ25IM————— Engindeniz(2005)16 DCF75IMTMD100IMEDR/DB——2020 Ellis(1993)25 IBU600POPCBNAPOEDR/DB/P——1010 Bigal(2001)23 MMZ1000IVPCBNAIVEDR/DB/P73329530 ————NA——withaura69355430 Krymchantowski(2008)24 MMZ1000IVLYC200IVEDR/SB93311515 StudyFirstAuthor(year) %PainFree%PainRelief %Sustained PainRelief%DisabilityFree%RequiringRescue %Patient Satisfaction G1G2G1G2G1G2G1G2G1G2G1G2 Seim(1998)19 ——5268————1714—— Jakubowski(2005)21 640—————————— Meredith(2003)20 ——7727———————— Larkin(1992)11 6301344————7338—— Harden(1996)9 ——4460———————— Plus———————————— alsovs———55———————— Duarte(1992)8 ——2420———————— Plus———————————— Klapper(1991b)22 337889100——6711—— Plus———————————— Davis(1995)7 222150645055—————— Plus———————————— Engindeniz(2005)16 453580806065657020208075 Ellis(1993)25 ——2931———————— Bigal(2001)23 ——7538———————— ——7623———————— Krymchantowski(2008)24 7387—————————— —=nodataobtained.Researchdesign–DB=doubleblind;P=placebocontrolled;R=randomized;SB=singleblind.Route–IM=intramuscular;IV=intravenous;NS=nasalspray;PO=oral; SQ=subcutaneous.Treatments=DHE=dihydroergotamine;HDX=hydroxyzine;MEP=meperidine;MTC=metoclopramide;PCB=placebo;PCZ=prochlorperazine;PMZ=promethazine; STP=sumatriptan;TMD=tramadol.Venue–CL=clinic;ED=emergencydepartment;NA=notapplicable. Headache 473
  8. 8. compared dexamethasone 24 mg IV with placebo/NS IV in preventing recurrence of severe headache.27 Although the percentage with severe headache at 48 hours was greater for placebo (18% vs 45%, P = .005), there was no difference in the frequency of experiencing any degree of headache recurrence (65% vs 67%). Thirty-seven adverse events were reported for dexamethasone and 47 for placebo, the most common being drowsiness (34%), restlessness (24%), and nausea (21%). Donaldson et al compared dexamethasone 24 mg IV with placebo/NS IV, and the rate of headache recurrence was similar in the 2 groups at both the 3-day (dexamethasone 35% vs placebo 45%, P = .38) and 30-day follow-up (43% vs 47%, P = .68).32 Feisseler et al compared either dex- amethasone 10 mg IV or prednisone 40 mg PO daily ¥2 days vs placebo (either NS IV or lactulose PO).33 Only patients with IV access were given IV steroid or placebo. Headache recurrence at 24-72 hours of follow-up was not significantly different for steroid vs placebo (22% vs 32%, respectively; P = .21). Table 3 summarizes results from the studies involving steroids. POST-DISCHARGE MEDICATIONS Many headache patients leave the ED without complete headache relief, and up to 60% still are experiencing significant pain 24 hours post- discharge.34-36 In addition, and as stated in the previ- ous section on steroids, even many of those who respond to initial treatment have recurrence of their headaches within 24-72 hours. In an open-label study, Akpunonu et al provided all patients with sumatriptan 100 mg PO to use if their headaches recurred after discharge; of the 92 patients (88% women, mean age 40) who had mild or no pain on discharge, 57 (62%) had recurrence of their head- ache, and 37/57 (65%) reported meaningful relief 1 hour after taking sumatriptan.37 Using a randomized, double-blind design, Friedman et al compared sumatriptan 100 mg PO with naproxen 500 mg PO for use as a rescue medication for post-discharge head- aches.38 The majority of the patients were treated with a parenterally administered dopamine antagonist prior to discharge.By 48 hours post-discharge,280/410 patients (68%) had experienced recurrent headache, 196 took medications, and response to rescue this therapy could be analyzed in 188 (naproxen: 96 patients and oral sumatriptan: 92 patients; 85% were women and mean age was 36). Pain reduction (11- PPS) was equivalent in the 2 groups (naproxen – 4.3 vs sumatriptan -4.1). The percentage of patients who reported they would utilize their assigned rescue medication again was similar (naproxen 71% vs sumatriptan 75%), as was the percent reporting side effects (naproxen 19% vs sumatriptan 26%), with the most common complaints in both groups