Monotherapy or polytherapy in migraine

The majority of current therapeutic papers concerns the prophylactic therapy of migraine using only one drug, very few advocating the simultaneous use of two drugs. The theoretical usefulness of polytherapy in migraine is examined with examples from personal experience, and found justified.     

Prophylactic pharmacotherapy for migraine headaches

Migraine therapeutics are pharmacological, including acute and preventive, nonpharmacological and/or both. Preventive pharmacological strategies serendipitously were discovered to be effective and include drugs from various pharmacological classes (e.g., beta-adrenergic blocker, anticonvulsant, tricyclic antidepressants, serotonin receptor antagonist). Converging level I evidence and clinical experience support the use of the antidepressant amitriptyline, the anticonvulsants divalproex and topiramate, and the beta-adrenergic blockers propranolol, timolol, and metoprolol in migraine prevention. Other options for migraine prophylaxis exist, but the level of evidence in support of their use is not as robust. All of these drugs have varying degrees of adverse effects, some of which can limit their use. Balancing potential efficacy with risk of adverse effects, addressing patients' expectations and desires, complying with management recommendations, adequate follow up, and accurate assessment of treatment goals are key to migraine prevention. Finally, future migraine-preventive drugs likely will target migraine mechanisms more specifically, which undoubtedly will enhance the therapeutic index.     

Prophylaxis of menstrual migraine with triptans: problems and possibilities

Menstruation is a prominent, predictable attack trigger for many women with migraine. If abortive therapy of menstrual attacks is ineffective, prophylactic therapy is used to prevent attacks or render them shorter and less resistant to acute therapy. Interest is increasing in the use of triptan medications for the prophylaxis of menstrual migraine, and clinical trials to evaluate this approach are underway. Potential problems with triptan prophylaxis of menstrual migraine that deserve attention include the lack of consensus on the definition of menstrual migraine and the difficulty in making a reliable diagnosis of the disorder. Unconvincing demonstrations of efficacy and unresolved cost and safety concerns should temper enthusiasm for their use in this manner. Further studies, using a consistent definition of menstrual association and employing diary validation of the diagnosis, are needed to determine the efficacy of the triptans in women who consistently experience migraine attacks associated with menstruation. Triptans would have to show compelling advantages over other therapy to be a plausible prophylactic treatment for menstrual migraine.     

Improving patient compliance to prophylactic migraine therapy

As in many other chronic conditions, adherence to prophylactic treatment in migraine is probably poor. In chronic diseases, compliance at one year does not exceed 50%. That could explain the low therapeutic gain seen with migraine preventive medications. It also renders difficult the evaluation of clinical trials on migraine prophylaxis since in most of these trials compliance is not properly assessed. From the patients' perspective, there are several factors that could explain poor adherence to recommended treatments. Essentially, these factors are the expression of the patients' subjective perception of their disease and potential remedies in a context of a positive patient-physician relationship. When migraine prophylactic treatment is considered, patients should be informed of the natural history of their disease and a diagnosis of an accelerated form of migraine should be confirmed. Prophylactic treatment at best would reduce by 50% the frequency of migraine attacks. In most studies, however, the therapeutic gain is in the order of 30-40%. Treatment should be instituted for a minimum time of two to three months and if effective maintained for 6-12 months. The outcome of prophylaxis can rarely be determined in a prospective way. The choice of prophylactic regimens remains empirical, often based on the physician's experience and perception of the mechanism of migraine. A better adherence to prophylactic treatment of migraine could possibly improve outcomes but current methods of improving adherence for chronic health problems are mostly complex and not very effective.     

Migraine: new treatment options from molecular biology

Migraine is a common, disabling, multifactorial, episodic neurovascular disorder of largely unknown etiology. The disease is typically characterized by recurrent attacks of headaches and associated autonomic and neurologic symptoms. Current acute and prophylactic treatment options are far from optimal and in many cases, empirically chosen. Clearly, improved treatment is desperately needed. New drug targets may emerge from molecular research as the unravelling of the molecular basis of migraine should improve our understanding of the disease, notably why patients experience attacks so frequently. The first two migraine genes discovered in families with hemiplegic migraine encode ion transporters, emphasising that dysfunction of ion transport may be an important factor in migraine. Therefore, ion transporters can be considered as novel targets for the development of future antimigraine drugs. Molecular biologic research will increasingly become important in understanding the pathophysiology of migraine and in identifying potential molecular targets for novel treatments.     

