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Drugs 2012;

Drugs 2012; 72 (17): 2187-2205 Adis ª 2012 Springer International Publishing AG. All rights reserved.
Advances in Drug Development forAcute MigraineRyan J. Cady,1 Candace L. Shade2 and Roger K. Cady2 1 Center of Biomedical & Life Sciences, Missouri State University, Springfield, MO, USA2 Banyan Group, Inc., Springfield, MO, USA Triptans revolutionized medical recognition and the acute treatment of migraine. Yet, throughout a lifetime, millions of patients who live withmigraine endure hundreds of days of disability due to their disease. Mostmigraine attacks respond to migraine-specific interventions, but attack responsedoes not predict patient response. Generally, migraine patients respond toacute treatment for some, but not necessarily all, attacks of migraine. Con-sequently, there remains a substantial unmet clinical need for better acutetreatment of migraine.
Numerous avenues of research and clinical observation provide insight into potential advances in acute treatment of migraine. These include betterdelivery systems for existing drugs, as well as the development of potentialnew therapeutic agents. In addition, new changes in migraine taxonomy andclinical observations of migraine suggest additional important therapeuticopportunities. Based on clinical observations, this article explores futureacute treatment needs, drugs in development for acute migraine, and newproducts that deliver established drugs to improve treatment response.
reproductive years. Yet, despite the clinical famil-iarity of migraine, its pathophysiology remains Migraine is a serious, disabling medical disease poorly understood.[3-5] Migraine is defined by its that significantly impacts the lives of millions of clinical phenomenology, as there is no diagnostic people worldwide, affecting their personal well- test or biological marker to confirm migraine. This being, families, social networks, and workplace.
ambiguity clearly hinders the development of Migraine's 1-year prevalence in adults is estimated therapeutic agents to treat or prevent this disease.
to be 12%,[1] but its lifetime prevalence is estimated Early scientific insight into migraine by Harold to be over 40%.[2] Migraine often begins in child- Wolff suggested that migraine was a vascular event hood or early adulthood, and increases in pre- initiated by vasoconstriction that caused aura fol- valence through the fourth decade of life, after lowed by vasodilation, which resulted in pain.[6] which migraine generally attenuates in frequency This model was based on elaborate studies utilizing and severity through mature adulthood. Migraine ergotamine. The vascular theory proposed by Wolff attacks are most common during an individual's dominated medical understanding of migraine for family-rearing and career-development years. It is nearly 50 years. However, with improved technol- more common in females, particularly during their ogy, Olesen et al.[7] demonstrated that the cerebral blood flow changes during migraine did not corre- Generally, in clinical trials of oral triptans, sub- late with the vasoconstriction and vasodilation that ject enrolments were not limited to triptan-naive occurred during aura and headache as predicted by subjects. In most cases, clinical studies often in- Wolff's vascular model.
cluded, or did not exclude, subjects already known In the 1980s, interest began to focus on the role of to respond to another oral triptan. In addition, serotonin in the pathogenesis of migraine. Anthony several studies excluded subjects who had experi- et al.[8] demonstrated that intravenous serotonin enced significant adverse events to another triptan could abort a migraine attack, but not without sig- (e.g. non-response, allergic reactions). These factors nificant associated adverse events. Subsequent re- may have enriched study populations and con- search identified a family of serotonin receptors that founded comparisons provided by various meta- mediated a wide range of physiological effects. This analyses. To date, no head-to-head study has been led to the discovery of a selective serotonin agonist, conducted to explore the differences and unique sumatriptan, by Humphrey et al.,[9] and with it, the attributes of the different oral triptan products in modern era of migraine.
terms of efficacy and tolerability in triptan-naive Sumatriptan is a selective serotonin agonist with populations and, despite intense marketing, no high affinity for the serotonin (5-HT)1B/D receptor.[10] single oral triptan has appeared to be superior.[14] Unlike serotonin, sumatriptan causes selective Further, no oral triptan was directly compared vasoconstriction of the cranial vasculature over co- with subcutaneous sumatriptan in terms of efficacy ronary vasculature. Like serotonin, sumatriptan in- or benefit to a patient's quality of life. Today, hibits the release of calcitonin gene-related peptide several of the oral triptans are generic and, conse- (CGRP), a potent vasodilator and inflammatory quently, research directed to find new oral triptans pain-signalling peptide considered central to mi- is significantly limited. Triptans are available over graine pathophysiology.[11] Clinically, an injection the counter (OTC) in Sweden, the UK, Romania of subcutaneous sumatriptan was observed to re- and Germany. This speaks volumes to the safety lieve migraine pain and associated symptoms in observed for these products since their introduc- 70% of subjects with moderate to severe headache tion in the early 1990s. However, OTC triptans are within 1 hour, with nearly 50% of subjects pain not available in the US.[16] Relative to subcutaneous sumatriptan, oral trip- The advent of subcutaneous sumatriptan fun- tans have slower onset of effect and lower efficacy.
damentally altered medical perception of migraine A meta-analysis of oral triptans that reviewed 53 and legitimized migraine as a biological, rather trials indicated that subjects taking sumatriptan than a psychosomatic, disease. It also heralded sig- 100 mg to treat migraine during moderate to severe nificant research investment, primarily from the headache achieved a mean rate of 29% for a 2-hour pharmaceutical industry, to develop new pharma- pain-free outcome.[17] This lower efficacy became cological treatments for migraine. The fruit of that more pronounced as the headache associated with effort was primarily the development and commer- migraine increased in severity. As a consequence, a cialization of six additional triptans, all of which treatment paradigm for oral triptan use called ‘early shared the same pharmacological mechanisms and intervention' became popular as a means to im- presumably successfully treated similar attacks of prove efficacy and reduce disability.
migraine in the same patient populations.[14,15] In regulatory trials, acute treatment was initiated Oral triptans made migraine therapy more con- when headache severity was moderate to severe, and venient and available to millions of people. How- generally had a full complement of associated mi- ever, it is a challenge to compare the efficacy and graine symptoms.[18-20] Early intervention was de- meaningful differences between oral triptans and fined as the initiation of acute therapy during the the contribution of new oral triptans, as they were mild headache phase of migraine. When utilized developed through the next decade, especially rel- effectively, early intervention generally increased ative to the established benefits of sumatriptan that 2-hour pain-free efficacy by 50–70%.[21-23] The suc- is injected subcutaneously.
cess of this treatment paradigm also reduced patient Adis ª 2012 Springer International Publishing AG. All rights reserved.
