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Home , Antimigraine drug, Migraine treatment, Pizotifen

J Pain (2001) 2:147–161 © Springer-Verlag 2001

Prophylactic treatment of

Medline, but also the result of the critical evaluation by a Introduction group of experts who discuss the results available in the lit- erature, taking into account their own experiences. In fact, The opportunity to choose a specific prophylactic therapy clinical reports may not be sufficient for giving a step for a patient depends upon the severity of the attacks and approach to treatment choice, particularly for not yet how these alter the quality of life. Prophylactic adequately evaluated, even if they are used by patients or treatment is usually recommended in the case of 3 or more prescribed by physicians [2–4]. severe attacks per month incompletely responding to symp- tomatic treatment and in the case of more than 4 days with headache per month. The main goals for preventive agents in migraine Management of pharmacological treatment treatment are to reduce the frequency and severity of migraine attacks and improve the quality of life. It is gen- To minimize the risk and improve the patient’s compli- erally accepted that a good response to prophylactic treat- ance, prophylactic treatment should be started at low ment is at least a 50% reduction in the frequency or doses, possibly as a monotherapy. Doses can be slowly severity of migraine attacks. Others goals are to expand increased until therapeutic goals are achieved in the the knowledge of preventive treatments, to promote stud- absence of side effects. The treatment should be main- ies in this field, and to avoid the development of a chron- tained for at least 3 months before stopping it. In fact, clin- ic daily headache as well as symptomatic abuse or ical benefit may take as long as 1–3 months after the onset misuse [1]. of response. To use a monotherapy at adequate doses and As for all therapeutic strategies, even the prophylactic for an adequate period of time is necessary in order to drugs for migraine should undergo a careful evaluation of underscore the relationship between drug efficacy and side their benefit/risk ratio. This implies that each treatment effects. should be used at the dosage with the least number of Long-acting or depot formulations can improve patient adverse drug reactions (ADRs) in order to reduce the num- compliance. When pharmacological resistance appears, a ber and severity of attacks for an adequate period until the new prophylactic treatment with another drug should be pre- treatment can be stopped. ceded by a washout period. The presence of any comorbid conditions should be con- Drugs contraindicated for any comorbid conditions (i.e. sidered in the choice of a preventive for beta-blockers in patients with ) and drugs that could migraine. worsen migraine (i.e. nifedipine for hypertension) should be avoided, when possible. Particular attention should be devoted to drug-drug or drug-food interactions, and it should be remembered that From evidence-based medicine to recommendations many prophylactic treatments may cause teratogenic effects. Therefore, prophylactic treatment during pregnan- Recommendations for the prophylactic treatment of cy should be limited to special situations, and in these rare migraine should be not just the simple sum of the findings cases, drugs with the lowest risk to the fetus should be of clinical trials from evidence-based papers, obtained from selected. 148

