J Headache Pain (2001) 2:120–146 © Springer-Verlag 2001

Symptomatic treatment of migraine

Two recent, prospective studies demonstrated that early 5-HT agonists 1B/1D oral administration of a triptan gives a better headache response [114, 115]. One study showed the possibility of Efficacy data preventing migraine attack when naratriptan was taken dur- ing prodromic symptoms [116]. Controlled studies have demonstrated the efficacy of 5- HT1B/1D agonists, not only on headache but also on accompa- nying symptoms (e.g. photophobia and phonophobia, nausea and vomiting) and on functional disability [1–64]. The con- Observations sistency of efficacy in the treatment of multiple attacks and the long-term efficacy have also been demonstrated, especial- If headache only slightly improves after the administration ly for sumatriptan administered subcutaneously or in tablets, of a triptan, one should wait at least two hours before taking zolmitriptan, rizatriptan, naratriptan, eletriptan, and almotrip- a second dose [117]. If no response is observed within two tan [55–77]. Slightly higher percentages of headache hours, an additional dose is not useful. response were found for subcutaneously administered suma- Rapid-dissolving oral formulations of rizatriptan and triptan compared with the other formulations of sumatriptan zolmitriptan are now available. They have an efficacy simi- [78, 79]. Although studies comparing the oral formulations of lar to the tablet formulations, and pharmacokinetic data do triptans are available, it is not possibile at the moment to iden- not suggest that the highest plasma levels are reached more tify a parameter of overall efficacy which establishes the rapidly [118, 119]. The formulations could, however, be greater efficacy of one triptan compared to the others [80–90]. useful because they are easier to take. As far as the speed of onset is concerned, a statistically sig- Approximately 25%–35% of patients do not respond to nificant headache response compared with placebo was found triptans. These percentages may be influenced by incorrect at 15–30 minutes for sumatriptan subcutaneously administered diagnoses. In fact, even in specialized headache centers and at 30–60 min for every other triptan formulation [91, 92]. diagnoses not in agreement with IHS criteria are in fact for- The administration of sumatriptan during aura appeared mulated in about 28% of the cases [120]. When the diagno- to neither shorten the aura duration nor prevent the subse- sis of migraine is confirmed, in the case of no response to quent headache [93]. The administration of zolmitriptan one of the triptans, the use of another triptan may be con- during aura has been shown to be effective on head pain but sidered. Recent open studies have demonstrated the possi- not on aura symptoms and was not accompanied by signifi- bility of using another triptan with success, when one trip- cant adverse events [94]. No data in this regard are available tan fails [121, 122]. In the case of no response to one trip- for the other triptans. The percentages of headache recur- tan, however, it is mandatory to reconsider the diagnosis. rence, emerging from the various efficacy studies, vary from Cases of daily use or abuse of triptans have been record- 20% to 40%, with slightly greater values for subcutaneous- ed, and this may cause migraine to become a chronic ly given sumatriptan [95–97]. For all triptans, in any formu- headache [123–128]. It is advisable not to exceed the rec- lation, the efficacy of a second dose on recurrent headache ommended doses. has been demonstrated [98–102]. The efficacy of the differ- Although use of oral triptan formulations is not recom- ent triptans has also been confirmed on migraine attacks mended below 18 years of age, recent studies suggest their related to the menstrual cycle [103–113]. efficacy and safety in this age group [129–136]. 121

Studies on the effects of different triptans in the treatment patients treated with other formulations. It can mimic an of migraine crises during pregnancy are not available, with the angina crisis and alarm a patient who is not adequately exception of results of international prospective studies informed. The mechanism underlying these chest symptoms [137–139] relative to the monitoring of migrainous pregnant is unknown: a spasm of esophageal muscles has been sug- women who used sumatriptan. These studies did not show a gested [172–176]. ECG modifications have rarely been greater incidence of malformations in the newborns of women recorded [177]. In a recent study carried out on healthy vol- who treated their migraine attacks with sumatriptan during unteers with positron emission tomography (PET), no sig- pregnancy compared to those in the general population, but in nificant variations in myocardial perfusion were shown after one of these studies a higher percentage of low birth-weight subcutaneous administration of sumatriptan [178]. newborns was associated with the use of sumatriptan as well The most significant pharmacological interactions, from as a greater incidence of preterm deliveries [137–139]. The a clinical point of view, are with ergot derivatives, selective results available at the moment do not lead to definitive con- serotonin-reuptake inhibitors (SSRIs), monoamine oxidase clusions. The use of triptans during pregnancy or by women (MAO) inhibitors, propranolol and drugs which are sub- who intend to become pregnant is not recommended. strates of CYP450. Insufficient data are available to evaluate the safety of After taking a triptan, it is necessary to wait at least six triptan use after 65 years of age. In this case, their use is not hours before taking an ergot derivative. Conversely, after recommended. taking an ergot derivative it is recommended to wait at least 24 hours before taking a triptan [139]. Likewise for coad- ministration of the different triptans, it is advisable to wait at least 24 hours between doses. Contraindications, adverse events and pharmacological In the case of the coadministration of one triptan with interactions antidepressants of the SSRI class, the occurrence of a sero- tonergic syndrome is possibile. It is characterized by motor The use of triptans is contraindicated in the case of positive incoordination, marked asthenia and hypereflexia [179–182]. history or suspicion of ischemic cardiopathy, coronary MAO-A inhibitors should be suspended at least two vasospasm, peripheral vascular disease, uncontrolled hyper- weeks before initiating treatment with a triptan [183–187]. tension, or basilar or hemiplegic migraine [140]. Recent The contemporary administration of propranolol increas- studies showed that an adjustment of the zolmitriptan dose es the plasma concentration of rizatriptan [188]. In the case is unnecessary in the case of mild hypertension or renal of the contemporary use of propranolol, the administration insufficiency [141–143]. If coronary disease or risk factors of the 5-mg dose of rizatriptan for the attack and the maxi- for cardiovascular diseases are suspected, an electrocardio- mum daily dose of 10 mg are recommended. Rizatriptan gram (ECG) should be carried out before beginning treat- should be taken at least two hours after taking propranolol. ment with a triptan [144, 145]. Theoretically, rizatriptan and zolmitriptan interact with The percentages of adverse events are variable in clini- drugs which are metabolized by CYP450 [189, 190]. The cal trials and in post-marketing studies. They are frequent clinical relevance of this observation should be clarified. for the subcutaneous formulation of sumatriptan and occa- sionally for the other triptan formulations. In the majority of cases, they are not clinically relevant, and of short duration (generally 10–15 min) [146–165]. The most frequent Administration and dosages adverse events are: local reactions in relationship with the route of administration (e.g. subcutaneous, rectal, nasal The following paragraphs summarize the mode of adminis- spray), sensation of chest tightness, constriction or pain, tration and the dosages of common triptans. Readers are flushing of the face and chest, asthenia, myalgia, somno- cautioned to consult the packaging for specific governmen- lence, warm or cold sensation of the head or arms, paresthe- tal regulations (e.g. rules, warnings, norms). sias, postural instability, dizziness and, sometimes, neck Sumatriptan is administered as follows: pain or sensation of neck stiffness. Among the severe – Subcutaneous route: 6-mg ampoule; maximum daily adverse events, which occur rarely, unstable angina, dose, 12 mg. myocardial infarction, cardiac arrest and ischemic stroke – Oral route: 50–100 mg tablets; maximum daily dose, 200 should be mentioned [166–171]. Other rare adverse events mg. are akathisia, dystonic crises and euphoria. – Rectal route: 25-mg suppository; maximum daily dose, In particular, the sensation of chest tightness or pain is 50 mg. referred by 4%–5% of patients treated with sumatriptan, – Nasal spray: 1 single-dose spray (20 mg); maximum subcutaneously administered, and by a lower percentage of daily dose, 40 mg. 122