Drugs 2012; 72 (17) Drug Development for Acute Migraine disability through the initiation of acute interven- migraine attack development. In this model, mi- tions before functional impairment associated with graine is divided into five phases: the premonitory moderate to severe headache was physiologically phase, which may be followed by an aura, head- ache phase, resolution of headache phase and post- For a variety of reasons (e.g. early nausea, drome. Early work by Raskin and Appenzellar[30] quantity limits placed on triptans by pharmacy be- and Mathew et al.[31] suggest a transformational nefit programmes), results from subsequent US progression of migraine from an episodic to a studies suggest that patients can use this early- chronic headache syndrome.
intervention paradigm in about 50% of triptan- Years later, the headache phase of migraine worthy migraine attacks, which dilutes the impact was further subdivided into mild, moderate and of ‘early intervention' as a clinical tool for oral severe.[32] Observed during clinical practice, the triptans.[24,25] Despite limitations, oral triptans are phase model of migraine and transformation the most common formulation of prescribed acute concept offer richer understanding of migraine migraine medication. Oral triptans account for 95% attacks and headache patients.[33] Pathophysio- of triptan prescriptions, while nasal formulations logical mechanisms for each phase allow for and subcutaneous sumatriptan each account for acute pharmacological interventions beyond approximately 5% of market share in the US.[26] those that are effective during moderate to severe Given the significant number of attacks not ef- headache.[34] To target acute therapy and reduce fectively treated by oral triptans, there remains the accumulated disability associated with de- a critical need for new pharmacological agents cades of repeat migraine attacks, there may be and improved formulations for treating acute mi- value in exploring pharmacological interventions graine.[27] Clinical models for acute migraine inter- in different phases of acute migraine. The in- vention have evolved slowly, so there is potential herent sensitivity of the phase model and mi- for improving efficacy and outcome through the graine transformation model may more readily development of novel treatment paradigms. This predict the variability of migraine attacks wit- article explores new and potential advances from nessed between or within patient presentations.
the perspective of both clinical observation and For example, treatment prior to onset of moder- ate to severe headache or post-dromal symptomspersisting between episodes of migraine may 2. Treatment Opportunities Based on provide more specific and robust treatment op- Clinical Observations of Migraine portunities. In turn, understanding and definingthis variability may provide a platform for in- In 1988, the International Headache Society dividualizing acute treatment based on unique (IHS) provided a symptom-based taxonomy for mi- attack characteristics rather than relying solely graine that has been used for all modern regulatory on IHS diagnosis (see figure 1).
studies of migraine medications.[28] The IHS criteriadivided headache disorders into ‘primary' and ‘sec- 3. Chronification of Migraine – A New ondary', with migraine defined as a primary head- Window of Opportunity for Acute Drug ache disorder. The 1988 criteria subdivided migraine Development for Migraine into ‘migraine without aura' and ‘migraine withaura'. Clinical trials of acute interventions for mi- In 2004, diagnostic criteria for migraine were graine that use IHS diagnostic criteria reflect a rather revised and, for the first time, included a diag- static definition of a complex neurobiological event.
nostic definition of chronic migraine.[35] Criteria Also, unlike 1988 IHS diagnostic criteria established were quickly revised in 2006 to more closely align for tension-type headache and cluster, migraine was with clinical observations of chronic migraine.[36] defined only as an episodic headache disorder.
In 2006, an appendix definition of chronic mi- In 1987, Blau[29] elaborated on a model of mi- graine was published by the ICHD-II committee, graine that explored clinical observations of acute which noted that episodic migraine (14 or fewer Adis ª 2012 Springer International Publishing AG. All rights reserved.
Drugs 2012; 72 (17) Headache diagnosis if process terminates at different stages Time (hours)
Fig. 1. Phase model of migraine: diagnostic and pathophysiological implications. Reproduced with permission by Primary Care Network, Inc.
days of IHS migraine per month) often precedes clinical trials of acute treatment medications. This chronic migraine (15 or more days of headache unmet clinical need offers important opportunities with 8 or more days that fulfil criteria for IHS for new and novel acute intervention strategies.
migraine) and that episodic migraine was a pre- In addition, patients with frequent episodic cursor to, and aetiologically related to, chronic and chronic migraine have a significantly in- migraine.[37] While the observation of migraine creased prevalence of co-morbid diseases (e.g.
chronification is generally accepted in the clinical anxiety, depression, other pain disorders). These community, it is also observed that there are no- occur with increased frequency as migraine be- table differences in the pharmacological responses comes more chronic (see table II),[45] which sug- of certain drugs used to treat episodic and chronic gests that, as migraine transforms from episodic migraine.[38-40] In addition, it is a widely held belief to chronic, it becomes a more pervasive neuro- that frequent use of acute medication (see table I) logical assault.[46] Few drug studies include mi- can transform migraine from episodic to chron- graine subjects with co-morbid disease as an ic,[41,42] and forms the basis for the diagnosis of outcome variable or confounding factor. This, medication overuse headache.[43] Acute medica- too, represents a significant opportunity to de- tions that are safe and effective for frequent use in velop pharmacological interventions for acute patients who require relief from frequent episodic migraine in these patient populations.
or chronic migraine are yet to be developed andstudied. Currently, the only medication approved 4. Classification of Migraine Medications by the US FDA specifically for chronic migraine isthe prophylactic treatment botulinum toxin A The pharmacological treatment of migraine is (onabotulinumtoxinA).[44] To date, patients with generally divided into two categories of med- chronic migraine have generally been excluded from ication: acute and preventive. Acute agents re- Adis ª 2012 Springer International Publishing AG. All rights reserved.