Calcium channel antagonists and the treatment of migraine

Despite ongoing dispute over the pathophysiologic basis of migraine, the vasospastic theory of pathogenesis has brought to the forefront a promising class of new antimigraine agents, the Ca2+ channel antagonists. Voltage-dependent Ca2+ channels, integral membrane proteins that permit extracellular Ca2+ to enter cells down their electrical and concentration gradients, have a universal role in stimulus-response coupling in excitable cells. Thus, they participate in translating electrical excitation into secretory and contractile events. Ca2+ channel antagonists, a structurally diverse group of organic compounds, inhibit ion flux through voltage-dependent Ca2+ channels by binding to specific, channel-associated drug receptor sites and thereby reduce the frequency of channel opening in response to membrane depolarization. Ca2+ channels in cardiac muscle, smooth muscle, and neurons all exhibit high affinity for Ca2+ channel antagonists, although neurons also contain a population of drug-resistant channels. Extensive clinical experience in the use of Ca2+ channel antagonists has accumulated from their application to nonneurologic, especially cardiovascular, disorders. Three such drugs, nifedipine, verapamil, and diltiazem, are currently available in the United States, although none are specifically approved for use in migraine. Other agents, such as nimodipine, are likely to be released in the near future. A large number of clinical studies have now addressed the efficacy of Ca2+ channel antagonists in the prophylaxis of migraine headache. Dihydropyridines (nifedipine and nimodipine), phenylalkylamines (verapamil), diphenylalkylamines (flunarizine), and benzothiazepines (diltiazem) have all been examined, and a beneficial effect has been noted in each case. The limited directly comparative data currently available and the difficulties involved in comparing the results of different studies do not presently support claims of superiority for any single agent. This is an issue that will require attention as these drugs achieve more widespread use in migraine. Existing evidence suggests that flunarizine, verapamil, nifedipine, and nimodipine are effective prophylactic agents in both common and classic migraine. Nifedipine and nimodipine also appear to be valuable for the treatment of cluster headache. Two case reports describing favorable responses to flunarizine in childhood hemiplegic migraine are the only available data concerning the utility of these drugs in "complicated" migraine syndromes. The role of Ca2+ channel antagonists in treating "muscle contraction" or "tension" headache has not been addressed in any detail.(ABSTRACT TRUNCATED AT 400 WORDS)     

Prophylactic treatments of migraine

Prophylactic treatment is mainly intended to reduce the frequency of migraine attacks. It is usually proposed to patients who suffer from two or more attacks per month. It should also be considered in patients who suffer from less frequent, but prolonged, disabling attacks with a poor response to abortive treatment, and who consider that their quality of life is reduced between attacks. Excessive intake of acute medication, more than twice a week, is a strong indication for prophylactic treatment. In order to obtain a good compliance to treatment, the patient must be informed of the expected efficacy of the drugs, and of their most frequent side effects. Thus, the choice of a prophylactic drug is made together with the patient. Based on the results of published controlled trials, the main prophylactic drugs are some betablockers, methysergide, pizotifene, oxetorone, flunarizine, amitriptyline, NSAIDs, and sodium valproate. Some less evaluated drugs such as aspirin, DHE, indoramine, verapamil, may be useful. Other substances such as riboflavin and new antiepileptic dugs are being evaluated. The choice of the drug to start with depends on several considerations. The first step is to make sure that there are no contra indications, and no possible interaction with the abortive medications. Then, possible side effects will be taken into account, for example, weight gain is a problem for most young women and patients who practice sports may not tolerate betablockers. Associated pathologies have to be checked. For example, a hypertensive migraine sufferers may benefit from betablockers; in a patient who suffers both from migraine and tension type headaches or from depression, amitriptyline is the first choice drug. The type of migraine should also be considered; for instance, in frequent attacks with aura, aspirin is recommended and betablockers avoided. In most cases, prophylaxis should be given as monotherapy, and it is often necessary to try successively several drugs before finding the most appropriate one. Doses should be increased gradually, in order to reach the recommended daily dose, only if tolerance permits. The treatment efficacy has to be assessed after 2 or 3 months, during which the patient must keep a headache diary. If the drug is judged ineffective, an overuse of symptomatic medications should be checked, as well as a poor compliance, either of which may be responsible. In case of a successful treatment, it should be continued for 6 or 12 months, and then, one should try to taper off the dose in order to stop the treatment or at least to find the minimum active dose. Relaxation, biofeedback, stress coping therapies, acupuncture are also susceptible to be effective in migraine prophylaxis.     

