ZYPREXA 10 mg, poudre pour solution injectable (Boîtes de 1 et 10 flacons) Laboratoires LILLY France S.A. olanzapine Liste I Date de l’AMM : 2 juillet 2001 Motif de la demande : inscription Collectivités I - CARACTERISTIQUES DU MEDICAMENT SELON LA COMMISSION DE TRANSPARENCE A PARTIR DE L'AUTORISATION DE MISE SUR LE MARCHE Principe actif Olanzapine Originalité
Preventive migraine treatmentMigraine is a central nervous system disorder that is characterized by moderate orsevere headaches that last 4 to 72 hours. The attacks are often aggravated by routinephysical activity and may be associated with a variety of other symptoms, includingphotophobia, phonophobia, osmophobia, nausea, or vomiting. Approximately 15%of patients experience attacks of migraine with aura. The typical aura consists ofvisual, sensory, or language symptoms. Aura usually develops over a period of at least5 minutes and lasts less than 1 hour. Attacks vary widely from patient to patient in re-gard to frequency, severity, duration, and impact on quality of life. The pharmacologictreatment of migraine may be acute (abortive) or preventive (prophylactic), andpatients with frequent or severe headaches often require both approaches.
Preventive therapy is used to try to reduce the frequency, duration, or severity of attacks. Additional benefits include enhancing the response to acute treatments,improving a patient’s ability to function, and reducing disability.Preventive treatmentmay also result in health care cost reductions.Recent US and European guidelineshave established the circumstances that might warrant preventive treatment. Theseinclude (1) recurring migraine that significantly interferes with a patient’s quality oflife and daily routine despite acute treatment; (2) four or more attacks per month; (3)failure of, contraindication to, or troublesome side effects from acute medications;and (4) frequent, extremely long, or uncomfortable auras.A migraine preventivedrug is considered successful if it reduces migraine attack frequency by at least50% within 3 months. A migraine diary is highly recommended for treatmentevaluation.
US evidence-based guidelines for preventive treatment of migraine include the 1. Recurring migraine that significantly interferes with the patient’s daily routine despite acute treatment (eg, two or more attacks a month that produce disabilitythat lasts 3 or more days, headache attacks that are infrequent but produceprofound disability) Department of Neurology, Jefferson Headache Center, Thomas Jefferson University Hospital,111 South Eleventh Street, Gibbon Building, Suite 8130, Philadelphia, PA 19107, USAE-mail address: Neurol Clin 27 (2009) 429–443doi:10.1016/j.ncl.2008.11.007 0733-8619/08/$ – see front matter ª 2009 Elsevier Inc. All rights reserved.
2. Failure of, contraindication to, or troublesome side effects from acute medications3. Overuse of acute medications4. Special circumstances, such as hemiplegic migraine or attacks with a risk for 5. Frequent headaches (more than two a week) or a pattern of increasing attacks over time, with the risk for developing medication overuse headache 6. Patient preference, that is, the desire to have as few acute attacks as possible Prevention is not being used to the extent that it should be; only 13% of all migrai- neurs currently use preventive therapy to control their attacks.According to theAmerican Migraine Prevalence and Prevention (AMPP) study, 38.8% of patientswho have migraine should be considered for (13.1%) or offered (25.7%) migrainepreventive therapy.
The major medication groups for preventive migraine treatment include anticonvul- sants, antidepressants, b-adrenergic blockers, calcium channel antagonists, sero-tonin antagonists, botulinum neurotoxins, nonsteroidal anti-inflammatory drugs, andothers (including riboflavin, magnesium, and petasites). If preventive medication isindicated, the agent should be chosen from one of the first-line categories based onthe drug’s relative efficacy in double-blind placebo-controlled trials, its side effectprofile, and the patient’s preference, in addition to coexistent and comorbidThe following are general principles of preventive therapy, based on theauthor’s experience.
Start the chosen drug at a low dose, and increase it slowly until therapeutic effects develop, the ceiling dose for the chosen drug is reached, or adverseevents (AEs) become intolerable.
Give each treatment an adequate trial. The full benefit of the drug may not be realized until 6 months have elapsed.
Set realistic goals. Success is defined as a 50% reduction in attack frequency, a significant decrease in attack duration, or an improved response to acutemedication.
Set realistic expectations regarding AEs. The risk and extent of AEs vary greatly from patient to patient, and we presently have no way of predicting the presenceor severity of AEs for an individual patient. Most AEs are self-limited and dose-dependent, and patients should be encouraged to tolerate the early AEs thatmay develop when a new medication is started.
Avoid acute headache medication overuse and drugs that are contraindicated because of coexistent or comorbid illnesses.
Re-evaluate therapy, and, if possible, taper or discontinue the drug after a sus- tained period of remission (6–9 months).
Be sure that a woman of childbearing potential is aware of any potential risks, and choose the medication that has the least potential for AE on a To maximize compliance, involve patients in their own care. Take patient preferences into account when deciding between drugs of relatively equivalentefficacy and tolerability.