Drugs 2012; 72 (17) Drug Development for Acute Migraine verse a migraine attack after it can be defined offer therapeutic opportunities to improve and clinically, while preventive medications protect develop future acute treatments, for example, an the nervous system from the migraine attack antiepileptic drug as an acute agent for migraine or being initiated. While these categories appear a single dose of a triptan used to prevent a pre- distinct, in reality, some pharmacological agents dictable attack of migraine.
have been shown to be effective in both acute and Acute medications are also considered mi- preventive roles. This has been demonstrated to a graine specific or non-specific. The distinction, limited degree for sodium divalproate,[47] trip- while in some ways vague, is based on the ability tans,[48] NSAIDs,[49] dihydroergotamine[50] and of the drug to relieve migraine-associated head- ergotamines.[51] Preventive medications are gen- ache, plus associated symptoms, or simply to re- erally taken on a daily basis. When migraine is lieve pain, or a limited number of, but not all, predictable, some acute pharmacological agents migraine-associated symptoms. This construct of have demonstrated efficacy when used as pre- migraine specificity does not imply that the effi- emptive or short-term prophylactics.[52-54] This cacy of a drug is confined only to migraine.[55] blurring of the distinction of a migraine medication However, this concept may be useful as it focuses being either an acute or a preventive treatment may the outcome of successful acute therapy for mi-graine on interventions that address the complexclinical expression of migraine and helps definemigraine as unique to other pain syndromes.
Table I. Approved drugs for acute migraine 5. Drug Development OpportunitiesBased on Current Pathophysiological Understanding of Migraine 5-HT1B/D receptor agonist Today, migraine is commonly considered to be the consequence of a genetically hyperexcitable 5-HT1B/D receptor agonist brain.[56-58] Interestingly, however, no distinct spe- 5-HT1B/D receptor agonist cific genetic mutation has been discovered that is 5-HT1B/D receptor agonist widely observed in the general migraine pop- 5-HT1B/D receptor agonist ulation. This leads to speculation that the clinical 5-HT1B/D receptor agonist expression of migraine is a final common pathway 5-HT1B/D receptor agonist for a heterogeneous group of mechanisms that 5-HT1B/D receptor agonist and share the capacity to initiate migraine. In other COX-1/COX-2 inhibitor words, it may be that several pathophysiological pathways increase CNS excitability and the like- Excedrin Migraine lihood of the initiation of a migraine. Fundamental to this ‘hyperexcitable brain' model of migraine are Aspirin (acetylsalicylic COX-1/COX-2 inhibitor genetic characteristics or mutations that increase CNS excitability or, alternatively, decrease central COX-1/COX-2 inhibitor inhibitory control of CNS processing pathways.
COX-1/COX-2 inhibitor Consequently, though perhaps overly simplistic, potential excitatory channelopathies have been 5-HT1A/B/D receptor agonist frequent targets of drug development for migraine 5-HT2 receptor antagonist especially in terms of preventing spreading cortical Dopaminergic and adrenergic receptor activity COX = cyclooxygenase; IM = intramuscular; IN = intranasal; ODT = Beyond this genetic predisposition, there orally disintegrating tablet; SC = subcutaneous; 5-HT = 5-hydroxy- needs to be an event(s) that triggers the nervous system to generate migraine. The physiological Adis ª 2012 Springer International Publishing AG. All rights reserved.
Drugs 2012; 72 (17) Table II. Comparison of chronic migraine vs episodic migraine co- their pathophysiological mechanisms serve as morbidities. Reproduced from Buse et al.,[45] with permission from potential targets for acute, and possibly prophy- BMJ Publishing Group Ltd lactic, drug development. Other than hormonal Chronic migraine (%) Episodic migraine (%) manipulations, treatment during aura, and pre- emptive treatment of predicable migraine with triptans, relatively few acute or short-term phar- macological interventions have been studied that may alter the ‘migraine threshold' or address specific migraine triggers.[53,54,69] 6. Acute Migraine Medications in Drugs in development for acute migraine are listed in table III.
point where migraine is initiated is called the‘migraine threshold'.[63] This threshold is de- 6.1 Serotonin Receptor Agonists termined largely by genetics, but is modulated bynumerous external and internal events. These Most currently available prescribed acute ‘triggering' events have the potential to alter pharmacological interventions for migraine are the susceptibility of the CNS in a manner that agonists or antagonists of receptors that, when influences, both positively and negatively, the oc- activated, temporarily reduce neuronal hyper- currence of migraine. This concept is critical to excitability. The most studied of these drugs are understanding the episodic nature of migraine as serotonin receptor agonists.[14,81] The most pop- well as widely accepted clinical constructs in mi- ular cellular targets are the 5-HT1B/D receptors, graine such as ‘triggers', behavioural interven- which are localized in the peripheral and central tions, and acute and preventive pharmacology.
nervous systems. Additional 5-HT1 sub-receptors Once the migraine threshold is breached, var- of interest in acute migraine include the 5-HT1D ious symptoms are expressed clinically, which are and 5-HT1F receptor.[82-84] Agonists of these recep- recognized as the premonitory phase or pro- tors are not associated with vasoconstriction. The drome associated with most migraine attacks.[64] 5-HT1D receptor inhibits neurogenic-mediated If migraine is not terminated at this phase, an extravasation, but a study of PNU-142633, a electrical/vascular/neuronal event called spread- 5-HT1D receptor agonist, proved ineffective and ing cortical depression may activate, which is there has been no further clinical research that considered the physiological basis of aura.[65] has utilized 5-HT1D receptor agonists. However, Auras occur in approximately 25% of migraine PNU-142633 has poor CNS penetration, which attacks. Subsequently, there is activation of the may explain the negative results of this study.[85] trigeminal-vascular system associated with a relative The 5-HT1F receptor is localized in the trigeminal decrease of inhibitory control of sensory input that ganglion and trigeminal nucleus caudalis, where feeds into the trigeminal nucleus caudalis as well as it inhibits neuronal activation. Early studies of other central sensory nuclei.[66] Sensory input from LY-334370 potent 5-HT1F receptor agonist demon- the trigeminal nerve, upper cervical dermatomes, strated efficacy in acute migraine, but caused and likely, other cranial nerves, are processed di- significant CNS adverse events and, in animal rectly or indirectly through the trigeminal nucleus studies, serious toxicity.[86] It is no longer under caudalis.[33] As migraine progresses, second- and third-order neurons sensitize and ultimately migraine Another highly selective 5-HT1F receptor ago- can become a centrally maintained pain syn- nist COL-144 (lasmiditan) demonstrated efficacy in drome.[67,68] These unique phases of migraine and a phase II study.[72] In this double-blind, placebo- Adis ª 2012 Springer International Publishing AG. All rights reserved.