Antiepileptic drugs: evolution of our knowledge and changes in drug trials

Clinical trials provide the evidence needed for rational use of medicines. The evolution of drug trials follows largely the evolution of regulatory requirements. This article summarizes methodological changes in antiepileptic drug trials and associated advances in knowledge starting from 1938, the year phenytoin was introduced and also the year when evidence of safety was made a requirement for the marketing of medicines in the United States. The first period (1938–1969) saw the introduction of over 20 new drugs for epilepsy, many of which did not withstand the test of time. Only few well controlled trials were completed in that period and trial designs were generally suboptimal due to methodological constraints. The intermediate period (1970–1988) did not see the introduction of any major new medication, but important therapeutic advances took place due to improved understanding of the properties of available drugs. The value of therapeutic drug monitoring and monotherapy were recognized during the intermediate period, which also saw major improvements in trial methodology. The last period (1989–2019) was dominated by the introduction of second-generation drugs, and further evolution in the design of monotherapy and adjunctive-therapy trials. The expansion of the pharmacological armamentarium has improved opportunities for tailoring drug treatment to the characteristics of the individual. However, there is still inadequate evidence from controlled trials to guide treatment selection for most epilepsy syndromes, particularly in children. Second-generation drugs had a very modest impact on drug resistance, and a change in paradigm for drug discovery and development is needed, focusing on treatments that target the causes and mechanisms of epilepsy rather than its symptoms. Testing potential disease modifying agents will require innovative trial designs and novel endpoints, and will hopefully lead to introduction of safer and more effective therapies.     

Controlled therapeutic trials in migraine: methodology and results

This review first brings justification to performing controlled therapeutic trials in migraine. It then describes the organisation of a prophylactic trial; the criteria for inclusion and exclusion, the various possible protocols, and the data analysis are discussed, while the many difficulties and pitfalls brought about by the natural characteristics of the disease are stressed. Some limitations inherent to prophylactic trials and to migraine when interpreting the results are emphasized. The findings of the prophylactic trials published to date are briefly summarized in three tables; the results indicate both the usefulness and the validity of this methodological approach in migraine. The main features and specific difficulties of the controlled trials of drugs the treatment of migraine attacks are briefly commented, and the literature review is broadly tabulated. Lastly, a brief account of the problems involved in controlled trials of non-chemical migraine therapy is given. Despite their numerous limitations, the controlled trials have considerably clarified the therapeutic approach of migraine.     

Levetiracetam in the prophylaxis of migraine with aura: a 6-month open-label study

OBJECTIVE: To evaluate the efficacy of levetiracetam as prophylactic treatment for migraine with aura with high frequency of attacks. BACKGROUND: Migraine with aura with high frequency of attacks could represent a very demanding therapeutic problem. Efficacy of the antiepileptic drug, lamotrigine, has been reported in this form of migraine. Levetiracetam is a new antiepileptic drug with an excellent tolerability profile. Mechanisms of action of this drug remain largely unknown, but recently, it has been shown to exert inhibitory effects on neuronal-type calcium channels. METHODS: We performed a small open-label trial treating 16 patients affected by migraine with aura with high frequency of attacks. After a 1-month run-in period, patients were treated with levetiracetam at a dosage of 1000 mg/d for 6 months. RESULTS: The number of attacks per month was significantly reduced during the first month (compared with run-in; P < 0.001), and it was reduced further during the second (second month vs first month; P < 0.001) and the third months (third month vs second month; P < 0.001) of the treatment. This improvement persisted unchanged for the remaining 3 months of treatment. In 7 (44%) of the 16 patients, the attacks were completely abolished after 3 months of treatment. Severity of headache and duration of headache and aura were also significantly reduced at the third and sixth months of treatment (P < 0.001). Levetiracetam was well tolerated (6 patients complained of slight dizziness, nervousness, and somnolence). CONCLUSIONS: Levetiracetam seems to be a safe and effective treatment for migraine with aura. Controlled trials are needed to confirm the observed results.     