Consider comorbidity, which is the presence of two or more disorders whose association is more likely than chance. Conditions that are comorbid withmigraine are shown in Mitral valve prolapse (migraine with aura) Preventive treatment is often recommended for only 6 to 9 months; however, to date, no randomized placebo-controlled trials have been performed to investigatemigraine frequency after the preventive treatment has been discontinued. Dienerand colleaguesassessed 818 patients who had migraine and were treated withtopiramate for 6 months to see the effects of topiramate discontinuation. Patientsreceived topiramate in a 26-week open-label phase. They were then randomly as-signed to continue this dose or to switch to placebo for a 26-week double-blind phase.
Of the 559 patients who completed the open-label phase, 514 entered the double-blind phase and were assigned to topiramate (n 5 255) or placebo (n 5 259). Themean increase in number of migraine days was greater in the placebo group (1.19days in 4 weeks, 95% confidence interval [CI]: 0.71–1.66; P<.0001) than in thetopiramate group (0.10 days in 4 weeks, 95% CI: À0.36–0.56; P 5 .5756). Patientsin the placebo group had a greater number of days on acute medication than did thosein the topiramate group (mean difference between groups 5 0.95, 95% CI: À1.49 toÀ0.41; P 5 .0007). Sustained benefit was reported after topiramate was discontinued,although the number of migraine days did increase. These findings suggest thatpatients should be treated for 6 months, with the option to continue to 12 months.
SPECIFIC MIGRAINE PREVENTIVE AGENTSb-Adrenergic Blockers Beta—blockers, the most widely used class of drugs in prophylactic migrainetreatment, are approximately 50% effective in producing a greater than 50% reductionin attack frequency (). Evidence has consistently demonstrated the effi-cacyof the nonselective beta-blocker and the selective b1-blocker Atenolol,bisoprolol,nadolol,and are also likely to be effective. Beta-blockers with intrinsic sympathomimetic activity(eg, acebutolol, alprenolol, oxprenolol, pindolol) are not effective for migraine preven-tion. Propranolol is effective for migraine prevention at a daily dose of 120 to 240 mg,but no correlation has been found between its dose and its clinical efficacy.
The action of beta—blockers is probably central and could be mediated by (1) inhib- iting central b-receptors that interfere with the vigilance-enhancing adrenergic path-ways, (2) interaction with 5—HT receptors (but not all effective beta—blockers bindto the 5—HT receptors), and (3) cross-modulation of the serotonin system.Propranolol inhibits nitric oxide (NO) production by blocking inducible NO synthase.
Propranolol also inhibits kainate-induced currents and is synergistic with N-methyl- D-aspartate blockers, which reduce neuronal activity and have membrane-stabilizingproperties.
Contraindications to the use of beta-blockers include asthma and chronic obstructive lung disease, congestive heart failure, atrioventricular conduction defects,Raynaud’s disease, peripheral vascular disease, and brittle diabetes. All beta— Table 1Beta-blockers and antidepressants in the preventive treatment of migraine Use qdFewer side effects than propranolol Use the short-acting form bidUse the long-acting form qd Use qidFewer side effects than propranolol Use the short-acting form bid or tidUse the long-acting form qd or bid1–2 mg/kg in children Start at 10–25 mg at bedtimeIf insomnia, give early in the morning Selective serotonin and norepinephrine reuptake inhibitors Abbreviations: bid, twice daily; qd, every day; tid, three times daily.
blockers can produce behavioral AEs, such as drowsiness, fatigue, lethargy, sleepdisorders, nightmares, depression, memory disturbance, and hallucinations.Otherpotential AEs include gastrointestinal complaints, decreased exercise tolerance,orthostatic hypotension, bradycardia, and impotence. Although stroke has been re-ported to occur after patients who had migraine with aura were started on beta—blockers, there is neither an absolute nor a relative contraindication to their use bypatients who have migraine, with or without aura.
Antidepressants consist of several different drug classes with different mechanisms ofaction (see Only one member of the class of tricyclic antidepressants (TCAs)(amitriptyline) has proved efficacy in Although the mechanism by whichantidepressants work to prevent migraine headache is uncertain, it does not resultfrom treating masked depression. Antidepressants are useful in treating many chronicpain states, including headache, independent of the presence of depression, and theresponse occurs sooner than the expected antidepressant effect.In animal painmodels, antidepressants potentiate the effects of coadministered The anti-depressants that are clinically effective in headache prevention inhibit noradrenalineand 5—HT reuptake or are antagonists at the 5—HT2 The TCA dose range is wide and must be individualized. Most TCAs are sedating.
Start with a low dose of the chosen TCA at bedtime, except when using protriptyline,which should be administered in the morning. If the TCA is too sedating, switch froma tertiary TCA (eg, amitriptyline, doxepin) to a secondary TCA (eg, nortriptyline,protriptyline). AEs are common with TCA use. Antimuscarinic AEs include dry mouth,a metallic taste, epigastric distress, constipation, dizziness, mental confusion,tachycardia, palpitations, blurred vision, and urinary retention. Other AEs includeweight gain (rarely seen with protriptyline), orthostatic hypotension, reflex tachycardia,and palpitations. Antidepressant treatment may change depression to hypomania orfrank mania (particularly in bipolar patients). Older patients may develop confusionor The muscarinic and adrenergic effects of these agents may poseincreased risks for cardiac conduction abnormalities, especially in the elderly, andthese patients should be carefully monitored or other agents should be considered.