Drugs 2012; 72 (17) Drug Development for Acute Migraine controlled study, 391 subjects received oral lasmi- ecules that are antagonists of the CGRP receptor ditan 50 mg, 100 mg, 200 mg, 400 mg or placebo in complex. Collectively, these compounds are called a ratio of 1 : 1 : 1 : 1 : 1. Results demonstrated effec- gepants. The CGRP receptor is a heterotridimeric tiveness over placebo for all doses, with doses G protein coupled receptor that consists of the greater than 100 mg showing greatest efficacy. Pain calcitonin receptor-like receptor (CLR) and an- relief at 2 hours was approximately 60% for doses other transmembrane protein named receptor of ‡100 mg versus placebo of 25%. Significant su- activity-modifying protein (RAMP)-1. RAMP1 is periority over placebo was observed for onset of responsible for the specificity of the CGRP re- headache relief within 30 minutes, as well as relief ceptor, whereas coupling of the CLR to RAMP2 of associated photophobia and phonophobia at or RAMP3 produces the adrenomedullin recep- or before 2 hours, and for nausea at or before tor.[88] Furthermore, a single amino acid in the 3 hours. At the 400 mg dose, pain-free efficacy was RAMP1 protein is responsible for the receptors' 29% at 2 hours versus 8% for placebo, and sus- affinity to small-molecule antagonists of the CGRP tained pain-free status at 24 hours was 38% versus 11% for placebo. Lasmiditan appeared to be rea- CGRP receptors are ubiquitous and are richly sonably well tolerated, with most adverse events represented in the peripheral and central nervous mild or moderate in intensity. Dizziness, at times system. They are localized in meningeal blood significant, was the most common treatment- vessels, trigeminal ganglion neurons, and trigem- emergent adverse event, followed by fatigue and inal nerves in the peripheral nervous system, as well vertigo.[87] The clinical tolerability of lasmiditan is as localized in significant concentrations centrally yet to be more completely determined by larger in structures like the spinal cord, trigeminal nucleus phase III studies.
caudalis, periaqueductal gray nucleus, and othercentral nuclei considered important in migraine.[90]Several drugs in this class are under investigation 6.2 Calcitonin Gene-Related Peptide (CGRP) and have demonstrated efficacy in phase II and Receptor Antagonists phase III studies of acute migraine.[70,91,92] As a Beyond serotonin receptor agonists, there has class, gepants lack vasoconstrictive properties and recently been considerable interest in a class of mol- are considered to have a safety advantage over Table III. Formulation advances and drugs in pipeline Drug, route of administration Development stage BI-44370 TA ,[70] oral CGRP receptor antagonist Ketorolac (ROX-188)[71] COX-1/COX-2 inhibitor Lasmiditan (COL-144),[72] oral 5-HT1F receptor agonist Dihydroergotamine (MAP0004),[73] orally inhaled 5-HT1A/B/D receptor agonist Awaiting FDA approval 5-HT2 receptor antagonista1 and 2 adrenergic agonistDopaminergic activity Sumatriptan nasal powder,[75] nasal 5-HT1B/D receptor agonist Oral diclofenac potassium,[76] buffered oral COX-1/COX-2 inhibitor FDA approved 2009 Sumatriptan injection,[77] needle-free injection 5-HT1B/D receptor agonist FDA approved 2009 Tezampanel (LY293558),[78] IV, SC AMPA/kainite receptor antagonist Sumatriptan (NP101),[79] transdermal patch 5-HT1B/D receptor agonist Awaiting FDA approval Sumatriptan injection,[80] auto injector 5-HT1B/D receptor agonist FDA approved 2010 CGRP = calcitonin gene-related peptide; COX = cyclooxygenase; IV = intravenous; OTC = over the counter; SC = subcutaneous; 5-HT =5-hydroxytryptophan (serotonin).
Adis ª 2012 Springer International Publishing AG. All rights reserved.
Drugs 2012; 72 (17) triptans, though there is little scientific evidence few subjects developed significant elevation of that triptans are associated with significant cardio- liver transaminases early (within weeks) of in- vascular or cerebrovascular risk. Given that CGRP itiating their course of therapy. Liver enzymes receptor antagonists, like triptans, inhibit CGRP, it returned to normal when therapy was discontin- is possible that these two drug classes will be effec- ued, but Merck decided to delay further devel- tive in a similar population of migraine attacks and opment of this compound. Given the tendency of patients. However, after reviewing data from a some migraineurs to treat frequently with abor- clinical trial that compared rizatriptan, telcagepant tive medications, this was a conservative but un- and placebo, Ho et al.[93] suggested that telcagepant was effective in migraineurs who did not respond to Another compound in development is BI 44370 TA, an orally available CGRP receptor antagonist The first published proof-of-concept study, with demonstrated efficacy in acute migraine. In a conducted by Olesen et al.,[94] demonstrated effi- multicentre phase II study, 461 subjects were ran- cacy of 66% for intravenous olcagepant 2.5 mg domized to BI 44370 TA (50 mg, 200 mg, 400 mg), versus 27% for placebo, and that the product had eletriptan 40 mg or placebo 1 : 1 : 1 : 1 : 1.[70] The an acceptable adverse event profile, with the most primary endpoint was to be pain free at or before 2 common adverse event being mild paraesthesia.
hours. The 400 mg dose was statistically superior However, this compound could not be adapted to both the 200 mg dose and placebo at 2 hours for oral formulation and was abandoned for (27.4% versus 21.5% [p < 0.005] and 8.6%, re- further clinical development.
spectively). Statistical benefit for BI-44370 TA The first oral CGRP receptor antagonist in 200 mg and 400 mg was achieved over placebo, clinical trials was telcagepant (MK-0974) and and pain-free status was sustained at 2 hours and was studied in a phase II, randomized, placebo- 24 hours, and 2 hours and 48 hours. Functional controlled comparator study with rizatriptan for disability and associated migraine symptoms of the acute treatment of migraine.[95] The study was photophobia and phonophobia were noted to conducted as a dose-range study with an adaptive improve for BI 44370 TA 400 mg. Eletriptan also design and demonstrated statistical superiority achieved statistical significance for all these for telcagepant over placebo at doses of 300 mg, 400 mg and 600 mg. Efficacy was similar to riza-triptan 10 mg at 300 mg and 600 mg doses. The 6.3 Dihydroergotamine: An Older Drug with 2-hour pain relief was 68% for 300 mg, 48% for 400 mg and 67% for 600 mg. The efficacy for ri-zatriptan 10 mg was 69% at 2 hours, compared Dihydroergotamine, a treatment for acute mi- with placebo response of 46%. Superiority over graine for over 60 years, has become a subject of placebo was also noted for pain free, associated renewed interest and study. Throughout the trip- symptoms and functional disability. In two sub- tan era, dihydroergotamine has continued to be sequent double-blind, placebo-controlled phase used by headache specialists worldwide, partic- III studies, telcagepant 150 mg and 300 mg were ularly when used intravenously and in a variety of compared with placebo.[91,96] These studies dem- repetitive-dose protocols attributed to Raskin.[97] onstrated telcagepant to be superior to placebo Dihydroergotamine formulations for migraine in- for all five co-primary endpoints: pain relief; pain clude intravenous, intramuscular or subcutaneous freedom; and absence of photophobia, phono- injection, and it is also available in a nasal spray phobia and nausea. This launched a flurry of clinic research on telcagepant to assess its con- Dihydroergotamine, like the triptans is a sistency across four attacks of migraine and an 5-HT1B/D receptor agonist, but there are important 18-month long-term safety study. However, in a receptor distinctions between dihydroergotamine phase II study of telcagepant as a preventive and triptans. Dihydroergotamine has significant agent administered twice daily for 3 months, a receptor binding and pharmacological effects at- Adis ª 2012 Springer International Publishing AG. All rights reserved.