Possible mechanisms of the action of drugs for hemicrania

Different classes of drugs are used in the pharmacological treatment of headache, both during migraine crisis and migraine prophylaxis. How these drugs exert their therapeutical effect in migraine is not clearly understood. Hypothetical mechanisms of action are discussed by the Authors in regard to the different pathogenetical events relevant to migraine. It is proposed that different pathological events can be modified by one drug and, conversely, one mechanism of action may be common to different drugs.     

Suppression of cortical spreading depression in migraine prophylaxis

OBJECTIVE: Topiramate, valproate, propranolol, amitriptyline, and methysergide have been widely prescribed for migraine prophylaxis, but their mechanism or site of action is uncertain. Cortical spreading depression (CSD) has been implicated in migraine and as a headache trigger and can be evoked in experimental animals by electrical or chemical stimulation. We hypothesized that migraine prophylactic agents suppress CSD as a common mechanism of action. METHODS: Rats were treated either acutely or chronically over weeks and months, with one of the above migraine prophylactic drugs, vehicle, or D-propranolol, a clinically ineffective drug. The impact of treatment was determined on the frequency of evoked CSDs after topical potassium application or on the incremental cathodal stimulation threshold to evoke CSD. RESULTS: Chronic daily administration of migraine prophylactic drugs dose-dependently suppressed CSD frequency by 40 to 80% and increased the cathodal stimulation threshold, whereas acute treatment was ineffective. Longer treatment durations produced stronger CSD suppression. Chronic D-propranolol treatment did not differ from saline control. INTERPRETATION: Our data suggest that CSD provides a common therapeutic target for widely prescribed migraine prophylactic drugs. Assessing CSD threshold may prove useful for developing new prophylactic drugs and improving upon existing ones.     

Dihydroergotamine: a review of its use in the treatment of migraine and other headaches.

Dihydroergotamine has been one of the main drugs used in the treatment of migraine for greater than 40 years. The recent introduction of the more selective 5-HT antagonist sumatriptan will challenge the place of dihydroergotamine in migraine therapy and indicates the need to review the evidence for the use of dihydroergotamine. Although there is little evidence from double-blind clinical trials, dihydroergotamine does appear to be effective in the treatment of acute attacks and in the prevention of migraine. Its place in treatment is in cases where simple analgesics alone or in combination with other agents fail to provide relief. Further studies are necessary to compare dihydroergotamine with sumatriptan for acute migraine and with beta-blockers in prophylaxis to determine its future role in migraine therapy.     

Prophylactic drug treatment of migraine

Prophylactic treatment is mainly intended to reduce the frequency of migraine attacks. Based on the results of published controlled trials, the main prophylactic drugs are some beta-blockers, methysergide, pizotifene, oxetorone, flunarizine, amitriptyline, NSAIDs, sodium valproate and topiramate. With these drugs, the frequency of attacks can be reduced by half in 50 percent of patients. Some less evaluated substances such as aspirin, DHE, indoramine, and angiotensin II inhibitors may be useful. The decision to treat with drugs and the choice of a prophylactic drug are made together with the patient. The superiority of one major drug over another has never been demonstrated in a comparative trial, thus the choice of the drug to start with depends on the possible side effects and contraindications, the characteristics of the migraine attacks, and the associated morbidities and possible interactions with abortive medications. Doses should be increased gradually, in order to reach the recommended daily dose, only if tolerance permits. Treatment efficacy has to be assessed after 2 or 3 months, and in case of failure or poor tolerance, another treatment should be started. If the treatment is successful, it should be continued for 6 to 12 months, and then tapered off. The moderate efficacy and the frequency of the side effects observed with prophylactic drugs explain the high rate of withdrawals. Some patients nevertheless dramatically improve, warranting trying several drugs successively in order to find the most appropriate one.     