Patient recommendations One or more precipitating factors are reported in 64%–90% of patients with migraine, and these are more The main problem in preventive therapies is always patient frequent in those with migraine without aura than with compliance. The compliance in prolonged treatments is aura. The most frequent factors are stress and psychologi- inversely related to the length of treatment and the number cal tension. of pills taken every day. Therefore, when possible, the num- A trivial trigger is considered food. Many people believe ber of drugs taken should be reduced and the patients should that by avoiding some specific foods it is possible to reduce be involved in the choice of their own treatment. Patients the frequency of migraine attacks. Putative allergic factors should be carefully informed about how and when to take are often considered responsible for migraine attacks, drugs, and about the potential adverse effects. Another rele- whereas, only in rare cases, a specific food directly causes vant point to address is the patient’s expectations of the actu- migraine. From 20% to 52% of patients report that alcoholic al therapeutic efficacy of the drug, and about the impact of drinks precipitate migraine, and conflicting data have been the treatment on the quality of life and disease evolution. reported with respect to differences between beer or red and For the evaluation of the efficacy of the treatment, white wine. Also, some foods are involved as precipitating patients should be educated to follow a formal management factors in percentages varying from 10% to 45%, namely: plan and to carefully fill out headache diaries that record chocolate, cheese, some fruits, citrus fruits, fatty foods and the frequency and duration of attacks, the severity of pain, fried foods. Peatfield [5] recorded 19% of patients reporting the functional impairment, disability and the drugs taken as sensitivity to cheese, chocolate, or both, and 11% of patients well as any adverse events. These parameters are necessary sensitive to citrus fruits. The exact mechanism of these to assess the modifications in migraine due to preventive migraine attacks is unknown, although migraine is general- treatment. ly believed to be caused by a chemical reaction consisting in the release of from the intestinal wall, or by an enzymatic defect, and not by allergic reactions. By contrast, fasting has been described to be a precipi- Primary prevention of migraine tating factor in 25% of children and in 40% of adults affect- ed by migraine. Migraine can be considered as a particular response of the Menstruation is a common precipitating factor in to a number of triggers, both internal and 24%–64% of women suffering from migraine without aura. external. Such response is probably genetically deter- In fact, hormonal factors can be considered as both precipi- mined. Migraine patients seem to present a lower thresh- tating and predisposing factors. old for attacks in certain brain areas compared with those Both too much or too little sleep as well as fatigue are of non-migraineurs. In this regard, the primary prophylax- believed to be precipitating factors. is of migraine should be focused on identifying the trig- Moreover, weather changes are often considered to be gers and carefully avoiding them by changing the patient’s precipitating factors for migraine in a percentage ranging lifestyle. Therefore, patients should be provided a list of from 7% to 43%, and patients even say that they are able to common triggers to avoid. Another easy method is predict the forecast. By contrast, specific studies did not encouraging patients to note all the migraine attacks and show a relationship between migraine attacks and either the potential triggers for each attack in their headache weather conditions or barometric changes. diary. Glaring, blinding and psychedelic lights are also report- The most frequent trigger factors are listed in Table 1. ed to be precipitating factors for migraine, and in a recent However, even a correct lifestyle cannot prevent all study these lights were recognized as precipitating factors migraine attacks in all patients. only in migraine with aura [6]. It has been hypothesized that migraine patients have a Other triggers could be angiographic procedures, head lowered threshold for trigger factors, perhaps genetically injuries, physical exercise, and altitude. By contrast, determined. So, a rational prophylactic treatment should be sexual activity does not seem able to cause a migraine focused to enhance this threshold and this, together with the attack. removal of trigger factors, when possible, should result in the reduction of the number and intensity of attacks. Precipitating factors are those factors able to elicit a migraine attack, after a short time of exposure. They are not Behavior modifications the cause of . They often need cofactors to precip- itate the attacks and, even in the same patients, one factor is The first recommendation for patients should be to avoid not enough to always induce the attack. trigger factors. To obtain this result, patients need to recog- 149 nize their specific trigger factors; therefore, it is necessary to (CNS). Failure of prophylactic treatment with one beta- carefully fill out the diary that should be evaluated at every blocker is not predictive of the activity of other beta-block- medical visit. ers, so that consecutive trials with these drugs are appropri- When stress is identified as the main trigger factor, it is ate. Physicians should start with low doses and increase useful to begin a formal behavioral treatment program to them slowly, if necessary. avoid stressors, since pharmacological therapy alone is When migraine attacks are controlled, doses can be unable to control migraine attacks. For this purpose, muscle reduced slowly. The abrupt suspension of beta-blockers can relaxation techniques, including biofeedback, are recom- induce rebound effects both increasing migraine attacks and mended. In some cases physical exercise can be useful to inducing adrenergic side effects and hypertension. reduce stress. Drug treatment should be used together with behavior modifications to obtain a significant reduction of migraine attacks and an improvement in the quality of life. Calcium channel blockers