Zolmitriptan is administrated orally as a: The efficacy of ASA and other NSAIDs on migraine – 2.5-mg tablet; maximum daily dose, 5 mg; or aura has not been investigated. – 2.5-mg rapimelt formulation; maximum daily dose, In migraine crises associated with the menstrual cycle, 5 mg. only the efficacy of mefenamic acid has been assessed. The Rizatriptan is given orally as a: drug appeared to be significantly more effective on head pain – 10-mg tablet; maximum daily dose, 20 mg; or and associated symptoms compared with placebo [236]. – 10-mg rapidly dissolving wafer; maximum daily dose, 20 mg. Naratriptan is unavailable in Italy; it is marketed in other countries as a 2.5-mg tablet; maximum daily dose, 5 mg. Observations Eletriptan is now available in Italy in the 20-mg and 40- mg dosages. The starting dose is 40 mg; the 80-mg dose is rec- ASA is recommended for patients with cardiovascular and ommended when a satisfactory response is not achieved after cerebrovascular diseases. an appropriate trial with 40 mg (failure to respond in 2 of 3 Acetaminophen is the first-choice drug for the treatment attacks) and the drug is well tolerated. The dosage of 20 mg is of migraine during pregnancy [237]. recommended in the case of liver or kidney insufficiency. Studies supporting the efficacy of ketorolac by the intra- Almotriptan is now marketed in Italy as a 12.5-mg tablet; muscular route in the treatment of migraine attacks are maximum daily dose, 25 mg. available. These non placebo-controlled studies were car- ried out in the hospital setting with a limited number of patients [226–228]. A recent study showed that the administration of naprox- Analgesics and non-steroidal anti-inflammatory drugs en sodium in association with sumatriptan reduces the per- centage of recurrence of migraine attacks [238]. This find- Efficacy data ing suggests the potential advantage of the contemporary administration of one NSAID and one triptan, although fur- The most consistent evidence of efficacy is available for ther studies confirming this observation are needed. acetylsalicylic acid (ASA), salicylates, naproxen sodium, The use of the rapid dissolving formulation of ASA, ibuprofen and diclofenac potassium, whereas the evidence of even if not in association with metoclopramide, results in efficacy for other non-steroidal anti-inflammatory drugs higher plasma levels in comparison with the non-chewable (NSAIDs) is more limited and weaker [191–232]. Only a few tablet formulations [239–241]. studies have investigated the efficacy of analgesics and The daily or almost daily intake of analgesics or NSAIDs on associated symptoms. The most consistent data NSAIDs can induce a chronic daily headache [242–246]. supporting the efficacy on associated symptoms concern This risk has also been pointed out in children and adoles- ASA, salicylates, ibuprofen and diclofenac [197–199, 207, cents affected by migraine [247]. Cases of abuse of a com- 208]. Studies into the long-term efficacy of the majority of bination drug containing indomethacin, caffeine and NSAIDs are lacking. Only one study, carried out on ASA, prochlorperazine associated with a chronic daily headache demonstrated the maintenance of efficacy in the treatment of have been reported [248]. Until now there is little evidence multiple, subsequent attacks [233]. The association of certain supporting the efficacy of this combination drug on NSAIDs with metoclopramide (aspirin, salicylates, tolfenam- migraine attack [249]. ic acid, etc.) or domperidone (acetaminophen) does not sig- It should be noted that the abuse of symptomatic drugs nificantly improve their anti-migraine effect [194, 196, 199, in general, with the exception of barbiturates and narcotics, 201, 202, 218, 222]. The association of certain NSAIDs (i.e. depends more consistently on the personality of the patient ASA, tolfenamic acid) with caffeine does not increase their than on the drug abused. efficacy [220, 221, 234]. Studies comparing the various NSAIDs did not reach conclusions about the greater efficacy of any one drug of this class [192, 193, 205, 221, 223]. Ketoprofen, naproxen Contraindications, adverse events and pharmacological sodium and tolfenamic acid showed a similar efficacy com- interactions pared with ergotamine in association with or without caf- feine [190, 191, 213, 215, 217, 231, 235]. Analgesics and NSAIDs are contraindicated, other than in The use of ASA is characterized by a low percentage of the case of known hypersensitivity to these products or cor- headache recurrence [198, 200, 201]. For the other anal- related drugs, in patients with hemorrhagic diatheses or gesics and NSAIDs, studies supporting their efficacy for hemocoagulative pathologies, gastric or duodenal ulcer and migraine did not investigate the percentages of recurrence. severe liver or kidney insufficiency [250–255]. Ibuprofen, 123 naproxen sodium, tolfenamic acid, piroxicam, diclofenac and adverse events due to acetaminophen are neutropenia, throm- ketorolac are contraindicated in the case of chronic conges- bocytopenia or pancytopenia, as well as liver or kidney tive heart failure. They are not to be given during pregnancy necrosis (massive ingestion). After the administration of (especially in the first trimester). The only analgesic which is ketoprofen, flurbiprofen and diclofenac, hydrosaline reten- indicated during pregnancy is acetaminophen [237]. tion and an increase in creatinine levels have been reported. Acetaminophen should not be administered to patients with Also for tolfenamic/mefenamic acid, intestinal disturbances glucose-6-phosphate-dehydrogenase deficiency and patients and autoimmune hemolytic anemia have been observed [250, with severe hemolytic anemia. Several NSAIDs should not 259]. The adverse events of indomethacin include visual dis- be used in patients under 14 years of age, and particular turbances and hematological disturbances (aplastic or attention should be given to their administration in the elder- hemolytic anemia, agranulocytosis, thrombocytopenia), dis- ly [249, 250]. Products containing acetylsalicylic acid should turbances of the central nervous system (CNS) such as con- not be used continuously in children, because of the potential fusion,vertigo, and less frequently, edema, hyperglycemia occurrence of Reye’s syndrome [252]. and glycosuria. The percentages of adverse events, found in clinical trials As far as the pharmacological interactions are con- with the aim of measuring the efficacy of analgesics and cerned, analgesics and NSAIDs should be carefully admin- NSAIDs in the treatment of migraine attacks, is consistently istered in the case of concomitant use of anticoagulants lower than those found in long-term studies which investi- (dicumarolic derivatives or heparin except for low molecu- gated the adverse events due to their chronic administration lar weight heparin) and steroids because of the greater risk [252]. These adverse events are generally occasional in of bleeding consequent to their concomitant use. Their use migraine patients, but they may reach the percentages report- should be avoided in association with alcohol. NSAIDs ed in the chronic administration of NSAIDs for other dis- increase the plasma concentration of digoxin, barbiturates eases, when they are taken daily or almost daily for migraine. and lithium, whereas they reduce the effect of aldosterone Adverse events consist of gastrointestinal symptoms, such as and potassium-sparing diuretics and antihypertensive drugs. gastralgias, gastric pyrosis, nausea, vomiting, and rarely gas- Other pharmacological interactions are specific for each tric or duodenal ulcers [253, 254]. The incidence of these analgesic and NSAIDs, and this information should be con- dose-dependent adverse events could be reduced by the use sulted in the package insert. of buffered effervescent tablets (e.g. ASA). Symptoms, such as somnolence, asthenia, or disturbances of blood cell crasis occur less frequently [250]. The occurrence of skin rashes or urticarial reactions, asthmatic crises, and anaphylactic reac- Administration and dosages tions are rare [256–258]. Kidney or liver intolerance to ASA is similar to that of acetaminophen [259–262]. Other rare Only the formulations for which there is evidence of efficacy adverse events have been reported for each analgesic and in the treatment of migraine attacks are reported in Table 1. NSAIDs. Sedation, polyuria and xerostomia have been Studies supporting the efficacy of other routes of administra- described after the administration of ketorolac. The daily tion and dosages are lacking. These formulations may be used administration of ketorolac should not exceed 7 days. Rare according to the indication of the physician or specialist.