Drugs 2012; 72 (17) Drug Development for Acute Migraine tributable to interactions with the 5-HT1A and graine. The primary endpoint of headache pain 5-HT2 receptors, as well as a1 and -2 adrenergic response at 2 hours was reached at the 40 mg dose, receptors.[100] Interestingly, dihydroergotamine but the 70 mg and 100 mg doses failed to reach binding to the a2-adrenergic receptor has been statistical significance.[108] This may represent a bi- shown to block ATP-sensitized trigeminal neurons phasic response as has been observed in other acute by decreasing membrane expression of the P2X3 migraine studies,[109] but more work needs to be receptor protein.[101] P2X3 activation has been conducted with tezampanel before conclusions can implicated in primary nociception, hyperalgesia and CGRP release.[102,103] In addition, dihydroer-gotamine may be penetrant of the blood-brain barrier.[104] The benefit of using a drug with multi- Nitric oxide (NO), a free radical, has been ple-receptor activity versus a ‘magic bullet' with implicated in migraine pathology. The infusion of limited, but more specific, activity in a complex NO has been shown to induce migraine-like at- biological event like migraine has not been ade- tacks.[110,111] Three different isoforms of NO quately investigated. Given the potential hetero- synthase exist and are responsible for NO pro- geneity of the migraine population, mechanisms duction.[112] Two of the isoforms (endothelial and clinical phenotypes explored as unique subsets eNOS, and neuronal nNOS) are responsible for could prove to be a line of investigation worthy of the constitutive release of NO. The inducible further study and drug development.
form (iNOS) can lead to a large increase in NOlevels and it has been implicated in inflammatory 6.4 AMPA/Kainite Receptor Antagonists disease.[113,114] Furthermore, release of NO in thetrigeminal ganglion has been shown to activate The free amino acid glutamate plays an ex- neurons, leading to the release of CGRP.[115] citatory role in neuronal transmission in both the While a variety of studies have looked at NOS peripheral and the central nervous systems, and is inhibitors in migraine, none have been effec- abundant in pain-processing structures in the tive.[116,117] Of particular curiosity is the failure of brain. It is released in response to inflammation iNOS inhibitor efficacy in migraine as, theoreti- and binds to a family of receptors that consist of cally, iNOS should be induced during the neuro- N-methyl-D-aspartate (NMDA), AMPA, kainite logical assault of migraine.
and metabotropic glutamate that allow the acti-vation of a variety of inflammatory pathways.[105] NMDA receptor antagonists are used to treat avariety of neuropathic pain conditions.[106,107] Ac- Elevated levels of prostaglandin E2 (PGE2) cordingly, the AMPA/kainite receptor antagonist have been found in blood and saliva during mi- LY293558 (tezampanel) has been shown to be ef- graine attacks.[118-121] There are at least four re- fective for migraine treatment.[78] In a multicentre, ceptors for PGE2, and most antagonist studies double-dummy, proof-of-concept trial with 45 have focused on the EP4 receptor, which med- subjects, LY293558 1.2 mg/kg was compared with iates smooth muscle contraction.[122] Several sumatriptan 6 mg and placebo. Two-hour head- EP4 receptor antagonists (AH23848, MF766, ache relief rates were 69% for LY293558, 86% for CJ-023423, and CJ-042794) have been effective in sumatriptan and 25% for placebo. Pain-free rates treating rodent models of hyperalgesia, and at 2 hours were 54% for LY293558, 60% for su- BGC20-1531 (an EPA-4 receptor antagonist), has matriptan and 6% for placebo. Adverse events were been effective in human trials for migraine treat- lower for LY293558 than for sumatriptan or pla- ment.[123] A phase II, randomized, double-blind, cebo, but this study sample was small. A phase IIb placebo-controlled, three-way intra-individual cross- multicentre study in 306 patients compared sub- over study completed in 2010 did not demonstrate cutaneous tezampanel 40 mg, 70 mg and 100 mg the efficacy of BGC20-1531 over placebo. However, versus placebo for a single episode of acute mi- there were only eight volunteers. Investigators Adis ª 2012 Springer International Publishing AG. All rights reserved.
Drugs 2012; 72 (17) believe further study is warranted, but development formulations have a quicker onset of action that is for this drug has stopped due to delays in the opti- highly desirable.[104] It should be noted that rigor- mization of drug product formulation.[124] ous direct comparator studies of these productshave not been conducted.