Calcium channel blockers act by modulating neurotrans- mission, inducing vasodilatation and exerting a cytopro- Re-evaluation of the diagnosis tective effect by preventing the influx of calcium ions into the cells and reducing cell damage due to hypoxia. The The diagnosis should be re-evaluated when: therapeutic effects become evident only after some – there is a case of high frequency of migraine attacks months of treatment, and are associated with a number of – there are changes in migraine characteristics (i.e. focal side effects. Among all available drugs of this class, the symptoms, variation of frequency, intensity or length of most used are (level of evidence A, recom- attacks, etc.) mendation level I) and (level of evidence B, – there is a lack of effects after three treatments with dif- recommendation level II) [57–77]. The efficacy of these ferent drugs drugs in reducing migraine attacks by at least 50% and – there is an abuse improving the quality of life is comparable with that obtained by beta-blockers at least for flunarizine. Less consistent are the findings with nimodipine and nifedip- ine [78–82]. Drugs for prophylactic treatment Some calcium channel blockers are contraindicated in , hypotension, heart failure, atrioventricular (AV) A few drugs for the prophylactic treatment of migraine have block, Parkinson’s disease and (e.g. flunarizine) been studied in adequate clinical trials according to evi- and in patients in therapy with beta-blockers and mono- dence-based medicine (EBM) criteria. The level and quality amine oxidase inhibitors (MAOI) (e.g. verapamil). of evidence for their use, and the overall recommendation level, are presented in Tables 2 and 3 respectively. Clinically relevant drug-drug interactions are given in Table 4. Serotonin antagonists

Pizotifen is one of the serotonin receptor antagonists with Beta-blockers weak antihistaminic and effects. Despite its effectiveness in migraine, with a clinical benefit in How beta-blockers can reduce attack frequency in mi- 50%–64% of the cases, it has side effects which include graneurs is not clear, although it is probably by acting on the weight gain and asthenia (level of evidence A, recom- central system and serotonin receptors. Not mendation level IIIb) [83–86]. is a semi- all these drugs are effective, and those used in migraine pro- synthetic derivative with activity as 5-HT1 phylaxis include , , and propra- and 5-HT2 receptor antagonists. It has been shown to be nolol [7–56]. Beta-blockers are contraindicated in patients active, particularly in cases with high frequency of attacks with chronic obstructive pulmonary disease, melli- not responsive to treatment [86]. Contraindications tus, heart failure and peripheral vascular diseases. There is a include pregnancy, peripheral vascular disorders, severe relative contraindication in pregnancy. arteriosclerosis, , severe hyperten- Atenolol and nadolol are excreted by the kidneys and sion, thrombophlebitis or cellulitis of the legs, peptic show fewer adverse effects in the central ulcer disease, fibrotic disorders, lung diseases, connective 150 tissue disease, liver or renal function impairment, valvu- Antiepileptic drugs lar heart disease, cachexia, or serious . Methysergide can induce retroperitoneal fibrosis and Sodium shows excellent results in preventing pleural and heart valve fibrosis with an estimated inci- migraine in clinical trials (level of evidence A; recommen- dence of 1 in 5000 treated patients. Therefore, it should be dation level I) [115–120]. reserved for severe cases in which other migraine preven- Care should be used when this drug is associated with tive drugs are not effective, taking carefully into account acetylsalicylic acid (ASA) and warfarin, because of the the risk-benefit ratio. Today this drug is not available in possibility of bleeding. The main side effects are nausea, Italy. alopecia, tremors and weight gain; chronic use may induce liver damage, mostly in children. This drug is ter- atogenic and should not be administered to pregnant women. , a GABAergic drug, has been shown to be effective in preventing migraine attacks [121, 122]. In a is useful in migraine, especially in patients recent multicenter double-blind placebo-controlled study, with concomitant tension-type headache (level of evidence this drug was significantly more effective than placebo in A, recommendation class I). The mechanism of action is reducing the frequency of migraine attacks [122]. The not related to its activity. Amitriptyline more frequent adverse effects were somnolence and modulates monoaminergic pathways, by inhibiting the dizziness. reuptake of both and serotonin. Moreover, it and lamotrigine have been used with moder- functionally down-regulates β-adrenergic and ate efficacy in migraine prophylaxis [123–130]. The most receptor expression in the central nervous system The frequent side effects of topiramate were cognitive dysfunc- effective dose varies [27, 87–91], starting with an initial tion, sedation, diarrhea, weight loss, and dizziness. Recently, dose of 10 mg, per os, every night, to be increased by 10 it has been reported that after one month of therapy with top- mg per week, up to a maximum of 50 mg per day. High iramate, some patients reported an acute reduction of vision, doses could be necessary in the case of concomitant myopia and acute narrow-angle . depression. Lamotrigine showed less efficacy in preventing migraine A lower risk of developing asthenia and without aura, whereas it was efficacious in preventing side effects has been observed for compared to attacks in the case of a high frequency of migraine with aura amitriptyline (level of evidence C). The contraindications crises [128–130]. The most frequent side effects were: rash include: severe cardiac, liver, renal, prostatic and thyroid (some fatal), fatigue, dizziness, headache, Stevens-Johnson diseases, glaucoma, hypotension, convulsive disorders and syndrome, toxic epidermal necrolysis and hypersensitivity concomitant use of MAOI. reactions. Tricyclic antidepressants should be used with caution in No recent studies have been carried out on carba- elderly patients because of anticholinergic effects. mazepine as a prophylactic and data are inconclusive about its efficacy [131, 132].