Table 1 Route of administration and dosages of analgesics and non-steroidal anti-inflammatory drugs, including combination drugs avail- able in Italy

Drug Indication Administration mode and dosage

Acetylsalicylic acid Migraine Oral route: 500- or 1000-mg tablet; maximum daily dose, 2000 mg Lysine acetylsalicylate Not indicated Oral route: 900–1800 mg powder, equivalent to 500–1000 mg acetylsalicylic acid; maximum daily dose, equivalent to 2000 mg acetylsalicylic acid Intravenous route: 900–1800 mg ampoule, equivalent to 500–1000 mg acetyl- salicylic acid; maximum daily dose, equivalent to 2000 mg acetylsalicylic acid Intramuscular route: 900–1800 mg ampoule, equivalent to 500–1000 mg acetyl- salicylic acid; maximum daily dose, equivalent to 2000 mg acetylsalicylic acid Acetaminophen Headache Oral route: 500-mg tablet, 1000-mg effervescent tablet, 125-mg effervescent powder, 300-mg powder; maximum daily dose, 2000 mg Diclofenac Not indicated Oral route: 46.5-mg soluble tablet; maximum daily dose, 186 mg

the table continues 124

Continuation of Table 1

Drug Indication Administration mode and dosage

Diclofenac potassium Not indicated Oral route: 50-mg tablet or 50-mg powder; maximum daily dose, 200 mg Diclofenac sodium Not indicated Oral route: 50-mg gastroresistant tablet, 75-mg tablet; 100-mg slow-acting tablet; maximum daily dose, 200 mg Rectal route: 100-mg suppository; maximum daily dose, 200 mg Intramuscular route: 75-mg ampoule; maximum daily dose, 150 mg Ketoprofen Not indicated Oral route: 25-mg tablet; 50- or 100- or 200-mg capsule; 200-mg slow-acting capsule; maximum daily dose, 200 mg Rectal route: 100- or 200-mg suppository; maximum daily dose, 200 mg Intramuscular route: 50–100 mg ampoule; maximum daily dose, 200 mg Intravenous route: 100-mg ampoule; maximum daily dose, 200 mg Ketoprofen sucralfate Not indicated Oral route: 225-mg tablet; maximum daily dose, 450 mg Ketorolac tromethamine Not indicated Oral route: 10-mg tablet; maximum daily dose, 30 mg Rectal route: 30-mg suppository; maximum daily dose, 60 mg Intramuscular route: 10-mg or 30-mg ampoule; maximum daily dose, 60 mg Ibuprofen Headache; Oral route: 200-mg effervescent tablet, 200-mg pill, 400- or 600-mg tablet, migraine 200–600-mg powder; maximum daily dose, 1800 mg Ibuprofen sodium salt Headache Oral route: 200-mg effervescent tablet; maximum daily dose, 1200 mg Rectal route: 600-mg suppository; maximum daily dose, 1800 mg Ibuprofen lysine salt Headache Oral route: 500-mg tablet; maximum daily dose, 1500 mg Intramuscular route: 400-mg ampoule; maximum daily dose, 1200 mg Ibuprofen/arginine Headache Oral route: 400-mg powder; maximum daily dose, 1200 mg Flurbiprofen Not indicated Oral route: 100-mg tablet or capsule; maximum daily dose, 300 mg Naproxen Not indicated Oral route: 250-, 500- or 750-mg tablet; 500-mg powder; maximum daily dose, 1500 mg Rectal route: 500-mg suppository; maximum daily dose, 1500 mg Naproxen sodium Migraine Oral route: 220- or 550-mg tablet; 275- or 550-mg capsule; 550-mg powder; maximum daily dose, 1650 mg Rectal route: 550-mg suppository; maximum daily dose, 1650 mg Nimesulide Not indicated Oral route: 100-mg tablet, 50–100-mg powder, 100-mg capsule; maximum daily dose, 300 mg Rectal route: 200-mg suppository; maximum daily dose, 400 mg Nimesulide beta-cyclodextrin Not indicated Oral route: 400-mg powder; maximum daily dose, 800 mg Piroxicam Not indicated Oral route: 20-mg tablet, 20-mg soluble tablet, 20-mg capsule; maximum daily dose, 40 mg Intramuscular route: 20-mg ampoule; maximum daily dose, 40 mg Rectal route: 20-mg suppository; maximum daily dose, 40 mg Mefenamic acid Not indicated Oral route: 250-mg capsule; maximum daily dose, 1500 mg Indomethacin Not indicated Oral route: 25- or 50-mg capsule; maximum daily dose, 150 mg Rectal route: 50- or 100-mg suppository; maximum daily dose, 150 mg Indomethacin, meglumine salt Not indicated Intramuscular route: 50-mg ampoule; maximum daily dose, 100 mg Pirprofen Not available in Italy Oral route: tablet. Dose tested, 400 mg Tolfenamic acid Not available in Italy Oral route: tablet. Doses tested, 200–1000 mg Combination drugs Lysine acetylsalicylate + Migraine Oral route: 1620-mg tablet, equivalent to 900 mg acetylsalicylic acid + 10 mg metoclopramide metoclopramide; maximum daily dose, 3240 mg equivalent to 1800 mg acetyl- salicylic acid + 20 mg metoclopramide Indomethacin + prochlorperazine Migraine Oral route: pill containing 25 mg indomethacin, 2 mg prochlorperazine and + caffeine 75 mg caffeine; maximum daily dose, 100 mg indomethacin + 8 mg prochlorperazine + 300 mg caffeine Rectal route: suppository containing 25 mg indomethacin, 4 mg prochlorperazine and 75 mg caffeine (a double-dose suppository is also available); maximum daily dose, 100 mg indomethacin + 16 mg prochlorperazine + 300 mg caffeine 125