Amitriptyline and doxepin are sedating TCAs. Patients with coexistent depression may require higher doses of these drugs to treat underlying depression. Start ata dose of 10 to 25 mg at bedtime. The usual effective dose for migraine rangesfrom 25 to 200 mg. Nortriptyline, a major metabolite of amitriptyline, is a secondaryamine that is less sedating than amitriptyline. Start at a dose of 10 to 25 mg at bedtime.
The dosage ranges from 10 to 150 mg/d. Protriptyline is a secondary amine that issimilar to nortriptyline. Start at a dose of 5 mg in the morning. The dosage rangesfrom 5 to 60 mg/d as a single or split dose.
Evidence for the use of selective serotonin reuptake inhibitors (SSRIs) or other anti- depressants for migraine prevention is poor. Fluoxetine at doses between 10 and 40mg was effective in three placebo-controlled trials and not effective in one.Otherantidepressants not effective in placebo-controlled trials were clomipramine andsertraline; for other antidepressants, only open or non–placebo-controlled trials areavailable. Because their tolerability profile is superior to that of tricyclics, SSRIs maybe helpful for patients with comorbid The most common AEs includesexual dysfunction, anxiety, nervousness, insomnia, drowsiness, fatigue, tremor,sweating, anorexia, nausea, vomiting, and dizziness or lightheadedness. Thecombination of an SSRI and a TCA can be beneficial in treating refractory depressionand, in the author’s experience, resistant cases of migraine. The combination may require the TCA dose to be adjusted, because TCA plasma levels may significantlyincrease.
Recently, venlafaxine, an SSRI and selective norepinephrine reuptake inhibitor (SNRI), has been shown to be effective in a double-blind placebo-controlled and in a separate placebo and amitriptyline controlled The usual effectivedosage is 150 mg/d. Start with the 37.5-mg extended-release tablet for 1 week,then the 75-mg tablet for 1 week, and then the 150-mg extended-release tablet inthe morning. AEs include insomnia, nervousness, mydriasis, and seizures.
Two types of calcium channels exist: calcium entry channels, which allow extracellularcalcium to enter the cell, and calcium release channels, which allow intracellularcalcium (in storage sites in organelles) to enter the cytoplasm (Calciumentry channel subtypes include voltage-gated, opened by depolarization; ligand-gated, opened by chemical messengers, such as glutamate; and capacitative,activated by depletion of intracellular calcium stores. The mechanism of action ofthe calcium channel antagonists in migraine prevention is uncertain, but possibilitiesinclude inhibition of 5—HT release, neurovascular inflammation, or the initiation andpropagation of cortical spreading Flunarizine, a nonselective calciumchannel antagonist with antidopaminergic properties, was superior to placebo in sixof seven randomized clinical The dose is 5 to 10 mg given at night(women seem to need lower doses than men). The most prominent AEs include weightgain, somnolence, dry mouth, dizziness, hypotension, occasional extrapyramidalreactions, and exacerbation of depression. Because of its side effect profile, flunari-zine should be considered as a second-line drug for migraine prevention, afterbeta-blockers. Flunarizine is widely used in Europe but is not available in the United Table 2Selected calcium channel blockers and selected anticonvulsants in the preventive treatment ofmigraine Start at 80 mg bid or tidSustained-release form can be given qd qd at bedtimeWeight gain is the most common side effect Start at 15–25 mg at bedtimeIncrease 15–25 mg/wkAttempt to reach 50–100 mgIncrease further if necessaryAssociated with weight loss rather than Start at 250–500 mg/dMonitor levels if compliance is an issueMaximum dosage is 60 mg/kg/d Abbreviations: bid, twice daily; qd, every day; tid, three times daily.
States, where verapamil is the recommended calcium channel antagonist. Verapamilwas more effective than placebo in two of three trials, but both positive trials weresmall and dropout rates were high, rendering the findings Rigorousrandomized controlled trial evidence does not exist to support the use of verapamilfor migraine. Nimodipine, nicardipine, diltiazem, and cyclandelate, other nonselectivecalcium channel antagonists, have not shown superiority over placebo in well-de-signed clinical trials and cannot be recommended for migraine prophylaxis.
Anticonvulsants are increasingly recommended for migraine prevention because ofwell-conducted placebo-controlled trials. With the exception of valproic acid, topira-mate, and zonisamide, anticonvulsants may substantially interfere with the efficacy oforal contraceptives.
The only placebo-controlled trial of carbamazepine that suggested a significantbenefit had several methodologic issues (see Carbamazepine, 600 to1200 mg/d, may be effective in preventive migraine treatment but it is rarely used inclinical practice for this purpose.
Gabapentin (1800–2400 mg) showed efficacy in a placebo-controlled double-blindtrial only when a modified intent-to-treat analysis was used (see Migraineattack frequency was reduced by 50% in approximately one third of patients.Themost common AEs were dizziness or giddiness and drowsiness.