being GI upset, dizziness, and drowsiness. Secobarbital is a relatively long-acting barbitu- rate with hypnotic action. In a randomized, double- blind, placebo-controlled trial, Gerhardt et al compared secobarbital 100 mg PO with placebo for prevention of migraine recurrence.39 Two tablets were provided to each patient upon discharge. One tablet was to be taken upon arriving at home. Patients were instructed to sleep, and if not asleep in 1 hour, to take a second dose. The percentage of patients with sus- tained headache relief at 24 hours was greater for secobarbital than placebo (94% vs 50%, P < .02). No adverse events were reported. DISCUSSION AND CONCLUSIONS: OPIOIDS, NSAIDS, STEROIDS, AND POST-DISCHARGE MEDICATIONS The opioids assessed, meperidine, tramadol, and nalbuphine, were superior to placebo in relieving migraine pain, although meperidine combined with promethazine was not. Meperidine 75 mg was supe- rior to ketorolac 30 mg IM in providing headache relief but was similar to ketorolac 60 mg IM even when combined with an antihistamine. Meperidine 75 mg IM or 1.5 mg/kg IV was similar in pain relief to DHE 0.5 mg IV but inferior to DHE 1 mg IV; a factor complicating the interpretation of these comparisons, however, is that both drugs were combined with dif- ferent anti-emetics/antihistamines in 3 out of the 4 studies. Meperidine was also similar to methotrime- prazine in pain relief but was inferior to chlor- perazine. Meperidine was not compared with prochlorperazine, droperidol, or sumatriptan. Lastly, tramadol 100 mg IM yielded pain relief similar to diclofenac 75 mg IM. 474 March 2012
  9. 9. Table3.—StudiesComparingMagnesiumandDexamethasone(DXM)IndividuallytoOtherAgentsforMigraineTherapy.SuperiorPerformanceisIndicatedbyBolding; ifTreatment1Superior,ThenAlsoUnderlined;ifTreatment2Superior,ThenAlsoItalicized StudyFirst Author(year) Group1(G1) Treatment mgor mg/kgRoute Group2(G2) Treatment mgor mg/kgRoute Venue– #IfMultipleSites Research Design%Women Mean Age Group1 #pts Group2 #pts Klapper(1991a)28 DXM6IVPCBNAIVCLR/DB/P——1110 MTC5-10IV Friedman(2007)30 DXM6IVPCBNAIVED4R/DB/P853710699 MTC5-10IVMTC5-10IV Innes(1999)27 DXM24IVPCBNAIVCLR/DB/P80354949 Donaldson(2008)32 DXM24IVPCBNAIVED2R/DB/P81366253 Rowe(2008)31 DXM15IVPCBNAIVED2R/DB/P81356462 Fiesseler(2011)33 DXM10IVPCBNAIVEDR/DB/P86379182 ORPRD40¥2POPCBX2PO Baden(2006)29 DXM10IVPCBNAIVEDR/DB/P64343124 StudyFirstAuthor(year) %PainFree%PainRelief %Sustained PainRelief %Disability Free %Requiring Rescue %Patient Satisfaction G1G2G1G2G1G2G1G2G1G2G1G2 Klapper(1991a)28 8220450 Friedman(2007)30 5547——2519675913137678 Innes(1999)27 8255 Donaldson(2008)32 65557271 Rowe(2008)31 7868 Fiesseler(2011)33 78683644 OR Baden(2006)29 70668742 —=nodataobtained.Researchdesign–DB=doubleblind;P=placebocontrolled;R=randomized;Route–IV=intravenous;PO=oral.Treatments–MTC= metoclopramide;PCB=placebo;PRD=prednisone.Venue–CL=clinic;ED=emergencydepartment;NA=notapplicable. Headache 475
  10. 10. Headaches treated with opioids have a high rate of recurrence after the analgesic effect of the opioid wears off. Opioids may, however, make the patient drowsy enough to sleep, which often termi- nates headaches. Side effects of opioids included sedation, dizziness, GI discomfort, nausea and vomiting, and akathisia (although the last occurs much less frequently than with the dopamine antagonists). Opiates/opioids often are used in treating patients with status migrainosus. In one study, however, patients in status became pain free after treatment with ketorolac and sumatriptan only if they had used no opiates/opioids whatsoever in the previous 6 months.22 This result reinforces the notion that opioids may exert a persistent pro-nociceptive effect – a “pain-memory state” – that prevents the reversal of central sensitization.4 Along the same line, Ho et al found that rizatriptan was less effective as a migraine abortive if patients had recent expo- sure to opioids.40 As such, concern for creating opiate/opioid