Combination analgesics because it was better tolerated than ergotamine tartrate, especially in out-patient settings, in the emergency Combination analgesics have the same indications of sim- department or hospital setting. In controlled studies vs. ple analgesics and NSAIDs. There are few well-conduct- either placebo or active drugs, dihydroergotamine was ed studies in this regard, and the majority of them are effective in alleviating head pain during a migraine dated [263–267]. Recent studies are available only for the attack [278–283]. combination of acetylsalicylic acid, acetaminophen and Dihydroergotamine nasal spray is effective in the caffeine, and they show significant efficacy on head pain course of migraine attacks with percentages analogous to in the treatment of migraine attack [268, 269]. This com- those found for ergotamine plus caffeine in relieving bination has been demonstrated to be effective in the treat- head pain, but with fewer side effects [284–294]. Less ment of migraine attacks associated with the menstrual conclusive results have been obtained for ergotamine cycle [270]. administered intramuscularly or intravenously, although The combination analgesics available in Italy contain they are indicative of a discrete but significant effective- acetylsalicylic acid, acetaminophen, indomethacin, with or ness in the symptomatic treatment of migraine attack without caffeine, or acetylsalicylic acid, acetaminophen and [282, 283]. propiphenazone. Dihydroergotamine, both in the subcutaneous and nasal The efficacy of the combination compounds containing spray formulations, is less effective than subcutaneously acetylsalicylic acid, acetaminophen, propiphenazone has not administered sumatriptan in relieving head pain and accom- been assessed for the treatment of migraine attacks, panying symptoms, but is associated with a small percent- although these drugs have, at least in Italy, the generic indi- age of headache recurrence [15]. cation for headache. A single trial with dihydroergotamine nasal spray The combination analgesics have the same contraindica- has shown its greater effectiveness statistically com- tions and adverse effects of each component. Caffeine in pared to placebo, in reducing prodromic symptoms of these combination analgesics may induce agitation and migraine [292]. insomnia. See the single active components for their instruc- tions for use. The risk of abuse of combination analgesics has been widely emphasized; this can lead to a chronic daily headache [271]. Observations

Caffeine doubles the rate of absorption of ergotamine and increases its peak blood concentration. This prompted the Ergot derivatives development of combination formulations containing ergot- amine and caffeine. Effectiveness data Because nausea and vomiting may be worsened by the administration of ergot derivatives, the contempo- Ergotamine tartrate, in association with caffeine or not, has rary administration of an antiemetic is generally indicat- been shown to be significantly effective in numerous con- ed. The formulation of dihydroergotamine nasal spray trolled studies, versus placebo or versus active drug, in alle- may be more manageable if nausea and vomiting are viating head pain in a migraine attack [272–277]. present. Ergotamine tartrate does not seem to be effective on the The intravenous formulation of dihydroergotamine is not associated symptoms of nausea and vomiting; rather, available in Italy. In America and in other European coun- because of the interaction with dopaminergic receptors, it tries this treatment is recommended: for migraine crises may itself induce or increase nausea and vomiting. Data to resistant to treatment, especially in an in-patient setting, in support the effectiveness of the association of ergotamine, the emergency department, in the treatment of status caffeine and aminophenazone in the treatment of a migraine migrainosus and in chronic daily headache associated with attack are lacking. analgesic or NSAIDs abuse [295, 296]. Ergotamine tartrate administration is associated with a Patients who regularly use ergot derivatives for more low incidence of headache recurrence (<30%). Its use is than 2–3 days/week can develop rebound headache [248, controversial for migraine aura, but studies in this regard 297–300]. The abuse of ergot derivatives may induce an are lacking. increase in the frequency of the attacks and develop into a Up to the advent of the triptans, dihydroergotamine chronic daily headache. Their use is not recommended in the by parenteral route (no longer distributed in Italy) had treatment of attacks of medium/high frequency, for the been the first-choice treatment for migraine attack, potential risk of abuse. 126