Selective serotonin-reuptake inhibitors Non-steroidal anti-inflammatory drugs Few studies are available on the use of this class of drugs in the prophylaxis of migraine [92–98]. At the moment, there The main mechanism of action of non-steroidal anti- is no definitive evidence supporting the use of these drugs in inflammatory drugs (NSAIDs) is the inhibition of preventing migraine attacks. cyclooxygenase in both isoforms, whereas, even in the absence of inflammation, NSAIDs are active in reducing migraine pain (level of evidence B, recommendation level II). Among this class of drugs, acetylsalicylic acid, flur- Alpha-2 agonists biprofen, lornoxicam, mefenamic acid, ketoprofen and both and naproxen sodium show a discrete effec- The majority of the studies on the prophylactic treatment of tiveness in migraine prophylaxis [2, 133–146]. Both migraine concern but failed to show more effica- naproxen and naproxen sodium are useful in the prevention cy compared with placebo [99–113]. Negative results were of menstrual migraine (level of evidence B; recommenda- also obtained with [114]. tion level II) [147, 148]. 151

NSAIDs should be used for intermittent prophylaxis in pain and diarrhea. This drug at these doses is not avail- menstrual migraine and not for prolonged periods of time able in Italy. because of their gastric and intestinal side effects (level of evidence B) [149, 150].

Estrogens

Dihydroergotamine Some clinical trials showed the efficacy of high doses of estradiol (1.5 mg/day in gel) in the prophylactic treat- in slow-release formulations at ment of menstrual migraine. They have been demonstrat- various doses was effective in preventing migraine ed to significantly reduce the number of attacks [157, attacks [151, 152]. Dihydroergokryptine also appeared to 158]. Lower doses (50 mg/day) were ineffective. be an effective drug for the prophylaxis of migraine Preliminary studies suggest a possible effectiveness of attacks [153]. the association of estradiol with flumedroxone and methysergide [86].

Lisuride Tanacetum parthenium has been proved to be effective and well-tolerated for migraine prophylaxis in some studies [154, 155]. In an The efficacy of feverfew in preventing migraine is not uni- open study, a reduction of more than 50% of attacks was versally accepted. Some studies show a reduction in pain observed in 61.4% of patients treated for a 3-month period, intensity and associated symptoms, whereas others show an with good tolerance [154]. increase in the frequency of attacks or no differences in comparison with placebo [159–162].

Riboflavin at high doses (up to 400 mg) showed good effectiveness in preventing migraine attacks [156] with a Magnesium showed efficacy in preventing migraine in three low rate of unwanted side effects, such as mild abdominal clinical trials [163–165].