Valproic acid is a simple 8-carbon, 2-chain fatty acid. Divalproex sodium (approved bythe US Food and Drug Administration [FDA]) is a combination of valproic acid andsodium valproate. Both are effective,as is an extended-release form of divalproexsodium.In 1992, Hering and evaluated the efficacy of sodium valproate inmigraine treatment in a double-blind, randomized, crossover study. Sodium valproatewas effective in preventing migraine or reducing the frequency, severity, and durationof attacks in 86.2% of 29 patients, whose attacks were reduced from 15.6 to 8.8a month. In 1994, Jensen and colleaguesstudied 43 patients who had migrainewithout aura in a triple-blind, placebo- and dose-controlled, crossover study ofslow-release sodium valproate. In the valproate group, 50% of the patients hada reduction in migraine frequency to 50% or less, compared with 18% for placebo.
Several subsequent randomized placebo-controlled studies have confirmed these results, with significant responder rates ranging between 43% and 48%anddosages ranging from 500–1500 mg/d. Extended-release divalproex sodium hasalso been shown to be effective for migraine prevention, and compliance and theside effect profile may be more favorable with this formulation.
Nausea, vomiting, and gastrointestinal distress are the AEs that occur most commonly; their incidence decreases, however, particularly after 6 months. Later,tremor and alopecia can occur. Valproate has little effect on cognitive functions andrarely causes sedation. Rare severe AEs include hepatitis and pancreatitis. Thefrequency varies with the number of concomitant medications used, the patient’sage, the presence of genetic and metabolic disorders, and the patient’s general stateof health. These idiosyncratic reactions are unpredictable.Valproate is teratogenic.
Hyperandrogenism, ovarian cysts, and obesity are of concern in young women whohave epilepsy and use Absolute contraindications are pregnancy anda history of pancreatitis or a hepatic disorder. Other contraindications are thrombocy-topenia, pancytopenia, and bleeding disorders.
Valproic acid is available as 250-mg capsules and as syrup (250 mg per 5 mL) (Divalproex sodium is available as 125-, 250-, and 500-mg capsules andas a sprinkle formulation. Start with 250 to 500 mg/d in divided doses, and slowlyincrease the dosage. Monitor serum levels if there is a question of toxicity orcompliance. The maximum recommended dosage is 60 mg/kg/d.
Topiramate was originally synthesized as part of a research project to discover struc-tural analogs of fructose-1, 6-diphosphate capable of inhibiting the enzyme fructose 1,6-bisphosphatase, thereby blocking gluconeogenesis, but it has no hypoglycemicactivity. Topiramate and divalproex sodium are the only two anticonvulsants thathave FDA approval for migraine prevention. Topiramate is not associated with signif-icant reductions in estrogen exposure at dosages less than 200 mg/d. At dosagesgreater than 200 mg/d, there may be a dose-related reduction in exposure to theestrogen component of oral contraceptives.
Two large, pivotal, multicenter, randomized, double-blind, placebo-controlled clinical trials assessed the efficacy and safety of topiramate (50, 100, and 200 mg/d) in migraineprevention. In the first trial, the responder rate (patients with R50% reduction in monthlymigraine frequency) was 52% with topiramate, 200 mg/d (P<.001); 54% with topira-mate, 100 mg/d (P<.001); and 36% with topiramate, 50 mg/d (P 5 .039), comparedwith 23% with placebo.The 200-mg dose was not significantly more effective thanthe 100-mg dose. The second pivotal trialhad significantly more patients who ex-hibited at least a 50% reduction in mean monthly migraines in the groups treatedwith topiramate at a dosage of 50 mg/d (39%; P 5 .009), 100 mg/d (49%; P 5 .001),and 200 mg/d (47%; P 5 .001).
A third randomized, double-blind, parallel-group, multicenter compared two dosages of topiramate (100 mg/d or 200 mg/d) with placebo or propranolol (160mg/d). Topiramate at a dosage of 100 mg/d was superior to placebo, as measuredby average monthly migraine period rate, average monthly migraine days, rate ofrescue medication use, and percentage of patients with a 50% or greater decreasein average monthly migraine period rate (37% responder rate). The topiramate Table 3Miscellaneous medication in the preventive treatment of migraine Angiotensin-Converting Enzyme and Angiotensin Receptor Antagonists (100 mg/d) and propranolol groups were similar in change from baseline to the coredouble-blind phase in average monthly migraine period rate and other secondaryefficacy variables.
The most common AE of topiramate is paresthesia; other common AEs are fatigue, decreased appetite, nausea, diarrhea, weight decrease, taste perversion, hypoesthe-sia, and abdominal pain. In the migraine trials, body weight was reduced an average of2.3% in the 50-mg group, 3.2% in the 100-mg group, and 3.8% in the 200-mg group.
Patients on propranolol gained 2.3% of their baseline body weight. The most commoncentral nervous system AEs were somnolence, insomnia, mood problems, anxiety,difficulty with memory, language problems, and difficulty with concentration. Renalcalculi can occur with topiramate use. The reported incidence is approximately1.5%, representing a two- to fourfold increase over the estimated occurrence in thegeneral population.