Contraindications, adverse events and pharmacological Ergotamine and caffeine are administered as follows: interactions – Oral route: tablet containing 1 mg ergotamine and 100 mg caffeine; daily maximum dose, 4 mg ergotamine and Ergotamine tartrate and dihydroergotamine are contraindi- 400-mg caffeine cated in pregnancy, in uncontrolled hypertension, and in – Rectal route: suppository containing 2.0 mg ergotamine the presence of arteriovenous shunts, mitral stenosis, and 100 mg caffeine; daily maximum dose, 4 mg ergot- ischemic cardiopathy, cerebrovascular disease, or liver or amine and 200 mg caffeine renal failure [301]. Ergotamine, caffeine and aminophenazone are adminis- The principal adverse events due to the use of ergota- tered via the rectal route: in suppositories containing 0.5 or mine tartrate are nausea and vomiting (10%). Abdominal 2.0 mg ergotamine, 100 mg caffeine and 250 mg pain, diarrhea and muscular cramps have also been record- aminophenazone; daily maximum dose, 4 mg ergotamine, ed, and, rarely, distal paresthesias [302]. 200 mg caffeine, 500 mg aminophenazone. Its chronic administration may induce ergotism, acro- cyanosis, ulcerous distal necrosis, ischemic neuropathies, and pericardial, pleural or retroperitoneal fibrosis [303]. The adverse events consequent to the administration of Antiemetics dihydroergotamine are analogous to those detected for ergo- tamine tartrate but they occur less frequently [304]. The Efficacy data nasal spray formulation of dihydroergotamine induces rare adverse events that include nasal obstruction and muscular Such a heterogeneous class includes various drugs, which cramps [293]. differ pharmacologically from each other. Relatively few As far as pharmacological interactions are concerned, studies have investigated their effectiveness in migraine ergot derivatives should not be administered within 6 hours crises, particularly for the oral formulations. Such studies after the administration of a triptan. concern, in the majority of cases, the combinations with An increase in the risk of peripheral vasoconstriction can ASA and other NSAIDs (e.g. naproxen, ketorolac, aceta- be observed in patients who are concomitantly treated with minophen, tolfenamic acid) and dihydroergotamine [64, beta-blockers. Although the majority of the patients are able 194, 196, 200–202, 220, 305–308]. These associations have to tolerate such association, caution is necessary in particu- been proposed to improve the absorption of the sympto- larly sensitive patients. matic drugs and to act as adjuvants in reducing the nausea Erythromycin, josamycin and other macrolide antibiotics and vomiting accompanying a migraine attack. slow the metabolization of the ergot derivatives, increasing No data are available for domperidone. The only find- their plasma levels. Both ergotamine and dihydroergotamine ings have been obtained in a limited number of migraine should not be administered together or temporally near to patients, which suggest a potential moderate effectiveness in other vasoconstrictive drugs, including triptans. preventing and reducing head pain intensity during a migraine attack [309]. There is no evidence in this sense for other antiemetics. Metoclopramide and prochlorperazine, administered by Administration and dosages rectal route, have also been shown to have a bland anti- migraine effect, besides a clear antiemetic effect [310–312]. Ergotamine is administered via the: A modest effectiveness in the treatment of migraine attacks – Oral route: 1-mg tablet; daily maximum dose, 6 mg, not has also been found for metoclopramide administered intra- to be repeated on the following four days, not to exceed muscularly or intravenously [313–316]. a total dose of 10 mg/week There are also data supporting a partial efficacy in the – Rectal route: 0.5–2.0 mg doses have been tested; daily symptomatic treatment of migraine of prochlorperazine and maximum dose, 4 mg, not to be repeated on the follow- chlorpromazine administered intramuscularly or intra- ing four days, not to exceed a total dose of 10 mg/week venously [317–322]. – Subcutaneous route: 0.25-mg vial; daily maximum dose, 0.50 mg – Intramuscular route: 0.25- or 0.50-mg ampoule; daily maximum dose, 0.50 mg Observations Dihydroergotamine is administered as an intranasal spray at a dosage of 1–2 mg (1 spray of 0.5 mg per nostril); The oral and rectal antiemetic formulations are to be con- if necessary sprays can be repeated after 10–15 minutes, 1 sidered adjuvants in the symptomatic therapy of migraine. spray per nostril; daily maximum dose, 2 mg. The intramuscular and intravenous formulations may be 127 used for the treatment of attacks of moderate or severe inten- tives, hypnotics and tranquilizers due to their synergistic sity, in which nausea and vomiting prevail and when other depressive effect on the CNS [328]. symptomatic drugs are contraindicated or sedation is neces- Prochlorperazine and chlorpromazine may lower the sary. Prochlorperazine and chlorpromazine may also be con- anticonvulsive threshold. They should therefore be used sidered as monotherapy for the treatment of migraine with caution in the epileptic patients [336]. For other inter- attacks, especially in determined clinical settings (i.e. emer- actions see the relative information for each active drug. gency departments). Current evidence is not enough to include drugs of the class of the 5-HT3 antagonists (e.g. granisetron, zatosetron) among the symptomatic treatments for migraine attacks as Administration and dosages monotherapy. In particular clinical settings (i.e. emergency departments) and in selected patients, it is possible, however, Metoclopramide is administered as follows: to consider such drugs as adjuvants in relieving nausea and – Oral route: 10-mg tablet, 0.4% drops, 0.1% syrup, 5-mg vomiting in the course of a migraine attack [323, 324]. It is granular effervescent powder; maximum daily dose, 30 mg important to remember that cases of headache induced by the – Intramuscular or intravenous route: 10-mg ampoule; administration of ondansetron have been reported [325]. maximum daily dose, 30 mg Domperidone is given via the: – Oral route: 10-mg tablet, 0.1% syrup, 5-mg effervescent powder; daily maximum dose, 30 mg Contraindications, adverse events, pharmacological inter- – Rectal route: 30-mg suppository; daily maximum dose, actions 30 mg Prochlorperazine can be administered by the: Metoclopramide is contraindicated in patients affected by – Oral route: available as a 5-mg dimaleate tablet; has not pheochromocytoma or epilepsy and in patients receiving been tested for the symptomatic treatment of migraine drugs which can potentially induce extrapyramidal reactions – Rectal route: 10-mg suppository; daily maximum dose, (e.g. monoamine oxidase inhibitors, neuroleptics such as 20 mg phenothiazines, butyrophenones). The use of domperidone – Intramuscular route: 10-mg dose has been tested is not recommended in patients with prolactinoma. The use – Intravenous route: 10-mg dose has been tested of metoclopramide, chlorpromazine and prochlorperazine Chlorpromazine is given via the: must be limited only to cases of extreme necessity in preg- – Oral route: available as 25- or 50-mg tablet, not tested nancy and during breast feeding. for the symptomatic treatment of migraine The occurrence of adverse events following administra- – Intramuscular route: tested at 0.1 mg/kg up to 3 doses tion of metoclopramide is rare and is represented by every 30 min; maximum dosage administered 1 mg/kg extrapyramidal symptoms (particularly dystonia) [326]. – Intravenous route: tested from 12.5 mg to 37.5 mg Such eventuality has not been found for domperidone that Granisetron is administered intravenously. A dose of 40 does not cross the blood-brain barrier [327]. The principal mg/kg body weight has been tested. adverse events emerging from various studies concerning Zatosetron, although not available in Italy, is given intra- the administration of chlorpromazine and prochlorperazine venously. The 13-mg dose has been tested. are drowsiness and sedation [328, 329]. Acute dystonic crises and akathisia have been rarely recorded [330–333]. An adverse event rarely found with chlorpromazine is pos- tural hypotension, particularly if the drug is coadministered Other therapeutic strategies with an antihypertensive drug [334, 335]. The occurrence of adverse events due to the administra- Analgesic opioids tion of phenothiazines is facilitated by the consumption of alcohol or by the administration of propranolol, which raises Different controlled studies have shown the effectiveness of its plasma levels [330]. acetaminophen in association with codeine, or with doxyl- As far as pharmacological interactions are concerned, it amine and buclizine on migraine headache [223, 264–267]. is important to note that anticholinergic drugs, antacids and Such association has been shown, nevertheless, to be no more antisecretory drugs may antagonize the effects of metoclo- effective than acetaminophen alone. In a more recent study pramide and domperidone on gastric motility. the combination of acetaminophen and codeine has not been Metoclopramide, prochlorperazine and chlorpromazine shown to be more effective than acetylsalicylic acid in reliev- must not be coadministered with analgesic narcotics, seda- ing the head pain of migraine attack [195]. A further study has 128 not shown the superiority of the association of acetylsalicylic of migraine attacks, especially in the case of headaches acid with dextropropoxiphene and phenazone in comparison resistant to treatment [348–351]. Steroids are therapeutic to ergotamine [275]. Also, butorphanol (not available in Italy) options for the treatment of status migrainosus. by intramusular route has not been shown to be more effec- tive than dihydroergotamine administered intramuscularly in association with metoclopramide [280]. Research comparing butorphanol nasal spray with other symptomatic therapies for Diazepam migraine are lacking [337–340]. Clinical trials which com- pared mepiramine with ketorolac administered by intramus- One study has shown that neither diazepam nor cular route, dihydroergotamine, chlorpromazine or clormezanone significantly improve the antimigraine effect metrotrimetazine in the treatment of migraine attacks have of the association of metoclopramide, intramuscularly not reached conclusive results on their real effectiveness on administered, and acetaminophen, orally administered head pain [224, 225, 282, 284, 302, 341]. [352]. The members of the Ad Hoc Committee concur not to The Ad Hoc Committee has unanimously decided that such recommend such a drug for migraine attack. a class of drugs does not represent a valid option for the treat- ment of migraine crises. This is due to the absence of a more significant headache response compared to that found for other symptomatic antimigraine drugs and because of the potential Isometheptene and combination drugs containing risk of developing a chronic daily headache [342–344]. isometheptene mucate Patients who frequently use analgesic opioids and con- sult different physicians for their prescriptions are generally Isometheptene has shown a modest effectiveness on characterized by a particular personality trait that may con- migraine crises of moderate intensity in dated studies tribute to maintain or to worsen abuse. In this sense, they [353–355]. Combination drugs containing isometheptene should be directed to and followed by specialized centers. mucate, acetaminophen and dichlorphenazone appeared to be more effective than the combination of ergotamine and caffeine (midrin) in relieving head pain, with a lower inci- dence of side effects, such as nausea and vomiting Barbiturates [356–358]. Such compounds are not available in Italy.