Migraine treatment

The goal of the Canadian Migraine Forum was to work towards improving the lives of Canadians with migraine by reducing their migraine-related disability. This paper focuses on migraine treatment in its many aspects, including symptomatic therapy of individual migraine headache attacks, prophylactic drug therapy, non-pharmacological interventions, and diagnosis and management of symptomatic medication overuse. Many patients with difficult migraine experience significant frustration in trying to obtain the help they need from our current medical system. Although many symptomatic medications are available for use in migraine, migraine specific medications are still underutilized. An ideal migraine preventative medication does not yet exist, but currently available preventatives do have utility, and are also thought to be underutilized. Behavioral approaches to migraine management as an adjunct to medication therapy show promise, but the availability of programs to bring these to patients is limited, and more research is needed on their efficacy. Symptomatic medication overuse in migraine sufferers remains a large problem in Canada, and better defined treatment paradigms and programs are needed both to prevent and to treat this problem. Such programs should include strong elements of public, patient, and health professional education. A potential solution to some of these problems may be to develop treatment approaches to migraine similar to those that are being developed for other chronic medical disorders. For patients with severe migraine, these would optimally include multidisciplinary teams so that the multiple facets of migraine management can be adequately addressed.     

The role of anti-CGRP antibodies in the pathophysiology of primary headaches

Calcitonin gene-related peptide (CGRP), a potent vasodilator and pain-signaling neuropeptide, is a validated therapeutic target for migraine and cluster headache. Four anti-CGRP monoclonal antibodies (mAbs) have been developed, representing the first specific, mechanism-based, migraine prophylactic treatment. CGRP mAbs demonstrated good efficacy coupled to excellent tolerability and safety in 5 phase II clinical trials. Notably, CGRP mAbs induced complete migraine remission in a patients’ subset. To date, more than 20 phase III trials using CGRP mAbs for of episodic and chronic migraine and cluster headache prevention are ongoing. Future investigations will shed light on migraine endophenotypes predictive of good CGRP mAbs responsiveness and provide answers on their long-term cardiovascular safety.     

Methodological aspects of drug trials in migraine

Treatment of migraine attacks and prophylactic treatment of migraine are each discussed under the four headings: patient selection, trial design, evaluation of results and statistics. Checklist of problems encountered in these trials are given in the tables. The unsuitability of currently used migraine definitions for scientific investigations is stressed. Operational diagnostic criteria for common and classic migraine are given. No clear separation of common migraine attacks and interval headaches is possible, but the problem can be reduced by setting an upper limit (4-6/month) on migraine attack frequency. For the treatment of migraine attacks, the crossover design should always be used. We suggest dose-response studies to solve the problem of equipotency of doses, when 2 drugs are compared. A prophylactic drug should be studied both with the crossover design and with the less powerful group comparison design. Evaluation of results should be based on patients' attack report forms and, in prophylactic studies, a headache diary. We suggest global rating of attack severity. A rather simple headache index (sum of severity scores for each day with migraine) and perhaps a sum of global scores should be used in prophylactic trials. Confidence limits and power should be given, particularly when statistically insignificant results are reported. Migraine frequency often decreases with time regardless of treatment, and this 'time effect' should be separated from the therapeutic effect by appropriate statistical methods.     