Table 1 Common trigger factors for migraine

Hormonal Menstruation, ovulation, oral contraceptives Diet , nitrites, monosodium glutamate, aspartame, chocolate, cheeses, fasting Psychological Stress, post-stress (weekends and holidays), , fear, depression Environmental Flashing lights, blinding lights, fluorescent lights, weather changes, perfumes, altitude Sleep Lack of or excessive sleep Drugs Nitroglycerin, , reserpine, hydralazine, , estrogens, cocaine, marijuana Others Head injuries, physical exercise 152 the table continues n dosing. Refer to published litera- Recommended dose to minimize side effects is 5 mg/day Recommended dose to minimize side effects Useful in patients with hypertension, anxiety and panic attacks. Should not be used in patients with coexisting asthma, cardiac failure or Raynaud's disease. May exacerbate depression. Do not use with Increase doses gradually . is used with , a lower dose of rizatriptan should be administered Depression and extrapyramidal symptoms may be The recommended dose observed in elderly patients. AEs is 5 mg/day to reduce Elevated cost AVof block. Could be a good alternative for beta-blockers in athletes. Recommended patients with stroke or prolonged aura, and in patients Avoid coexisting hypertension and tachycardia. association with beta-blockers evidence of evidence effectiveness C NA ? Occasional, not severe similar to other drugs of this class. Tolerability a DT, 40–240 mg/day DT, ED, 80–240 mg/day 80–240 mg/day DT, ED, 80–240 mg/day 50–300 mg/day DT, ED, 200 mg/day 3–10 mg/day DT, ED, 3–10 mg/day 75–150 mg/day DT, ED, 75–150 mg/day 60–120 mg/day DT, ED, 120 mg/day ED, 240 mg/day DT, 100 mg/dayDT, ED, 100 mg/day A ++ +++ Occasional, not severeAEs are asthenia, fatigue and dizziness. Frequent Evidence for prophylactic drug treatments in migraine. Dose ranges are indicative only. Recommendations are not made for regime Evidence for prophylactic drug treatments in migraine. Dose ranges are indicative only. PropranololNadololMetoprolol A +++Flunarizine B B + +++ ++Nimodipine A Occasional, not severeWhen Same as for atenolol, plus essential tremor. Verapamil +++ ++ B ++ B + Occasional, not severe Same as for atenolol +++ Occasional, not severeDiltiazem Same as for atenolol + B Occasional, not severe are weight gain and sedation. Most frequent side effects + + + Occasional, not severe Drowsiness and weight gain + Occasional, not severe Abdominal discomfort is usual. Occasional, not severe Constipation is common. Do not use in the presence Atenolol Table 2 Table ture for specific dosing information. No information is provided treatments not evidence-based (Level C) Drug Level of Scientific strength Clinical Adverse events Comments Calcium channel blockers Beta-blockers 153 the table continues anxiety disorders atypical migraine aura. Not recommended in patients A with liver disease and hemorrhagic diatheses. progressive increase in doses is recommended with repeated monitoring of drug plasma levels in the AE like nausea, asthenia early months of treatment. and somnolence are frequently seen when higher include weight doses are used. Other side effects and teratogenic potential gain, hair loss, tremor, are common. Particularly useful in patients with depression, migraine and tension-type headache. A progressive increase in doses is recommended until AEs maintenance doses are reached in order to reduce (recommended doses, 10–75 mg/day) interactions. Benefits are less than potential risks glaucoma frequent. Used as an adjunct treatment in depressed There are drug interactions with 5-HTpatients. agonists Acute myopia and narrow-angle (100 mg/day). potentially severe restrictions; shows a high risk of severe drug-drug C NA + Frequent, not severeTCAs See other B ++ ? Occasional, not severeAE, stones and weight loss Occasional CNS evidence of evidence effectiveness C NA ? Frequent and Requires complex management with special dietary a a a a a DT, 800–1550 mg/day DT, Serum level, 50 mg/l ED, 900–1500 mg/day 900–1200 mg/day DT, ED, 30–150 mg/day DT, 25–150 mg/day DT, DT, 10–40 mg/day DT, Sodium valproate A +++ ++ Frequent, not severe Recommended for patients with prolonged or GabapentinTopiramate A ++ ++ Occasional, not severe NortriptylineDoxepin, C NA + Frequent, not severe Better tolerated than amitriptyline (doses, 10–75 mg/day) Amitriptyline A +++ +++ Frequent, not severeAEs Drowsiness, weight gain and anticholinergic , mertazepine,, C NA + Occasional, not severe Could be useful in patients with depression and Fluvoxamine, ,sertraline C NA + Occasional, not severe Same as for Fluoxetine B ++ + Occasional, not severe Insomnia, fatigue, tremor and stomach pain