Data are not available to support the effectiveness of barbi- turates in the treatment of migraine attacks. Their use should be avoided for the potential occurrence of abuse or rebound Level of evidence, scientific strength of evidence, headache, and for the development of a chronic daily assessment of clinical effectiveness headache. Drugs used in the symptomatic treatment of migraine are reported in Table 2 with the respective level of evidence, sci- entific strength of evidence and assessment of clinical effec- Lidocaine tiveness. The frequency of adverse events is also shown. The definitions of frequency and severity of adverse There is no evidence to support the effectiveness of lidocaine events are given in the Glossary. Information on frequency administered intravenously for the treatment of migraine and severity of adverse events from post-marketing studies attack. The results of two prospective studies point out a mod- carried out on large samples of migraineurs is available only est, but significant effectiveness, although it is accompanied for triptans. For the other drugs, only the percentages of by too frequent and early headache recurrence [345–347]. adverse events registered on a limited number of patients are available. These percentages may also differ consistently from those registered in the case of chronic use of certain drugs, such as non-steroidal anti-inflammatory drugs. Dexamethasone and hydrocortisone The recommendation groups, based on the level of evi- dence, scientific strength of evidence, assessment of clinical Three studies have been carried out on limited numbers of effectiveness as well as on the frequency and severity of patients. They have furnished conflicting results that do not adverse events for symptomatic antimigraine therapy are allow definitive conclusions to be drawn on the effective- reported in Table 3. The principal pharmacological interactions ness of intravenously administered steroids in the treatment of these drugs in migraine treatment are reported in Table 4. 129 the table continues rugs used in the symptomatic treatment not possible (when nausea or vomiting are present) or vomiting prevail) is not preferred or vomiting prevail) is not preferred. evidence of evidence effectiveness A +++ +++A Occasional, not severe Easy to use +++ NA Occasional, not severe Good tolerability profile and low recurrence a a a Agonists Levels of evidence, scientific strength of evidence, assessment of clinical effectiveness, adverse events and observations on d Levels of evidence, scientific strength assessment clinical effectiveness, DT, 2.5 mg DT, 2–150 mg DT, DT, 5–40 mg DT, SED, 10-mg tablet 10 mg DT, 20–80 mg DT, SED, 20- or 40-mg tablet 1–25 mg DT, SED, 2.5-mg tablet 500–1000 mg DT, SED, 2.5 mg rapimelt SED, 12.5-mg tablet SED, 500–1000 mg per os SED, 6 mg SC 25, 50, 100 mg DT, SED, 50- or 100-mg tablet 6.5, 12.5, 25, 100 mg DT, SED, 25-mg suppository 1–40 mg DT, SED, 20-mg nasal spray 2.5–5.0 mg DT, SED, 2.5-mg tablet DT, 1–8 mg DT, 1B/1D Zolmitriptan RizatriptanRizatriptan RPD EletriptanAlmotriptan Naratriptan A A +++Acetylsalicylic acid +++ A +++ +++ +++ A Occasional, not severe Occasional, not severe Good tolerability profile A Easy to use NA ++ +++ Occasional, not severe Good tolerability profile and low recurrence NA ++ Occasional, not severe Less rapid onset of action and a lower recurrence Occasional, not severe profile Good efficacy/tolerability SumatriptanSumatriptanSumatriptanZolmitriptan A +++ A +++ A +++ +++ A ++ Occasional, not severe +++ Good tolerability profile ++ Occasional, not severe Useful when oral route is not possible (when nausea +++ Occasional, not severe Useful when oral route is not possible (when nausea Occasional, not severe Good tolerability profile Sumatriptan A +++ +++ Frequent, not severe Rapid onset of action. Useful if oral administration is 5-HT Table 2 Table of migraine Drug Level of Scientific strength Clinical Adverse events Observations anti-inflammatory drugs (NSAIDs) Analgesics and non-steroidal 130 the table continues particular clinical settings (emergency department) particular clinical settings (emergency compound. Insomnia evidence of evidence effectiveness A +++ ++B Occasional, not severe For use predominantly in a clinical setting +++C ++ + Occasional, not severe + Frequent, not severe b a SED, 75 mg IM SED, 25–50 mg per os or suppository SED, 750–1500 mg per os SED, 30–60 mg IM SED, 500 mg per os 750–1250 mg DT, DT, 25–50 mg + 4–8 75–150 DT, 100 mg IM DT, SED, 100 mg IM 30–60 mg IM DT, possible DT, 50–100 mg DT, SED, 100 mg per os SED, 100–300 mg per os 400–2400 mg DT, SED, 400–1200 mg per os 25 mg + 2 75 DT, possible DT, dose equivalent to 1000 mg acetylsalicylic acid Mefenamic acid Naproxen B +++ B + ++ Occasional, not severe in menstrual migraine Effective ++ Occasional, not severe Ketoprofen Ketorolac B ++ B +++ ++ ++ Frequent, not severe Frequent, not severe In published studies it was predominantly used in to 500-1000 mg of acetylsalicylic acid) per os acetylsalicylate, equivalent to 1000 mg Lysine Diclofenac potassium Diclofenac sodium Flurbiprofen Ibuprofen AIndomethacin ++Indomethacin +proclorperazine + per oscaffeine, Indomethacin +proclorperazine + caffeine,suppository B C ++ C + A + + Occasional, not severe ++ + + + ++ Occasional, not severe Those of each active Those of each active Risk of abuse and CDH Risk of abuse and CDH Occasional, not severe compound. Insomnia Lysine acetylsalicylate (dosages equivalentLysine AASA IV +++Calcium carbasalate + metoclopramideASA equivalent to 900 mg DT, +10 mg metoclopramide, per os B ++ + Occasional, not severe For use predominantly in a clinical setting NA Occasional, not severe For use predominantly in a clinical setting Continuation of Table 2 Table Continuation of Drug Level of Scientific strength Clinical Adverse events Observations 131 the table continues of menstrual migraine compound. Insomnia possible repeated use sedation, asthenia, nausea, vertigo extrapyramidal signs (in particular dystonia) and sedation evidence of evidence effectiveness A +++ ++C 0 Those of each active in menstrual migraine. Risk of CDH with Effective 0 Occasional: Adjuvant for nausea and vomiting a a acetylsalicylic acid + DT, 200–400 mg per