6.7 Orexins (Hypocretins) 7.2 Sumavel DosePro Orexins are neuropeptides excreted in the hy- pothalamus that are excitatory neuronal trans- Sumavel DosePro (Zogenix, San Diego, CA, mitters to monoamine and serotoninergic nuclei USA) is a novel parenteral delivery system that throughout the brain.[125,126] They appear to in- injects sumatriptan into the subcutaneous tissue fluence many physiological responses such as through use of a needle-free device. The single-use sleep, eating and reward.[127,128] device uses a nitrogen-containing cylinder to ad- Orexin receptors are in neuronal networks that vance a piston that injects sumatriptan through the project to pain-processing areas of the CNS, skin and into the subcutaneous space in approxi- brainstem and spinal cord. Possibly analogous to mately 0.1 second. When injected, it is recommen- the migraine threshold described in section 5, ded it be administered into the thigh or abdomen.
they have been implicated in maintenance of the Sumavel DosePro was approved by the basal nociceptive threshold. Accompanied by the FDA based on bioequivalence studies against fact that sleep is associated with recovery from needle-based injectable sumatriptan. It has the acute migraine, this observation has led to spec- same efficacy and triptan-associated adverse ulation that orexin antagonists may be beneficial event profile as subcutaneous sumatriptan. It is in acute migraine.[129] Furthermore, animal stud- indicated for migraine with or without aura and ies suggest a complex role for orexins in the cluster headache in individuals over 18 years of modulation of pain.[125] Currently, there are on- age.[131] A second dose can be given within a going proof-of-concept studies of the orexin an- 24-hour period by subcutaneous, nasal or oral tagonist MK-6096 for migraine prevention.[130] administration. Advantages of the needle-free The role of MK-6096 as an acute treatment for device are ease of use, no requirement for needle migraine is unknown. Given the relationship of disposal, and patients with needle phobias could many primary headache disorders to sleep (e.g. for use the device comfortably. In an outpatient migraine, cluster and hypnic headache), orexins are population that used at least one needle-free sys- promising compounds for future development.
tem device, 51 (98.1%) used it successfully in theirfirst attempt. Second attempts were successful for 7. Specific Improved Products Emerging 95.6% of 45 patients, and 100% of 28 patients for Treatment of Acute Migraine achieved success on the third attempt.[132] In an open-label, multicentre, phase IV study of 7.1 Parenteral Delivery of Serotonin Receptor 212 patients, the revised Patient Perception of Mi- graine Questionnaire (PPMQ-R) and Overall Sat- Several clinical studies of available triptans have isfaction and Confidence score (primary endpoint) been conducted on the premise that drug delivery is increased significantly from baseline to the end of critical to successful treatment of recurrent acute treatment (mean – SD 65.7 – 19.8 vs 73.7 – 29.1; migraine attacks. The rationale for improving the p = 0.0007). The percentage of patients who were delivery of acute migraine medications is that poor ‘‘satisfied'' or ‘‘very satisfied'' increased sig- absorption of many oral acute migraine drugs nificantly from baseline (36.3%) to the end of during migraine may be the root of their rather low treatment (64.0%) for all global satisfaction do- efficacy and inconsistency compared with par- mains including ‘overall satisfaction'. In addition, enteral administration of the same drug, especially patients also reported statistically significant effi- when used over multiple episodes of migraine. In cacy results of 85.9% for pain relief, 60.7% for addition, according to patient surveys, parenteral pain-free response and 66.3% sustained 24-hour Adis ª 2012 Springer International Publishing AG. All rights reserved.
Drugs 2012; 72 (17) Drug Development for Acute Migraine pain relief. Observed adverse events with the nee- dle-free injection system were primarily pain at in-jection site and local reactions.[77] A second novel delivery system is the sumatriptan Another important advance from marketing iontophorectic transdermal patch (Zecuity, for- the needle-free delivery system is that Zogenix merly NP101, NuPathe, Inc., Conshohocken, promotes their product not for specific patients, PA, USA). This product is a single-use transder- but for those who experience specific phenotypes mal patch that contains sumatriptan 86 mg, de- or attacks of acute migraine that most clinicians signed to transdermally deliver approximately consider more effectively treated with injection 6.5 mg of sumatriptan over 4 hours in a self- rather than oral intervention. Promoting this at- contained delivery system that utilizes ionto- tack-based approach to migraine management phoresis. In a randomized, placebo-controlled, creates a ‘toolbox' for patients to individualize phase III study of 469 subjects, Zecuity was treatment need based on individual attack char- well tolerated and superior to placebo for pain- acteristics. Specific migraine phenotypes where free response at 2 hours (18% vs 9%, respectively; Sumavel DosePro may provide clinical value p = 0.0092), which was the primary endpoint. It are early-morning migraine, attacks with nausea/ was also statistically superior to placebo for pain vomiting or gastric atony, rapid-onset migraine, relief and fewer associated symptoms of nausea and those that require rescue. Additionally, (83.6% with the sumatriptan iontophoretic trans- patients who have needle phobias or concern dermal system; 63.2% with placebo); photophobia about needle disposal would be good candidates (51% vs 36%, respectively; p = 0.0028) and pho- for this product.
nophobia (55% vs 39%, respectively; p = 0.0002).[79]Patients reported a significantly higher percen-tage of headache pain relief 2 hours post-dose (52.9% vs 28.6%, respectively; p < 0.0001) when A second new product for acute migraine is using the sumatriptan iontophoretic transdermal Alsuma (Pfizer, NY, USA), a subcutaneous patch. The higher response percentage continued needle-based injection that delivers 6 mg of su- after 2 hours for the transdermal system group matriptan. Approved in bioequivalence studies, it for photophobia free (51% vs 36%, respectively; has a similar efficacy and adverse event profile to p = 0.0028) and phonophobia free (55% vs 39%, other formulations of subcutaneous sumatriptan.
respectively; p = 0.0002). In a long-term safety It is indicated for migraine with or without aura study, NP101 maintained consistency and effi- and cluster headache in patients over 18 years cacy in up to 12 treated attacks and was pro- of age. Alsuma delivers subcutaneous suma- moted for patients with migraine-related nausea, triptan 6 mg by injection, and the device is easier vomiting or gastroparesis.[133] Despite positive to use than other needle-based devices. In a us- clinical trials that used this delivery system, the ability study, 100% of subjects reported using it FDA has not yet approved Zecuity, expressing correctly with their first injection.[80] On the pa- concern about manufacturing and asking for tient questionnaire, 100% agreed the written in- additional information. NuPathe, the maker of structions were clear and easy to follow, and 99% Zecuity, has recently resubmitted their new indicated the auto-injector was easy to use. Gen- drug application (NDA) to the FDA. Zecuity erally, 76.7% indicated they preferred the new appears to be a successful addition to acute mi- auto-injector over the traditional needle-based graine therapeutics for an important subset of auto-injector. Oral or nasal formulations of attacks associated with poor oral absorption, Alsuma can be repeated after 1 hour, or repeat nausea or vomiting. Zecuity also works well for doses as required at appropriate time intervals.
patients with needle phobias or non-response to This product may be useful in early-morning oral or nasal formulations.
migraine, attacks with nausea/vomiting, sudden- This product may be beneficial for migraine onset of severe migraine, gastric atony or as rescue.
attacks associated with nausea/vomiting or gastric Adis ª 2012 Springer International Publishing AG. All rights reserved.