A rare AE is acute myopia associated with secondary angle closure glaucoma. No cases of this condition were reported in the clinical studies.Oligohidrosis has beenreported in association with an elevation in body temperature. Most reports haveinvolved children.
Start at a dosage of 15 to 25 mg/d given at bedtime (see Increase dosage by 15 to 25 mg/wk. Do not increase the dose if bothersome AEs develop; wait untilthey resolve (they usually do). If they do not resolve, decrease the drug to the lasttolerable dose and then increase to a lower dose more slowly. Attempt to reacha dosage of 50 to 100 mg given twice a day. It is the author’s experience that patientswho tolerate the lower doses with only partial improvement often have increasedbenefit with higher doses. The dosage can be increased to 600 mg/d or higher.
Lamotrigine blocks voltage-sensitive sodium channels, leading to inhibition ofneuronal glutamate release of glutamate. Chen and reported on twopatients who had migraine with persistent aura-like visual phenomena for months toyears. After 2 weeks of lamotrigine treatment, both had resolution of the visualsymptoms.
Although open-label studies have suggested that lamotrigine may have a select role in the treatment of patients with frequent or prolonged aura, results from a placebo-controlled study in migraine were negative. Steiner and colleaguescompared thesafety and efficacy of lamotrigine (200 mg/d) and placebo in migraine prophylaxis ina double-blind, randomized, parallel-group trial. Improvements were greater onplacebo, and these changes, which were not statistically significant, indicate thatlamotrigine was ineffective for migraine prophylaxis. There were more AEs onlamotrigine than on placebo, most commonly rash. With slow dose escalation, theirfrequency was reduced, and the rate of withdrawal attributable to AEs was similarin both treatment groups.
Open-label studies have suggested that lamotrigine may have a select role in the treatment of migraine with aura, but no placebo-controlled studies have yet beenconducted in this patient population. Lamotrigine and topiramatemay have a specialrole in the treatment of migraine with aura.
OTHER DRUGSAngiotensin-Converting Enzyme Inhibitors and Angiotensin II Receptor Antagonists Schrader and colleaguesconducted a double-blind, placebo-controlled, crossoverstudy of lisinopril, an angiotensin-converting enzyme inhibitor, in migraine prophylaxis (see Days with migraine were reduced by at least 50% in 14 participants foractive treatment versus placebo and in 17 patients for active treatment versus run-inperiod. Days with migraine were fewer by at least 50% in 14 participants for activetreatment versus placebo. Tronvik and colleaguesperformed a randomized,double-blind, placebo-controlled, crossover study of candesartan (16 mg), anangiotensin II receptor blocker, in migraine prevention. In a period of 12 weeks, themean number of days with headache was 18.5 with placebo versus 13.6 withcandesartan (P 5 .001) in the intention-to-treat analysis (n 5 57). The number ofcandesartan responders (reduction of R50% compared with placebo) was 18(31.6%) of 57 for days with headache and 23 (40.4%) of 57 for days with migraine.
AEs were similar in the two periods. In this study, the angiotensin II receptor blockercandesartan was effective, with a tolerability profile comparable to that of placebo.
The mechanism by which botulinum toxin may prevent migraine remains poorlyunderstood, but it is unlikely to be related to relief of muscle spasticity. Developingevidence suggests that it may modulate release of neuropeptides, such as calcitoningene-related peptide, and influence the process of central sensitization that is associ-ated with migraine.
Botulinum toxin type A (Botox; 0, 25, or 75 U) has not been convincingly shown to be effective for the prevention of episodic migraine with or without aura. Although theresults of an early placebo-controlled study were positive using a dose of 25 U, theresults were confounded by no efficacy at the higher dose (75 U) used in this Three recent placebo-controlled trialsshowed no difference between differentdoses of botulinum toxin (105–260 U) and placebo, however. Based on a significantresponse to botulinum toxin type A in a subgroup of patients who had chronic migraineand were not on other preventive two large, pivotal, placebo-controlledstudies evaluating the efficacy of botulinum toxin type A for chronic migraine arecurrently underway.
Feverfew (Tanacetum parthenium) is a medicinal herb whose effectiveness has notbeen totally established.Riboflavin (400 mg) was effective in one placebo-controlleddouble-blind trial. More than half of the patients petasites hybridus(butterbur) root is a perennial shrub, a standardized extract of which (75 mg adminis-tered twice daily) was effective in a double-blind placebo-controlled study.The mostcommon AE was belching.
The goals of preventive treatment are to reduce the frequency, duration, or severity ofattacks; improve responsiveness to acute attack treatment; improve function; andreduce disability (). The preventive medications with the best-documentedefficacy are the beta-blockers and amitriptyline, divalproex, and topiramate. Choiceis made based on a drug’s proved efficacy, the physician’s informed belief aboutmedications not yet evaluated in controlled trials, the drug’s AEs, the patient’spreferences and headache profile, and the presence or absence of coexistingdisorders (see ).Coexistent diseases have important implications for treat-ment. In some instances, two or more conditions may be treated with a single drug.