dependency in migraine patients may not be the most important reason for not recommending this class of drugs as first-line therapy. Even so, the habituation rate associated with the use of opioids for migraine treatment is estimated at 13 out of 1 million patients, and ED staff rightfully are con- cerned at the prospect of contributing to an already established habituation or even true addiction, espe- cially in patients with the latter who misrepresent themselves as having headaches.40,41 When one con- siders that the opioids studied were superior only to placebo and ketorolac 30 mg IM, the issue of their potential pro-nociceptive effect, abuse/addiction issues, and the evidence that the use of opioids appears to render relatively migraine-specific abor- tive medications less effective, it is recommended that opiates/opioids not be used as first-line therapy for migraine pain in the ED or clinic. Ketorolac is a cyclooxygenase COX1/COX2 inhibitor that appears to be able to reverse both peripheral sensitization by inhibiting the neuro- inflammatory cascade in the meninges and central sensitization associated with cutaneous allodynia. Ketorolac effectively treated acute migraine in patients with cutaneous allodynia who did not respond to sumatriptan SQ. Ketorolac 30 mg IV or 60 mg IM is more efficacious than sumatriptan nasal spray and less efficacious than prochlorperazine or DHE plus metoclopramide but similar to meperidine plus promethazine or hydroxyzine. In the only study which included a placebo arm, an unusually high rate of pain relief was reported by the both the ketorolac and placebo groups. Halving its IM dose to 30 mg resulted in ketorolac being less efficacious in reducing pain than meperidine. Two studies investigated the pain-reducing efficacy of IV MMZ (not an NSAID) and LC (an NSAID), 2 parenteral medications commonly used for pain relief in Brazil but not available in the USA. Pain reduction was greater with MMZ than placebo for migraine both with and without aura. LC, in turn, outperformed MMZ in terms of the percentage pain free at 90 minutes, although the response rates for both were fairly impressive (LC 86.7% vs MMZ 73%). Diclofenac sodium was as effective as tramadol in reducing migraine pain, but ibuprofen PO was not more effective than placebo. The NSAIDs are nonsedating and can be com- bined with most other medications.While side effects can occur even after a single dose, these side effects generally are fewer and milder than those associated with narcotics, opiates/opioids, and dopamine anta- gonists. Contraindications to NSAID use include a history of GI bleeding, other bleeding risks, and renal impairment. Due to a recent report demonstrating a significantly increased risk of miscarriage, pregnancy now may represent a contraindication to NSAID use, and NSAIDs should not be administered to nursing mothers. There was a significant difference in the percent- age of patients with sustained headache relief in 2 of the 6 studies that compared dexamethasone IV (6-24 mg single dose in ED) or oral prednisone (40 mg times 2 days) with placebo. In all 4 remaining studies, the number of patients with sustained pain relief was greater in the steroid groups, although not sufficient to be significant. Using a paired t-test on the percentage headache relief from these 6 studies, there is an overall significant difference between these scores for patients receiving dexamethasone com- 476 March 2012