Drugs 2012; 72 (17) atony. It will also be useful as an option for trointestinal upset, nausea and vomiting asso- patients who do not want injections.
ciated with oral migraine therapy, intranasaltherapy promises to be an alternative. Patients (140) were enrolled in a phase II, multicentre,double-blind, placebo-controlled study random- OptiNose (OptiNose US Inc., Yardley, PA, ized 1 : 1 to self-treat with ROX-828 (ketorolac USA) is an effort to improve on the efficacy of tromethamine 31.5 mg/200 mL, which contains 6% already available transnasal formulations of su- lidocaine) or placebo (with 6% lidocaine).[71] Sub- matriptan. With this device, sumatriptan is de- jects were instructed to treat a new migraine attack livered in the nasal mucosa as a powder during within 4 hours of at least moderate pain intensity.
oral exhalation, which causes closure of the na- More patients achieved pain-free status with sopharynx and greater deposition of drug into ROX-828 than with placebo at 1.5, 3, 4, 24 and the nasal cavity.[134] The rationale for this deliv- 48 hours (p < 0.05); significance at the 2-hour time ery system is that many liquid nasal sprays ulti- point, the primary endpoint, was not met.
mately convert to oral doses through the act of Nasal discomfort was the most common adverse swallowing, as the liquid nasal spray reaches the event. Data indicated sufficient preliminary evi- posterior nasal pharynx or simply leaks from the dence that self-administration of intranasal ROX- nares after administration. With this device, su- 828 can relieve migraine pain. Self-administered matriptan is a fine powder that adheres to the intranasal ROX-828 was well tolerated. Although nasal mucosa where it is easily absorbed.
the primary endpoint was not met, the results pro- In a multicentre, randomized, single-attack, vide preliminary evidence that ROX-828 improves placebo-controlled study of 117 subjects, statistical migraine pain, which warrants further investigation.
superiority for sumatriptan nasal powder 10 mg This product may be useful in attacks asso- and 20 mg versus placebo was observed. At 120 ciated with triptan non-response, cutaneous al- minutes post-dose, 54% (10 mg) and 57% (20 mg) lodynia, nausea/vomiting or gastric atony, or versus 25% (placebo) were pain free (p < 0.05). Sig- nificant benefits were also observed for pain relief at2 hours (84% and 87% vs 44%; p < 0.001/0.01) and48 subjects sustained pain free status (p < 0.05).[75] 8. New Products with Unique Mechanisms For the sumatriptan 10 mg group, at both 90 min-utes and 120 minutes, patients reported a statisti- 8.1 Orally Inhaled Dihydroergotamine cally significant reduction of photophobia versus An orally-inhaled dihydroergotamine (Levadex, placebo (13% vs 34%; p < 0.05). Nausea reductions MAP Pharmaceuticals, Mountain View, CA, USA) were not significant when compared with placebo formulation, MAP0004, has recently been in- for either the 10 mg or the 20 mg treatment group.
vestigated, and clinical trials suggest significant A phase III study has been completed and reported efficacy and a low incidence of side effects. Data to be positive, but is not yet published.
from phase III studies of orally inhaled dihydro- This product may be useful as a first-line ergotamine demonstrate pain relief in as little treatment requiring rapid action onset and as 10 minutes, which is similar to pain relief patients with frequent migraine associated with provided by subcutaneous triptans.[73] A higher nausea/vomiting or gastric atony.
percentage of patients were pain free at 2 hoursfollowing treatment with MAP0004 than with placebo (28.4% vs 10.1%; p < 0.0001). In addition, A new intranasal formulation of ketorolac, MAP0004 was superior to placebo in pain relief tromethamine (SPRIX, Regency Therapeutics, (58.7% vs 34.5%; p < 0.0001). Co-primary endpoints Shirley, NY, USA), is in clinical trials for short- for MAP0004 compared with placebo were also term management of moderate to severe migraine, numerically significant. The photophobia-free rate with and without aura. In an effort to avoid gas- was 47% vs 27% (p < 0.0001), the phonophobia-free Adis ª 2012 Springer International Publishing AG. All rights reserved.
Drugs 2012; 72 (17) Drug Development for Acute Migraine rate was 53% vs 34% (p < 0.0001) and the nausea- 8.2 Prostagladins free rate was 67% vs 59% (p = 0.0210). Comparedwith intravenous dihydroergotamine, MAP0004 Prostaglandins are another target of interest recipients experienced a lower incidence of nausea for drug development in acute migraine. Pros- (25% vs 62%) and dizziness (25% vs 44%). This may tagladins are a metabolite of cyclooxygenase be due to a lower peak plasma drug concentration (COX) pathways and their involvement is un- (Cmax) observed in pharmacokinetic and pharma- derstood to be in pain signalling. Earlier research codynamic studies of orally inhaled dihydroergo- on the selective COX-2 inhibitor, rofecoxib, tamine versus injection. The Cmax with intravenous demonstrated efficacy in migraine shortly before dihydroergotamine 1 mg is 12–40 times greater its removal from the market due to potential than four and two inhalations of MAP0004, re- cardiovascular risk.[139] Interestingly, a study spectively.[135] The differences in Cmax create a that combined rizatriptan with low doses (25 mg) tidy hypothesis for the reported higher adverse of rofecoxib showed promising efficacy and events in intravenous dihydroergotamine.[99] Im- lower recurrence rates than with rizatriptan portantly, patients who used inhaled dihydroergo- tamine reported a lower recurrence rate for More recently, an oral solution of diclofenac migraine at both 24 and 48 hours (6.5% and 10.3%, potassium (Cambia, Nautilus Neurosciences, respectively) than did triptan users at the same time Inc., Bedminster, NJ, USA) received FDA approval points (22% and 29%), although this is not based on for acute migraine.[76] In two multicentre trials, one head-to-head studies.[136] However, it is consistent European and the other US, the pain-free response with scientific data that dihydroergotamine binds to was 24.7% for the oral solution diclofenac po- 5HT1B and 5-HT1D receptors for 8–14 times longer tassium (p < 0.0001), 18.5% for the diclofenac tablet than sumatriptan.[102] Furthermore, unlike the oral and 11.7% for placebo (p < 0.0001). Pain relief triptans, dihydroergotamine is equally effective at at 2 hours was 46% for diclofenac potassium oral treating migraine early or late in attack.[137] solution compared with 41.6% (p < 0.0035) for In addition to demonstrating the efficacy of oral- diclofenac tablets and 24.1% (p < 0.0001) for ly inhaled dihydroergotamine in acute migraine, placebo. Sustained pain-free efficacy at 24 hours safety studies have been conducted in healthy vol- was statistically superior for both formulations of unteers, smokers and patients with asthma. In these diclofenac over placebo and the oral solution over studies, baseline measurements of forced expiratory tablet (p < 0.0001, 0.0005, 0.0077, respectively).