Efficacy and tolerability of almotriptan in postmarketing surveillance studies

While randomized, double-blind, placebo-controlled trials are considered the gold standard of clinical evidence, they are limited by patient numbers, duration of patient exposure, and restricted patient populations. Data from controlled trials may not be generalizable to all individuals likely to take the drug under investigation. Postmarketing surveillance studies are designed to measure efficacy and safety in larger and more diverse populations, allowing them to detect less common and delayed adverse events. However, postmarketing surveillance studies are limited by their lack of randomization, open-label design that can result in patient and physician bias, incomplete follow-up, less than rigorous outcome measurement, and lack of a contemporaneous control group. With regard to acute treatment of migraine, clinical trials using per protocol primary endpoints do not reflect the more favorable experience with triptans in general practice. Postmarketing surveillance studies have been performed to determine whether the high levels of efficacy and tolerability of almotriptan reported in controlled clinical trials can been reproduced in routine practice. An observational study conducted in Spain with 2,074 migraine sufferers (4,183 attacks) reported a 2-hour pain-relief rate of 86.9%, a 2-hour pain-free rate of 51.5%, and a sustained pain-free rate of 46.0%; 1.1% of patients reported adverse reactions. A German postmarketing study in 899 patients (2,131 attacks) with acute migraine treated with almotriptan 12.5 mg reported 2-hour pain relief in 84.5% of attacks and 2-hour pain free in 41.4%; 1.1% of patients reported adverse reactions. The consistency of response (at least two out of three attacks successfully treated) with almotriptan 12.5 mg was 87.3%. Regarding satisfaction, 88.5% of patients were satisfied or very satisfied and 80.3% of patients stated that almotriptan was better compared to their prior therapy; 92% of physicians indicated that they would continue treating their patients' migraines with almotriptan. The results of these studies demonstrate that the high levels of efficacy and tolerability seen with almotriptan in controlled clinical trials are achieved in real-world clinical settings. In conclusion, a combination of controlled clinical trials, postmarketing surveillance studies, and physician's experience in the general population can give us a better understanding of the efficacy and tolerability of acute migraine agents.     

Treatment guidelines for preventive treatment of migraine

The Treatment Guideline Subcommittee of the Taiwan Headache Society evaluated the medications currently used for preventive therapy of migraine in Taiwan according to the principles of evidence-based medicine. We assessed the quality of clinical trials, levels of evidence, and referred to other treatment guidelines proposed by Western countries. Throughout several panel discussions, we merged opinions from the subcommittee members in order to propose a Taiwan consensus about the major roles, recommended levels, clinical efficacy, adverse events and cautions of clinical practice for these medications in preventive treatment of migraine. Migraine preventive medications currently available in Taiwan can be categorized into s-blockers, antidepressants, calcium channel blockers, anticonvulsants, nonsteroid anti-inflammatory drugs, botulinum toxin type A and miscellaneous medications. Propranolol has the best level of evidence, and is recommended as the first-line medication for migraine prevention. Valproic acid, topiramate, flunarizine and amitriptyline are suggested as the second-line medications. The rest medications are used when the above medications fail. Botulinum toxin type A did not differ from placebo for episodic migraine prevention but its efficacy in chronic migraine is not determined yet. It is not recommended to use migraine preventive medication during pregnancy. For those women with menstrual migraine, nonsteroid anti-inflammatory drug and triptans can be used for prevention during the menstrual period. The levels of evidence for migraine preventive medications in children/adolescents and elderly population are low. The preventive medications should follow the "start low and go slow" doctrine to reach an effective dosage. This can prevent adverse events and increase tolerance. The efficacy of preventive medications can not be evaluated until 3 to 4 weeks after treatment. If the improvement of migraine maintains for 4 to 6 months, physicians can gradually taper down or off the medications. Physicians should notify the patients not to overuse acute medications during migraine prevention treatment.     

Are antidepressants overrated? A review of methodological problems in antidepressant trials

There are no signs that the rapidly escalating use of antidepressants is reducing the burden of depressive disorders. This may be due to the fact that the evidence base for antidepressants is weaker than is commonly assumed. There are a number of methodological problems that may bias the results of clinical trials. Unblinding may inflate the response of people taking an active drug when compared with those taking an inert placebo. Modern measurement techniques may exaggerate the benefit of drug treatment. Excluding some randomized subjects from analysis may inflate the apparent effect of antidepressant drugs and publication bias means that published studies may not represent an accurate picture of the effects of treatment. In trials of long-term treatment discontinuation-related effects may masquerade as clinical efficacy. A brief survey of evidence from controlled trials does not present a consistently positive picture. Two of the largest and most reputable trials found only negligible differences between tricyclic antidepressants and placebo. The evidence on whether antidepressants are specific treatments is also inconclusive. Many other drugs not classed as antidepressants have shown positive effects in depression in controlled clinical trials. It is suggested that the interests of the pharmaceutical industry and the psychiatric profession have helped to establish the notion of the efficacy and specificity of antidepressant drugs.