  11. 11. pared with those receiving placebo (dexamethasone 69% vs placebo 51%, t = 2.9, d.f. = 5, P = .03). Side effects of single-dose dexamethasone were relatively few and benign. Patients receiving dexa- methasone were more likely to report dizziness and less likely to report nausea than patients receiving placebo. There were equally low frequencies of reported numbness/tingling, drowsiness, restlessness, and swelling in the both steroid and placebo arms. Repeated long-term use of steroids may increase the risk for osteoporosis and aseptic osteonecrosis of the femoral head and knees.43 Steroids should be used with caution in patients with diabetes. When patients are treated in the outpatient setting for headache lasting more than 72 hours, they may receive a course of steroids (dexamethasone, prednisone) for 3-5 days or more until headache free for 24 hours.27 A single dose of dexamethasone IV (or 2 daily doses of prednisone used in 1 study) may not be sufficient to produce much of an effect on the rate of headache recurrence. Patients in the 2 studies designed to treat head- ache recurrence experienced a recurrence rate exceeding 60%. The study designed to prevent head- ache recurrence by inducing sleep with secobarbital demonstrated a 6% headache recurrence rate in the secobarbital group vs 50% in the placebo group. Both oral sumatriptan 100 mg and naproxen sodium 500 mg appear effective more often than not in reliev- ing headache that recurs after ED discharge. The use of secobarbital, with its sedative and sleep-inducing properties, appears to increase the percentage pain relief after ED discharge compared with those patients in the placebo group. GENERAL DISCUSSION AND CONCLUSIONS This section is intended as a general discussion of all the studies presented in this 3-part review of physician-administered rescue therapy for acute migraine in the ED, urgent care, and headache clinic infusion center settings.The conclusions are based on the current paper and those published previously in this journal.44,45 Analysis of the large number of studies presented in this review confirms that a definitive and optimally effective ED migraine rescue regimen cannot be determined on the basis of current published data. In an attempt to compare migraine treatments without relying solely on the pair-wise comparisons typical of the methodology used in the studies reviewed, the author determined and compared weighted averages of the percentages of pain relief.These weighted aver- ages were computed for all medications for which there were 2 or more randomized trials with the medication used as a single agent (that is, was not combined with any other medications).The following lists these average percentages of pain relief from greatest to least (total number of patients repre- sented is in parentheses): droperidol 82% (229), sumatriptan 78% (351), prochlorperazine 77% (312), tramadol 76% (37), metamizole (not available in the USA) 75% (164), metoclopramide IV 70% (184), DHE 67% (188), chlorpromazine 65% (158), ketoro- lac 30 mg IV 60% (77), meperidine 58% (79), meto- clopramide IM 45% (128), magnesium 43% (169), ketorolac 60 mg IM 37% (64), and valproate 32% (39) (Fig. 1). Of note, promethazine is not listed here in this analysis because it was only studied in combi- nation with meperidine. The weighted averages for percentages of patients who were pain free were also computed for all medications for which there were 2 or more ran- domized trials where the medication was used as a % Patients with Pain Relief Valproate 32% Ketorolac IM 37% Magnesium 43% Metoclopramide IM 45% Meperidine 58% Ketorolac IV 60% Chlorpromazine 65% DHE 67% Metoclopramide IV 70% Metamizole 75% Prochlorperazine 77% Sumatriptan 78% Droperidol 82% 100%0% Medication Fig 1.—Weighted averages of the percentages of pain relief for all medications for which there were Ն2 randomized trials with the medication used as a single agent. DHE = dihydroergotamine; IM = intramuscular; IV = intravenous. Headache 477