volume in 1 second (FEV1) were compared with The US study compared the oral diclofenac those taken 4 hours post-dose of orally inhaled di- potassium suspension with placebo and demon- hydroergotamine. FEV1 is sensitive to bronchial strated similar efficacy, pain-free at 2 hours, and constriction, and data did not suggest adverse ef- somewhat higher pain relief efficacy at 2 hours fects or significant respiratory adverse events when compared with the European study. In both healthy volunteers, asthmatics and smokers were studies, diclofenac potassium was statistically superior to placebo for relief of associated mi- MAP Pharmaceuticals submitted their data graine symptoms and was well tolerated. The for an NDA, but the FDA required further infor- most common adverse event was nausea (4.6% vs mation, specifically regarding manufacturing. These data have recently been provided in a resubmission.
While NSAIDs are effective at blocking pros- Orally inhaled DHE may be useful in migraine taglandins and are beneficial in migraine, they attacks associated with nausea/vomiting or gastric have rare but potentially serious side effects such atony, rapid-onset migraine, migraine of longer as gastrointestinal bleeding. This is especially duration or frequent recurrence, and possibly in relevant when migraine attacks require frequent patients with a sub-optimal response to triptans. It drug treatment with NSAIDs.
may also have a unique role in outpatient man- The diclofenac potassium oral solution may be agement of medication overuse headache.
valuable as a first-line treatment or as an ad- Adis ª 2012 Springer International Publishing AG. All rights reserved.
Drugs 2012; 72 (17) Table IV. Comparison of emerging compounds' efficacy (active/placebo [%]) 24-hour pain relief Ketorolac (ROX-188)[71] Lasmiditan (COL-144)[72] Feverfew/ginger[74] a Sumatriptan nasal powder[75] Oral diclofenac potassium[76] Sumatriptan needle-free[77] b Tezampanel (LY293558)[ 78] Sumatriptan transdermal patch (NP101)[79] Treated at mild.
Treatment efficacy.
NA = not available.
junctive treatment with a triptan. Its use as a it is compatible with all other acute treatment possible rescue for attacks that fail to respond to triptans has not been studied but, theoretically, itmay have benefits.
8.3 Sublingual Feverfew/Ginger In many ways, acute treatment of migraine has reached an exciting new juncture in its evolution. In LipiGesicM (PuraMed BioScience, Inc., the last 2 decades, considerable research has fo- Schofield, WI, USA) is an OTC homeopathic cused on creating a superior oral triptan. This focus formulation of feverfew and ginger that delivers has in some ways stagnated innovative research of acute treatment for migraine sublingually. A dou- other novel acute interventions. Today, new acute ble-blind, placebo-controlled pilot study on the therapy merges clinical observation and advances in efficacy of lipid-based sublingual feverfew/ginger migraine classification with new drug development in the acute treatment of migraine was completed (see table IV). The opportunity for clinicians in this in 2010.[74] The primary objective was to assess exciting direction of research is to individualize the efficacy of feverfew/ginger for migraine relief acute treatment based on attack needs and not pa- and associated symptoms when administered tient diagnosis. Many novel targets and compounds early during the clinical evolution of migraine.
are in development for acute treatment. In addition, Study results indicate that 32% of subjects ob- several products provide unique delivery methods tained 2-hour pain-free status compared with the for established drugs. Finally, there are clinical 16% who used placebo (p = 0.02). At 2 hours post- observations that can provide insights for future dose, 64% of patients rated their headache in- development of acute therapies. Given the con- tensity as ‘‘no pain'' or ‘‘mild pain'' after taking siderable unmet clinical need of the migraine sublingual feverfew/ginger compared with 39% population for acute medications, there is a lot of for the placebo group (p = 0.003). Further studies promise for investment in acute migraine therapy.
of better design are warranted for this product.
Advantages of this product include lower cost, OTC availability, and it is not likely to producemedication overuse headache. It is an excellent The authors received no external funding or support first-line therapy for very early intervention, as for the preparation of this manuscript. The authors wish to Adis ª 2012 Springer International Publishing AG. All rights reserved.
Drugs 2012; 72 (17) Drug Development for Acute Migraine acknowledge the contributions of Jessica Hall for assistance 15. Belvı´s R, Pagonabarraga J, Kulisevsky J. Individual triptan with writing the manuscript.
selection in migraine attack therapy. Recent Pat CNS Dr Roger Cady currently serves on several advisory Drug Discov 2009 Jan; 4 (1): 70-81 boards: Allergan, Astellas, MAP Pharmaceuticals, Merck & 16. Jonsson P, Hedenrud T, Linde M. Epidemiology of med- Co, Inc., Novartis, Ortho-McNeil Neurologics and Zogenix.
ication overuse headache in the general Swedish pop- He also receives research grants from Allergan, Boston ulation. Cephalalgia 2011 Jul; 31 (9): 1015-22 Scientific, Bristol Myers, GlaxoSmithKline, Merck & Co., 17. Ferrari MD, Roon KI, Lipton RB, et al. Oral triptans (sero- Inc., Opti Nose, Pura Med Bioscience and Zogenix. Dr Cady tonin 5-HT1B/1D agonists) in acute migraine treatment: a has provided consulting services for Allergan, Astellas, meta-analysis of 53 trials. Lancet 2001; 358: 1668-75 GlaxoSmithKline, Merck & Co., Inc. and Ortho-McNeil 18. Hu XH, Ng-Mak D, Cady R. Does early migraine treat- ment shorten time to headache peak and reduce its se- Candace Shade has no conflicts of interest that are directly verity? Headache 2008; 48: 914-20 relevant to the content of this article. Ryan Cady has no 19. Cady RK, Sheftell F, Lipton RB, et al. Effect of early in- conflicts of interest that are directly relevant to the content of tervention with sumatriptan on migraine pain: retro- this article.
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Drugs 2012; 72 (17)

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