os DT, 500 mg + 130 DT, SED, 10-mg suppository SED, 10 mg IM DT, 650–1500 mg DT, SED, 500–1000 mg per os 40 mg RPD per os DT, SED, 40 mg RPD per os 400 mg per os DT, 400–650 mg + 6–25 DT, 10 mgDT, SED, 10-mg suppository 10 mg IMDT, metoclopramide, per os metoclopramide, per os DT, 750–1750 mg DT, SED, 750–1500 mg per os SED, 200 mg per os Tolfenamic acid Tolfenamic Acetaminophen + caffeine BMetoclopramide + NA Occasional, not severe Acetaminophen Piroxicam Pirprofen B + BParacetamol + codeine ++ B ++ + Rare, not severe + BMetoclopramide ++ NAMetoclopramide Occasional, not severe Occasional, not severe ++ C Frequent, not severe; + C Risk of CDH with repeated use + + + Same as for Same as for Same as for metoclopramide, per os Same as for metoclopramide, per os Naproxen sodium Nimesulide A ++ C 0 ++ Occasional, not severe + Occasional, not severe Used in a single study the intermittent prophylaxis Continuation of Table 2 Table Continuation of Drug Level of Scientific strength Clinical Adverse eventsCombination analgesics, per os Observations Opioid analgesics, per os Antiemetics 132 the table continues abuse ergotism can occur abuse ergotism frequent is sedation The most Rare. Adjuvant for nausea and vomiting sedation, orthostatic hypotension hypotension with the oral formulation frequent is sedation of sedation department) particular clinical settings (emergency restlessness anxiety, From frequent to dysphoria, flushing, evidence of evidence effectiveness B + NA Frequent, not severe a a 1- to 3-times per day c c c c a 0.1 mg/kg 1- to 3-times per day; DT, 2–6 mg ergotamine + 2–6 mg ergotamine DT, 200–600 mg caffeine maximum dose, 10 mg SED, 10 mg IM DT, 10 mg IV DT, 0.1 mg/kg to 3 doses every 30 min; DT, maximum dosage, 1 mg/kg body weight 12.5–37.5 mgDT, 30–120 mg per os or suppository DT, SED, 10–30 mg per os or suppository 1–6 mg per os, SC, IM; 1–4 DT, suppository SED, 1–2 mg per os, suppository, SC, IM sedation, orthostatic department) particular clinical settings (emergency can occur abuse ergotism SED, 10 mg IM SED, 10 mg IV DT, 1 mg IM mg 1 DT, IMSED, mg 1 occasional, not severe: nausea, vomiting, DT, DT, 0.5–4.0 mgDT, SED, 2 mg nasal spray nausea and vomiting nasal congestion, Ergostine (2 mg) + caffeine (200 mg) (2 mg) + caffeine Ergostine Prochlorperazine, 20-mg suppositoryProchlorperazine B B ++Prochlorperazine ++Chlorpromazine ++ Chlorpromazine IV ++Domperidone BThe most Rare. ++ Adjuvant for nausea and vomiting Ergotamine C B + ++ ++ (200 mg), (2 mg) + caffeine Ergotamine per os or suppository C B occurrence Greater + + + ++ than metoclopramide. Used in More efficacious B Occasional, not severe: Adjuvant for nausea and vomiting Occasional, not severe: + Adjuvant for nausea and vomiting. Used in + NA Frequent, not severe Rare NA Risk of abuse and developing CDH; in the case Frequent, not severe Risk of abuse and developing CDH; in the case Adjuvant for nausea and vomiting Metoclopramide, 0.1 mg/kg body weight IV B + + More frequent than Used in particular clinical settings Dihydroergotamine Dihydroergotamine A +++ B ++ ++ Occasional, not severe: NA than with ergotamine Fewer side effects Ergot alkaloids and ergot derivatives alkaloids and ergot Ergot Continuation of Table 2 Table Continuation of Drug Level of Scientific strength Clinical Adverse events Observations 133 , acetylsalicylic ASA omethacin and caffeine. Per os: 2 mg prochlor- omethacin and caffeine. , intramuscularly administered; status migrainosus status migrainosus IM id (900 mg) in association with metoclopramide (10 mg). acid, due to the lack of studies which directly investigat- formulations frequent is sedation From frequent to Risk of abuse and CDH nausea,vomiting, dysphoria, flushing, restlessness anxiety, occasional; the most frequent is sedation sympathetic hyperactivity) dysfunction (e.g. sympathetic hyperactivity) , intravenously administered; IV , not applicable in Italy NA , subcutaneously administered; SC evidence of evidence effectiveness B ++ B +++ NA NA More frequent than for than the SC and IM formulations More efficacious Frequent Association with metoclopramide reduces nausea B + NA Can induce autonomic , chronic daily headache; a CDH a a a a , suggested efficacious doses; , suggested efficacious a a SED , rapidly dissolving formulation; 6-times per day DT, 0.5–4.0 mg DT, + 0.5–1.0 mg dihydroergotamine DT, 10 mg metoclopramide 50 mg + 325 40 DT, 130–780 mgDT, the SC and IM of dihydroergotamine and vomiting dysfunction (e.g. DT, 1 mg SC DT, SED, 1 mg SC 50 mg + 325 40 30 DT, 6 mg IV DT, 50 mg IV DT, 4% solution, 1–4 dropsDT, 65 mg + 325 100 mg, 2- to DT, irritation headache RPD Isometheptene mucate + acetaminophen dichloralphenazone, per os B + NA Can induce autonomic Dihydroergotamine + metoclopramide IV Dihydroergotamine Butalbital + acetylsalicylic acid per oscaffeine, +Butalbital + acetylsalicylic acid caffeine codeine, per os C B + ++ NA ++ From frequent to Risk of abuse and CDH or rebound headache occasional; the most Dihydroergotamine B +++ NA Occasional, not severe: Dihydroergotamine, IV Dihydroergotamine, Dexamethasone Hydrocortisone Lidocaine, intranasalIsometheptene, per os C C B + + ++ + NA + Rare Occasional; nasal Rare Short duration of action and possible recurrence Use should be limited to a short period. Indicated in Use should be limited to a short period. Indicated in , doses tested; Prochlorperazine in these formulations is not available in Italy. It is available, however, as a combination analgesic with ind It is available, however, Prochlorperazine in these formulations is not available Italy. Introduction of lysine acetylsalicylic acid, per os, has been carried out according to the equivalent doses for Not available in Italy acid; perazine, 25 mg indomethacin, 75 mg caffeine; suppository: 8 mg prochlorperazine, 50 indomethacin, 150 caffeine perazine, 25 mg indomethacin, 75 caffeine; DT ed the oral formulations with these dosages. Only one study assessed the efficacy of the equivalent dose for acetylsalicylic ac ed the oral formulations with these dosages. Only one study assessed efficacy Continuation of Table 2 Table Continuation of Drug Level of Scientific strength Clinical Adverse events Observations a b c Barbiturate hypnotics Other drugs 134