  12. 12. single agent. These are presented from greatest to least as follows (total number of patients represented is in parentheses): 53% for both prochlorperazine (90) and chlorpromazine (115), droperidol 40% (214), magnesium 36% (91), sumatriptan 35% (166), tramadol 32% (37), and DHE 21% (34) (Fig. 2). Mag- nesium fared much better in this analysis than in the analysis of headache relief. The choice of headache treatment should be based on considerations of efficacy, side effects, and cost. The calculated expense of a treatment should include not only immediate ED treatment, but also the hidden costs of continuing headache, early head- ache recurrence, functional disability, return trips to the ED, and the need for follow-up care in an outpa- tient clinic. Headache recurs in more than 50% of patients after ED discharge. Ducharme et al found that those who are pain free at discharge are signifi- cantly less likely to have recurrence, but Friedman et al could not independently support this finding.1 When they looked at their ED records for adminis- tered medications, Sheftell et al also reported a link between low recurrence and pain-free response with naratriptan PO.46 Overall, it seems reasonable that a concerted effort should be made to discharge patients from the ED pain free. Parenterally administered dopamine antagonists are not only effective anti-emetics but also can reduce or terminate migraine headache. As a class, however, they frequently cause side effects (including sedation, akathisia, and dystonia) that can outlast the symp- toms of the migraine itself and thereby prolong patients’ functional disability. There is a need to pre- dose patients receiving phenothiazines (especially chlorpromazine) with IV fluid to prevent postural hypotension, as well as with a drug possessing anti- cholinergic properties to reduce the likelihood of extrapyramidal side effects. Droperidol and haloperi- dol are not recommended as first-line therapy because of potential QTc prolongation and the con- sequent need for electrocardiogram monitoring. For a variety of reasons (discussed in some detail earlier in this paper), opiates/opioids generally are not recommended as first-line treatment for migraine. One argument used in support of using opioids for first-line treatment is that they are quick to adminis- ter and act rapidly, such that patients can be dis- charged in a timely fashion. It remains unclear, however, whether the use of opioids does indeed save time. Coleman et al assessed migraine treatment pat- terns in 5 linked Canadian EDs.47 Opiates/opioids were used as first-line treatment for 59.6% of the migraine patients. The odds of receiving an opioid as first-line therapy was increased in patients who took medications prior to ED admission and was decreased in patients who had a longer-lasting head- ache or a more urgent triage score. Those who received opioids first line spent less total time in the ED (177 minutes vs 237 minutes, P < .001). This con- trasts with the findings of Tornabene et al, who found that patients who received opioids spent more time in their ED than patients who did not (160 minutes vs 125 minutes, P = .015), regardless of whether they often sought treatment for headache in the ED.48 Sumatriptan SQ, a relatively migraine-specific medication, is as effective as droperidol and prochlor- perazine in providing pain relief. When limited to patients with no contraindications, it is very well tol- erated. Adverse events are generally limited to tran- sient chest tightness, shoulder pain, and neck pain, all of which rarely outlast the migraine pain itself and require no treatment to resolve. An argument can be made for the use of fixed drug combinations to treat migraine. These combina- tions can target multiple symptoms and have syner- % Patients Pain-Free Ketorolac IM 22% Magnesium 36% Metoclopramide IM 14% Meperidine 30% Chlorpromazine 53% DHE 21% Metoclopramide IV 41% Prochlorperazine 53% Sumatriptan 35% Droperidol 40% %001%0 Medication Fig 2.—Weighted averages of the percentages of pain free for all medications for which there were Ն2 randomized trials with the medication used as a single agent. DHE = dihydroergotamine; IM = intramuscular; IV = intravenous. 478 March 2012