are Tricyclic antidepressants (TCAs) Tricyclic Antiepileptics Antidepressants Other antidepressants Continuation of Table 2 Table Continuation of Drug Level of Scientific strength Clinical Adverse events Comments Monoamine oxidase inhibitors Selective serotonin-reuptake inhibitors Selective serotonin-reuptake 154 the table continues drowsiness. Not recommended because of poor and a high incidence of side effects efficacy prevention of migraine frequency of attacks AE are common prophylaxis attacks of low frequency and in case no response be To to . Do not use within 6 h after used in mild to moderate migraine attacks when NSAIDs are not tolerated. Useful for short-term prophylactic therapy are frequent. May be useful for patients with arthritis and previous stroke B ++ 0 Frequent, not severe Common adverse events are dizziness, vertigo, A ++ +++ Rare, not severe Alternative drug for moderate to severe migraine evidence of evidence effectiveness CA NA ++ + + Frequent, not severeB gain and fatigue Weight Used in pediatric migraine. Occasional, not severeAt low doses useful for migraine Not available in Italy. ++ ? Occasional, not severe – a a a DT, 0.05–0.225 mg/day DT, DT, 600 mg/day DT, ED, 0.075–0.15 mg/day 150 mg/day DT, ED, 150 mg/day ED, 150 mg/day DT, 10 mg/day DT, DT, 325–1300 mg/day DT, ED, 10 mg/day ED, 1300 mg/day DT, 100 mg/day DT, mg/day 1100 DT, mg/day ED, 1100 150 mg/day DT, a Clonidine B 0 0 Frequent, not severe CNS adverse events frequent, no clinical benefit for PizotifenCyproheptadine A ++ +++ Frequent, not severe Somnolence and weight gain are common Acetylsalicylic acid B + ? Occasional, not severe Abdominal discomfort, and occult GI bleeding Lornoxicam Lamotrigine B ++ ? Frequent, not severe Recommended for migraine with aura a high Naproxen, naproxen sodium BKetoprofen ++ B ? ++ Occasional, not severe Used as short-term prophylaxis in menstrual migraine ? Occasional, not severe – Alpha-2 agonists Serotonin antagonists Serotonin Lisuride TR Dihydroergotamine NSAIDs Continuation of Table 2 Table Continuation of Drug Level of Scientific strength Clinical Adverse events Comments 155 , DT , gastrointestinal; GI women, and drowsiness decreased libido in men and further studies are needed. Visual field constriction Visual and further studies are needed. AE has been described as rebound frequency of headaches jaundice, porphyria, menstrual disturbances in May be useful in patients with menstrual migraine with rebound frequency of headaches everywhere restrictions. High potential for drug-drug interactions. May be helpful in patients with coexisting depression or when antidepressants from other classes fail. AE include orthostatic hypotension, fatigue, vertigo and psychotic disturbances , non-steroidal anti-inflammatory drugs; NSAIDs , not applicable; ?, undetermined NA , atrioventricular; AV , not recommended; NR , time-released; Based on body weight , tricyclic antidepressants; b TR TCAs evidence of evidence effectiveness BC ++ NA ? ?B Occasional C +A Frequent NA Clinical experience and published data are lacking +++ ? Requires complex management with special dietary ? ? Not severe Frequent Rare but potentially Should be reserved for severe cases in which other could be associated with Withdrawal Mild side effects. May be used in menstrual-associated migraine , adverse events; AE a a b a a , efficacious doses in clinical trials; , efficacious ED ED, 10–30 mg/day DT, 1000–2000 mg/day DT, 20 mg/day DT, 2–10 mg/dayDT, ED, 6 mg 10–30 mg/day DT, severe migraine preventive drugs are not effective DT, 15 mg/day for 1 weekDT, ED, 15 mg/day for 1 week 400 mg/day DT, ED, 400 mg/day 400–600 mg/day DT, migraine. Percutaneous use ED, 400–600 mg/day 50–82 mg/day DT, ED, 50–82 mg/day 20–30 mg/day DT, ED, 20–30 mg/day Phenelzine Methylergonovine Flumedroxone B + ? Occasional to frequentAE are hepatic disease, hemorrhage, cholestatic Rare Estradiol B2Vitamin Magnesium B B ++ B +++Vigabatrin + ++ ++ Rare, not severe + Rare, not severe Used for the short-term prevention of menstrual AE. Unknown drug-drug interactions Rare Rare, not severe Non-chelated formulations can induce diarrhea. Methysergide Tanacetum partheniumTanacetum ABotulinum toxin B ++ B ++ ? ++ Rare, not severeDihydroergokryptine could be associated Withdrawal Mild side effects. Rare, not severe A of administration are not easy and applicable Techniques ++ ? Infrequent – , central nervous system; Efficacious dose not established in controlled trials; Efficacious Others Drugs not available or used in Italy Continuation of Table 2 Table Continuation of Drug Level of Scientific strength Clinical Adverse events Comments a CNS doses tested; 156