If individuals have more than one disease, certain categories of treatment may berelatively contraindicated.
Propranolol, timolol, amitriptyline, valproate, topiramate, and flunarizine Nonsteroidal anti-inflammatory drugs: aspirin, flurbiprofen, ketoprofen, and naproxensodium Beta-blockers: atenolol, metoprolol, and nadolol Antidepressants: doxepin, nortriptyline, imipramine, protriptyline, venlafaxine,fluvoxamine, mirtazapine, paroxetine, protriptyline, sertraline, and trazodone Acebutolol, carbamazepine, clomipramine, clonazepam, indomethacin, lamotrigine,nabumetone, nicardipine, nifedipine, and pindolol The presence of a second illness provides therapeutic opportunities but also imposes certain therapeutic limitations. In some instances, two or more conditionsmay be treated with a single drug. There are limitations to using a single medicationto treat two illnesses, however. Giving a single medication may not treat two differentconditions optimally; although one of the two conditions may be adequately treated,the second illness may require a higher or lower dose, and the patient is thus at riskfor the second illness not being adequately treated. Therapeutic independence maybe needed should monotherapy fail. Avoiding drug interactions or increased AEs isa primary concern when using polypharmacy.
For some patients, a single medication may adequately manage comorbid conditions. This is likely to be the exception rather than the rule, however. Polytherapymay enable therapeutic adjustments based on the status of each illness. TCAs areoften recommended for patients who have migraine and depression.Appropriatemanagement of depression often requires higher doses of TCAs, however, whichmay be associated with more AEs. A better approach might be to treat the depressionwith an SSRI or SNRI and treat the migraine with an anticonvulsant. For the patientwho has migraine and epilepsy,one may achieve control of both conditions withan antiepileptic drug, such as topiramate or divalproex sodium. Divalproex and topir-amate are the drugs of choice for the patient who has migraine and bipolar illness.When individuals have more than one disease, certain categories of treatment may berelatively contraindicated. For example, beta-blockers should be used with caution forthe depressed migraineur, whereas TCAs or neuroleptics may lower the seizurethreshold and should be used with caution for the epileptic migraineur.
Although monotherapy is preferred, it is often not the best choice, and it may be necessary to combine preventive medications. Antidepressants are often used with beta-blockers or calcium channel blockers, and topiramate or divalproex sodium maybe used in combination with any of these medications.
Preventive therapy plays an important role in migraine management. With the additionof a preventive medication, patients may experience reduced attack frequency andimproved response to acute treatment, which can result in reduced health careresource use and improved quality of life. Despite research suggesting that a largepercentage of patients who have migraine are candidates for prevention, only afraction of these patients are receiving or have ever received preventive migrainemedication.
Many preventive medications are available, and guidelines for their selection and use have been established. Because comorbid medical and psychologic illnessesare prevalent in patients who have migraine, one must consider comorbidity whenchoosing preventive drugs. Drug therapy may be beneficial for both disorders;however, it is also a potential confounder of optimal treatment of either.
No clinical trial data exist to predict among the various therapeutic options and biologic or clinical parameters. The impact of prevention on the natural history ofmigraine remains to be fully investigated.
1. Lipton RB, Silberstein SD. Why study the comorbidity of migraine? Neurology 2. Silberstein SD, Winner PK, Chmiel JJ. Migraine preventive medication reduces resource utilization. Headache: The Journal of Head and Face Pain 2003;43:171–8.
3. Silberstein SD. Headaches in pregnancy. Neurol Clin 2004;22:727–56.
4. Lipton RB, Diamond M, Freitag F, et al. Migraine prevention patterns in a commu- nity sample: results from the American Migraine Prevalence and Prevention(AMPP) study. Headache 2005;45:792–3 [abstract].
5. Silberstein S, Diamond S, Loder E, et al. Prevalence of migraine sufferers who are candidates for preventive therapy: results from the American Migraine Prevalenceand Prevention (AMPP) study. Headache 2005;45:770–1 [abstract].
6. Tfelt-Hansen P. Prioritizing acute pharmacotherapy of migraine. In: Olesen J, Tfelt-Hansen P, Welch KMA, editors. The headaches. 2nd edition. New York:Lippincott Williams & Wilkins; 2000. p. 453–6.
7. Silberstein SD. Migraine and pregnancy. Neurol Clin 1997;15:209–31.
8. Olerud B, Gustavsson CL, Furberg B. Nadolol and propranolol in migraine management. Headache 1986;26:490–3.
9. Ryan RE, Sudilovsky A. Nadolol: its use in the prophylactic treatment of migraine.
10. Ryan RE. Comparative study of nadolol and propranolol in prophylactic treatment of migraine. Am Heart J 1984;108:1156–9.
11. Sudilovsky A, Stern MA, Meyer JH. Nadolol: the benefits of an adequate trial duration in the prophylaxis of migraine. Headache 1986;26:325.