  13. 13. gistic effects, and there is also the possibility that 1 or more medications can counteract side effects of another medication when they are combined. One such combination is DHE combined with metoclo- pramide intravenously, with the latter treating the nausea induced by the former. Both of these medica- tions were individually as effective as chlorpromazine in providing pain relief, although the combination did not appear to have additional pain-relieving effects. Magnesium can be an effective agent in migraine treatment, either alone or as adjuvant treatment, especially in those patients who have aura. It pro- vided as much freedom from migraine pain (with and without aura) as did sumatriptan or ketorolac IV, although average pain relief was relatively low, only surpassing ketorolac IM and valproate. There is some support for using corticosteroids to prevent headache recurrence, especially if the presenting migraine has lasted longer than 72 hours. The optimal regimen likely involves IV doses in the ED followed by oral dosing for several days post-discharge. It is recommended that all future studies be randomized and double blinded (including double dummy). For those rescue treatments for which there have been insufficient studies employing a placebo arm, it is recommended that this be done to ascertain effectiveness more accurately. When drug combinations are compared, the same second agent should be used in both or all arms. An ideal design for studying drug combinations would have 4 arms: drug A/placebo B, drug B/ placebo A, drug A/ drug B, and placebo A/ placebo B. Recording of headache status should be done at 2 hours (in addition to any other outcome measures), even if this involves the patient reporting their status post-discharge, in order to determine the percent pain free at 2 hours. All studies should include 24-72 hour follow-up evaluations. In summary, the ideal acute migraine rescue therapy administered in the urgent care or ED setting would provide complete headache relief, possess no side effects, and prevent early headache recurrence. Because no such therapy currently exists, treatment must be tailored to the needs of the individual patient. Triptans and DHE are most effective in inject- able formulations and should be avoided in those at risk for vascular complications. DHE is particularly effective when given IV but can cause increased nausea. NSAIDs such as ketorolac have the advantage of being appropriate for patients with vascular risk factors, and they do not cause sedation. They can be combined with most other treatments for increased efficacy. Dopamine antagonists can be given alone or with other agents. As this review indicates, they are surprisingly effective for migraine, even late in the attack, and they are inexpensive. When used alone, prochlorperazine, droperidol, and metoclopramide were superior to placebo. Droperidol and prochlor- perazine were superior or equal in efficacy to all other treatments, but they commonly cause side effects that are especially unpleasant for patients (notably dystonia and akathisia). Metoclopramide was equivalent to prochlorperazine, and, when combined with diphenhydramine, was superior in efficacy to triptans and NSAIDs. Meperidine was arguably equivalent when compared with ketorolac and DHE but was inferior to chlorprom- azine and equivalent to the other neuroleptics. Sumatriptan was inferior or equivalent to the neu- roleptics and equivalent to DHE when considering only paired comparisons. The overall percen- tage of patients with pain relief after taking sumatriptan was equivalent to droperidol and prochlorperazine. Once again, opiate/opioid rescue sometimes can be effective, but such therapy also may lead to early headache recurrence, central sensitization, sedation, nausea and dizziness, as well as raise concerns for overuse and abuse.While commonly administered for treatment of acute migraine, ideally, these medica- tions should be a last resort. Magnesium can be an effective treatment for migraineurs with aura and can reduce the photopho- bia and phonophobia of all migraineurs. It can be added on to any of the said medications to boost effectiveness without sedation. Magnesium also can be very useful as a therapy for pregnancy-associated migraine. Headache 479