Table 3 Drugs for symptomatic treatment of migraine grouped by level of recommendation, based on the level of evidence, scientific strength of evidence, and assessment of clinical effectiveness. Drugs are listed in alphabetical order

Level I Level II Level III Level IV

Acetylsalicylic acid, per os Acetaminophen, per os Acetaminophen, per osa Butalbital + propiphenazone + Almotriptan, per os Acetaminophen + Acetylsalicylic acid + butalbital caffeine, per os, suppository Dihydroergotamine, nasal spray acetylsalicylic acid + + caffeine, per osa Dexamethasone IV Dihydroergotamine, IM IV* caffeine, per os* Ergotamine, per osa, * Domperidone, per os (also in association with Acetaminophen + codeine, per os Ergostine + caffeine, per osa Granisetron IV an antiemetic) Acetylsalicylic acid + butalbital Ergotamine + caffeine, per osa Hydrocortisone IV Eletriptan, per os + caffeine + codeine, per osb Indomethacin + prochlorperazine + Metoclopramide, per os Ibuprofen, per os Chlorpromazine IM, IV caffeine, per os, suppositorya Nimesulide, per os Lysine acetylsalicylate, per os Diclofenac, per os Isometheptene and isometheptene Zatosetron IV* Lysine acetylsalicylate + Ergotamine IM, SC mucate, per osa, * metoclopramide, per os Flurbiprofen, per os Lidocaine IVa Naproxen sodium, per os Ketoprofen, per os Metoclopramide IM, Naratriptan, per os* Ketorolac IM suppositorya Rizatriptan, per os Lidocaine, intranasal Piroxicam, rapidly dissolving Sumatriptan SC, nasal spray, Metoclopramide IV formulation, per osa per os, suppository Naproxen, per os Pirprofen, per osa,* Zolmitriptan, per os Prochlorperazine IM, IVa

* Not available in Italy; a Drugs with no severe adverse events IM, intramuscularly; IV, intravenously; SC, subcutaneously

Table 4 Major pharmacological interactions among drugs for the symptomatic treatment of migraine

Triptans Serotonergic agonists Other triptans Ergotamine derivatives Sibutramin Ergot derivatives Beta-blockers Triptans NSAIDs Other NSAIDs Heparin Diclofenac Methotrexate Tacrolimus Ketorolac Lithium Salicylates Oral anticoagulants Tramadol Tricyclic antidepressants Neuroleptics SSRIs Antiemetics Domperidone Lithium Phenothiazines Cisapride Lithium Tramadol Metoclopramide Digoxin Butalbital Oral anticoagulants

NSAIDs, non-steroidal anti-inflammatory drugs; SSRIs, selective serotonin-reuptake inhibitors 135

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