12. Diener HC, Agosti R, Allais G, et al. Cessation versus continuation of 6-month migraine preventive therapy with topiramate (PROMPT): a randomised, double-blind, placebo-controlled trial. Lancet Neurol 2007;6:1054–62.
13. Gray RN, Goslin RE, McCrory DC, et al. Drug treatments for the prevention of migraine headache. Prepared for the Agency for Health Care Policy and Research, contact no. 290-94-2025. Available from the National Technical Infor-mation Service 1999; Accession No. 127953.
14. Silberstein SD. Practice parameter—evidence-based guidelines for migraine headache (an evidence-based review): report of the Quality Standards Subcom-mittee of the American Academy of Neurology for the United States HeadacheConsortium. Neurology 2000;55:754–62.
15. Andersson K, Vinge E. Beta-adrenoceptor blockers and calcium antagonists in the prophylaxis and treatment of migraine. Drugs 1990;39:355–73.
16. Koella WP. CNS-related (side-)effects of beta-blockers with special reference to mechanisms of action. Eur J Clin Pharmacol 1985;28:55–63.
17. Ramadan NM. Prophylactic migraine therapy: mechanisms and evidence. Curr 18. Cortelli P, Sacquegna T, Albani F, et al. Propranolol plasma levels and relief of migraine. Arch Neurol 1985;42:46–8.
19. Sudilovsky A, Elkind AH, Ryan RE, et al. Comparative efficacy of nadolol and propranolol in the management of migraine. Headache 1987;27:421–6.
20. Tfelt-Hansen P, Standnes B, Kangasniemi P, et al. Timolol vs propranolol vs placebo in common migraine prophylaxis: a double-blind multicenter trial. ActaNeurol Scand 1984;69:1–8.
21. Panerai AE, Monza G, Movilia P, et al. A randomized, within-patient, cross-over, placebo-controlled trial on the efficacy and tolerability of the tricyclic antidepres-sants chlorimipramine and nortriptyline in central pain. Acta Neurol Scand 1990;82:34–8.
22. Kishore-Kumar R, Max MB, Schafer SC, et al. Desipramine relieves post-herpetic neuralgia. Clin Pharmacol Ther 1990;47:305–12.
23. Feinmann C. Pain relief by antidepressants: possible modes of action. Pain 1985;23:1–8.
24. Richelson E. Antidepressants and brain neurochemistry. Mayo Clin Proc 1990;65: 25. Baldessarini RJ. Drugs and the treatment of psychiatric disorders. In: Gilman AG, Rall TW, Nies AS, et al, editors. The pharmacological basis of therapeutics. 8thedition. New York: Pergamon; 1990. p. 383–435.
26. Abramowicz M. Fluoxetine (Prozac) revisited. Med Lett Drugs Ther 1990;32:83–5.
27. Silberstein SD, Saper JR, Freitag F. Migraine: diagnosis and treatment. In: Silberstein SD, Lipton RB, Dalessio DJ, editors. Wolff’s headache and otherhead pain. 7th edition. New York: Oxford University Press; 2001. p. 121–237.
28. Silberstein SD, Lipton RB, Breslau N. Migraine: association with personality characteristics and psychopathology. Cephalalgia 1995;15:337–69.
29. Mathew NT, Saper JR, Silberstein SD, et al. Migraine prophylaxis with divalproex.
30. Lipton RB, Gobel H, Wilks K, et al. Efficacy of petasites (an extract from Petasites rhizone) 50 and 75 mg for prophylaxis of migraine: results of a randomized,double-blind, placebo-controlled study. Neurology 2002;58:A472 [abstract].
31. Bowden CL, Brugger AM, Swann AC. Efficacy of divalproex vs lithium and placebo in the treatment of mania. JAMA 1994;271:918–24.
32. Ozyalcin SN, Talu GK, Kiziltan E, et al. The efficacy and safety of venlafaxine in the prophylaxis of migraine. Headache 2005;45:144–52.
33. Bulut S, Berilgen MS, Baran A, et al. Venlafaxine versus amitriptyline in the prophylactic treatment of migraine: randomized, double-blind, crossover study.
Clin Neurol Neurosurg 2004;107:44–8.
34. Greenberg DA. Calcium channels in neurological disease. Ann Neurol 1997;42: 35. Wauquier A, Ashton D, Marranes R. The effects of flunarizine in experimental models related to the pathogenesis of migraine. Cephalalgia 1985;5:119–20.
36. Solomon GD. Verapamil and propranolol in migraine prophylaxis: a double-blind crossover study. Headache 1986;26:325.
37. Markley HG, Cleronis JCD, Piepko RW. Verapamil prophylactic therapy of migraine. Neurology 1984;34:973–6.
38. Riopelle R, McCans JL. A pilot study of the calcium channel antagonist diltiazem in migraine syndrome prophylaxis. Can J Neurol Sci 1982;9:269.
39. Smith R, Schwartz A. Diltiazem prophylaxis in refractory migraine. N Engl J Med 40. Reveiz-Herault L, Cardona AF, Ospina EG, et al. [Effectiveness of flunarizine in the prophylaxis of migraine: a meta-analytical review of the literature]. Rev Neurol2003;36:907–12, in Spanish.