Table 3 Drugs for prophylactic treatment of migraine grouped by level of recommendation

Level I Level II Level III (a, b) Level IV

Amitriptyline Cinnarizine Acetylsalicylic acidb Bupropion Atenolol Dihydroergotamine TR Aa Carbamazepine Flunarizine Fluoxetine Diltiazema Clonidine Propranolol Gabapentin Fluvoxaminea Dihydroergokryptine* Sodium valproate Lamotrigine Lisuridea Lornoxicam Magnesiuma Estradiol Metoprolol Methylergonovineb* Flumedroxone* Nadolol Nimodipinea Imipramine Naproxen Nortriptylinea Ketoprofen Naproxen sodium Paroxetinea Mertazepine Topiramate Pizotifenb Methysergide* Verapamil Sertralinea Phenelzine* B2 Tanacetum parthenium Timolol* Trazodone Venlafaxine Vigabatrin*

The names of the drugs are listed in alphabetical order * Drugs unavailable or not used in Italy a and b refer to the two subgroups of Level 3 reported in Table 7 “Levels of recommendation for the treatment of migraine and ” of the Methodology section a Drugs with no severe adverse events b Unsafe drugs or with complex indication for use (e.g. special diets) or important pharmacological interactions

Table 4 Clinically relevant drug-drug interactions among antimigraine drugs

Drug 1 Drug 2 Effect Onset Probable mechanism of action

Acetylsalicylic acid (ASA) GI lesions Rapid Gastric irritation Indomethacin GI lesions Delayed Gastric irritation COX-2 inhibitors Increased risk of GI bleeding Delayed Gastric irritation

Ergotamine Triptans Vasoconstriction Rapid Additive vasoconstrictive effects

Methysergide Triptans Prolonged vasoconstriction Rapid Additive vasoconstrictive effects

NSAIDs NSAIDs Peptic ulcer; gastritis; Rapid Gastric irritation GI bleeding

Propranolol Rizatriptan Increased rizatriptan levels Rapid Inhibition of rizatriptan

SSRIs Triptans Rapid Excessive 5-HT stimulation MAOI Serotonin syndrome Rapid Excessive 5-HT stimulation

TCAs Sertraline Serotonin syndrome Rapid Excessive 5-HT stimulation

Triptans Triptans Prolonged vasoconstriction Rapid Additive vasoconstrictive effects MAOI Serotonin syndrome Rapid Excessive 5-HT stimulation

Valproate Amitriptyline Increased amitriptyline levels Delayed Inhibition of amitriptyline metabolism

Verapamil Beta-blockers Hypotension, bradycardia Rapid Additive cardiovascular effects, reduced metabolism of beta-blockers

GI, gastrointestinal; NSAIDs, non-steroidal anti-inflammatory drugs; SSRIs, selective serotonin-reuptake inhibitors; TCAs, tricyclic anti- ; MAOI, monoamine oxidase inhibitors 157

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