  14. 14. STATEMENT OF AUTHORSHIP Category 1 (a) Conception and Design Nancy E. Kelley, Deborah E. Tepper (b) Acquisition of Data Nancy E. Kelley, Deborah E. Tepper (c) Analysis and Interpretation of Data Nancy E. Kelley, Deborah E. Tepper Category 2 (a) Drafting the Article Nancy E. Kelley, Deborah E. Tepper (b) Revising It for Intellectual Content Nancy E. Kelley, Deborah E. Tepper Category 3 (a) Final Approval of the Completed Article Nancy E. Kelley, Deborah E. Tepper REFERENCES 1. Friedman BW, Hochberg ML, Esses D, et al. Recurrence of primary headache disorders after emergency department discharge: Frequency and predictors of poor pain and functional outcomes. Ann Emerg Med. 2008;52:696-704. 2. Tek D, Mellon M. The effectiveness of nalbuphine and hydroxyzine for the emergency treatment of severe headache. Ann Emerg Med. 1987;16:308-313. 3. Alemdar M, Pekdemir M, Selekler HM. Single-dose intravenous tramadol for acute migraine pain in adults: A single-blind, prospective, randomized, placebo-controlled clinical trial. Clin Ther. 2007;29: 1441-1447. 4. Bigal ME, Lipton RB. Excessive acute migraine medication use and migraine progression. Neuro- logy. 2008;71:1821-1828. 5. Klapper JA, Stanton JS. Current emergency treat- ment of severe migraine headaches. Headache. 1993;33:560-562. 6. Carleton SC, Shesser RF, Pietrzak MP, et al. Double-blind, multicenter trial to compare the efficacy of intramuscular dihydroergotamine plus hydroxyzine versus intramuscular meperidine plus hydroxyzine for the emergency department treat- ment of acute migraine headache. Ann Emerg Med. 1998;32:129-138. 7. Davis CP, Torrre PR, Williams C, et al. Ketorolac versus meperidine-plus-promethazine treatment of migraine headache: Evaluations by patients. Am J Emerg Med. 1995;13:146-150. 8. Duarte C, Dunaway F, Turner L, Aldag J, Frederick R. Ketorolac versus meperidine and hydroxyzine in the treatment of acute migraine headache: A ran- domized, prospective, double-blind trial. Ann Emerg Med. 1992;21:1116-1121. 9. Harden RN, Gracely RH, Carter T, Warner G. The placebo effect in acute headache management: Ketorolac, meperidine, and saline in the emergency department. Headache. 1996;36:352-356. 10. Lane PL, McLellan BA, Baggoley CJ. Comparative efficacy of chlorpromazine and meperidine with dimenhydrinate in migraine headache. Ann Emerg Med. 1989;18:360-365. 11. Larkin GL, Prescott JE. A randomized, double- blind, comparative study of the efficacy of ketorolac tromethamine versus meperidine in the treatment of severe migraine. Ann Emerg Med. 1992;21:919- 924. 12. Richman PB, Allegra J, Eskin B, et al. A random- ized clinical trial to assess the efficacy of intramus- cular droperidol for the treatment of acute migraine headache. Am J Emerg Med. 2002;20:39-42. 13. Belgrade MJ,Ling LJ,Schleevogt MB,Ettinger MG, Ruiz E. Comparison of single-dose meperidine, butorphanol, and dihydroergotamine in the treat- ment of vascular headache. Neurology. 1989;39: 590-592. 14. Scherl ER, Wilson JF. Comparison of dihydroer- gotamine with metoclopramide versus meperidine with promethazine in the treatment of acute migraine. Headache. 1995;35:256-259. 15. Stiell IG, Dufour DG, Moher D, Yen M, Beilby WJ, Smith NA. Methotrimeprazine versus meperidine and dimenhydrinate in the treatment of severe migraine: A randomized, controlled trial. Ann Emerg Med. 1991;20:1201-1205. 16. Engindeniz Z, Demircan C, Karli N, et al. Intramuscular tramadol vs.diclofenac sodium for the treatment of acute migraine attacks in emergency department: A prospective, randomized, double- blind study. J Headache Pain. 2005;6:143-148. 17. Cicek M, Karcioglu O, Parlak I, et al. Prospective, randomised, double blind, controlled comparison of metoclopramide and pethidine in the emergency treatment of acute primary vascular and tension type headache episodes. Emerg Med J. 2004;21:323- 326. 480 March 2012
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