41. Hanston PP, Horn JR. Drug interaction. Newsletter 1985;5:7–10.
42. Rompel H, Bauermeister PW. Aetiology of migraine and prevention with carbamazepine (Tegretol). S Afr Med J 1970;44:75–80.
43. Mathew NT, Rapoport A, Saper J, et al. Efficacy of gabapentin in migraine prophylaxis. Headache 2001;41:119–28.
44. Coulam CB, Annagers JR. New anticonvulsants reduce the efficacy of oral contraception. Epilepsia 1979;20:519–25.
45. Klapper JA. Divalproex sodium in migraine prophylaxis: a dose-controlled study.
46. Klapper JA. An open label crossover comparison of divalproex sodium and propranolol HCl in the prevention of migraine headaches. Headache Quarterly1995;5:50–3.
47. Freitag FG, Collins SD, Carlson HA, et al. A randomized trial of divalproex sodium extended-release tablets in migraine prophylaxis. For the Depakote ER MigraineStudy Group. Neurology 2003;58:1652–9.
48. Hering R, Kuritzky A. Sodium valproate in the prophylactic treatment of migraine: a double-blind study versus placebo. Cephalalgia 1992;12:81–4.
49. Jensen R, Brinck T, Olesen J. Sodium valproate has prophylactic effect in migraine without aura: a triple-blind, placebo-controlled crossover study.
50. Pellock JM, Willmore LJ. A rational guide to routine blood monitoring in patients receiving antiepileptic drugs. Neurology 1991;41:961–4.
51. Silberstein SD. Divalproex sodium in headache—literature review and clinical guidelines. Headache 1996;36:547–55.
52. Vainionpaa LK, Rattya J, Knip M, et al. Valproate-induced hyperandrogenism during pubertal maturation in girls with epilepsy. Ann Neurol 1999;45:444–50.
53. Silberstein SD, Neto W, Schmitt J, et al. Topiramate in the prevention of migraine headache: a randomized, double-blind, placebo-controlled, multiple-dose study.
For the MIGR-001 Study Group. Arch Neurol 2004;61:490–5.
54. Brandes JL, Saper JR, Diamond M, et al. Topiramate for migraine prevention: a randomized controlled trial. JAMA 2004;291:965–73.
55. Diener HC, Tfelt-Hansen P, Dahlof C, et al. Topiramate in migraine prophylaxis— results from a placebo-controlled trial with propranolol as an active control.
J Neurol 2004;251:943–50.
56. Sachedo RC, Reife RA, Lim P, et al. Topiramate monotherapy for partial onset seizures. Epilepsia 1997;38:294–300.
57. Thomson Healthcare. Physicians’ desk reference. 57th edition. Montvale (NJ): 58. Chen WT, Fuh JL, Lu SR, et al. Persistent migrainous visual phenomena might be responsive to lamotrigine. Headache 2001;41:823–5.
59. Steiner TJ, Findley LJ, Yuen AW. Lamotrigine versus placebo in the prophylaxis of migraine with and without aura. Cephalalgia 1997;17:109–12.
60. Freitag FG. Topiramate prophylaxis in patients suffering from migraine with aura: results from a randomized, double-blind, placebo-controlled trial. AdvancedStudies in Medicine 2003;3:S562–4.
61. Schrader H, Stovner LJ, Helde G, et al. Prophylactic treatment of migraine with angiotensin converting enzyme inhibitor (lisinopril): randomized, placebo-controlled, crossover study. Br Med J 2001;322:19–22.
62. Tronvik E, Stovner LJ, Helde G, et al. Prophylactic treatment of migraine with an angiotensin II receptor blocker: a randomized controlled trial. JAMA 2003;289:65–9.
63. Silberstein SD, Mathew N, Saper J, et al. Botulinum toxin type A as a migraine preventive treatment. Headache 2000;40:445–50.
64. Evers S, Vollmer-Haase J, Schwaag S, et al. Botulinum toxin A in the prophylactic treatment of migraine—a randomized, double-blind, placebo-controlled study.
65. Elkind AH, O’Carroll P, Blumenfeld A, et al. A series of three sequential, randomized, controlled studies of repeated treatments with botulinum toxintype A for migraine prophylaxis. J Pain 2006;7:688–96.
66. Saper JR, Mathew NT, Loder EW, et al. A double-blind, randomized, placebo- controlled comparison of botulinum toxin type A injection sites and doses inthe prevention of episodic migraine. Pain Med, In press.
67. Dodick DW, Mauskop A, Elkind AH, et al. Botulinum toxin type A for the prophylaxis of chronic daily headache: subgroup analysis of patients notreceiving other prophylactic medications: a randomized double-blind, placebo-controlled study. Headache 2005;45:315–24.
68. Vogler BK, Pittler MH, Ernst E. Feverfew as a preventive treatment for migraine: a systematic review. Cephalalgia 1998;18:704–8.
69. Schoenen J, Jacquy J, Lenaerts M. Effectiveness of high-dose riboflavin in migraine prophylaxis. A randomized controlled trial. Neurology 1998;50:466–70.
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