What is the best drug-delivery approach for the acute treatment of migraine?

Keywords::

• acute treatment
• drug delivery
• migraine
• neurostimulation
• stratified care

The best approach to the acute treatment of migraine is stratified care, defined as matching treatment to patient or migraine attack characteristics. A plethora of new formulations and classes of acute migraine medications have been released or are in development. Careful diagnosis, followed by consideration of attack impact, speed of onset, presence or absence of nausea, and vomiting or allodynia, all help in proper selection of medication type and delivery system. Delivery systems currently available or under study include conventional oral tablets, rapid-release tablet systems, dissolvable liquid preparations and nasal, inhalational, transdermal, injectable and rectal drug conveyance products. Stimulators are also being developed for acute migraine relief for patients with contraindications to, failure with or intolerance to medications.

What is the best drug-delivery approach for the acute treatment of migraine? The question is far from a new one, being raised every time innovations occur in the therapy of an illness. In the burgeoning field of pain research, the interested reader need look no further than the study of cancer pain management, a field of study that predates the latest resurgence of interest in migraine treatment by a decade or two. In the last 30 years, the clinician has been presented with an extensive menu of oral and parenteral drugs, assorted drug-delivery systems and invasive stimulation devices. Medicine can offer the cancer pain patient oral, sublingual, transdermal, intravenous (intermittent, continuous or with patient-controlled access), intramuscular, subcutaneous (intermittent, continuous or with patient-controlled access), intrathecal, epidural (intermittent, continuous or with patient-controlled access), and intracerebroventricular opioid analgesics and nonopioid analgesics. In addition, there are now newer neuromodulation techniques involving all levels of the neuraxis, as well as older, destructive procedures, now used less frequently.

In treating pain, success or failure depends on a variety of factors. These include, first and foremost, making the correct diagnosis, then treating the pain early and aggressively, while taking into account the medication’s pharmacokinetics and pharmacodynamics, the mode of drug delivery, the patient’s personal preference and the particular disease state.

Headache patients have been presented with an ever-expanding, enticing smorgasbord of abortive therapies for migraine headaches, in addition to those available for the last 20 years. Current traditional treatment options can be grouped into triptan, ergot, opioid, antiemetic and NSAID classes of drugs, and are variously available by nasal spray, injection (intravenous, subcutaneous or intramuscular), oral or rectal routes.

The new menu will include a series of novel or innovative approaches to migraine treatment. Some of these new approaches are established medications in new or novel formulations and devices developed to provide improved delivery, efficacy or tolerability. The other options for patients will be new classes of acute medications in conventional forms, such as oral tablets.

Among the novel nonoral delivery systems already available are: a needle-free injection of sumatriptan, available in the USA as trade name SUMAVEL^® (Zogenix); an epipen-type needle injection of sumatriptan, available in the USA as trade name ALSUMA™ (Pfizer Inc.); rapid-dissolution oral tablets of sumatriptan, available worldwide as IMITREX^® RT (GlaxoSmithKline) or IMIGRAN^® FDT, RRT, RADIS or RECOVERY (GlaxoSmithKline); soluble oral diclofenac, available in the USA, the EU and New Zealand under trade names CAMBIA™ (Nautilus Neurosciences) and Voltfast^® (Novartis); and intranasal ketorolac, available in the USA as trade name SPRIX^® (Regency Therapeutics). Among the new delivery systems currently before the US FDA at the time of writing are an oral pulmonary inhalational device for dihydroergotamine, trade name LEVADEX^® (MAP Pharmaceuticals, Inc.); and an iontophoretic transdermal delivery of sumatriptan, trade name Zelrix™ (Nupathe). At varying stages of development are an intranasal dry powder of sumatriptan with a new delivery device, developed by OptiNose; a lingual spray of sumatriptan; liposomal transdermal delivery systems for NSAIDs, such as diclofenac, and triptans such as rizatriptan; inhalational neuroleptics; and intranasal carbon dioxide. There are also new stimulation devices, such as transcranial magnetic stimulation or direct electrical stimulation of the peripheral or central nervous system. Except for soluble diclofenac, which proved superior to conventional oral tablets of diclofenac [1], none of these newer formulations has been studied against traditional, approved acute migraine therapy or against each other, since the FDA requires only placebo-controlled, double-blind, randomized studies in the approval process. Studies of one novel formulation against another would require a double-dummy design, would be expensive and might not yield illumination.

Newly developed classes of acute migraine medications in conventional oral tablet formulations include the calcitonin gene-related peptide antagonists. Many of the specific calcitonin gene-related peptide receptor antagonist programs have been discontinued (e.g., olcegepant, telcagepant and MK-3207), but at least one continues in clinical development at the time of writing (BMS-927711). Another class is the serotonin-1_F receptor agonists, including lasmitidan, in development as of late 2011. There are also novel combination serotonin–nitric oxide medications being studied, such as NXN-188.

Where does one start when confronted with a patient complaining of an acute migraine attack? The goal is the right treatment, first time.

As in all pain management efforts, begin with a face-to-face encounter with the patient. An accurate history is invaluable in making the correct diagnosis; it enables the diagnostician to cull out migraine mimics and lookalikes that portend a potentially ominous, alternative diagnosis or a contraindication to certain acute medications. In addition, an accurate history gauges accompanying symptoms that might predict success or failure with a particular therapy.

Stratified care is a term defined as matching patient and disease characteristics to treatment. In the treatment of acute migraine, moderate-to-severe disability or impact from attacks correlates to a need for migraine-specific, as opposed to merely analgesic or anti-emetic, treatment [2]. Other ways to stratify care include consideration of time to peak in an attack, presence of nausea or vomiting, and duration of attacks. Thus, a very quick attack onset, as occurs in adolescents or crash migraine, would lead to recommendation for an injectable, inhalational or nasal formulation.

There is now a body of data documenting that the nausea accompanying migraine is indicative of gastroparesis and inadequate absorption of orally administered drugs by the GI tract [3]. In fact, migraineurs seem to exhibit varied manifestations of autonomic instability, and prominent among these manifestations may be this gastroparesis, which diminishes the effective use of many swallowed acute agents. Injected, inhaled, nasal, transdermal and rectal preparations might be preferred when the oral route is compromised, either by nausea or vomiting. Another approach in the setting of migraine-induced gastroparesis is the use of rapid-dissolution formulations not relying on peristalsis, such as the liquid solubilized diclofenac or rapid-release oral sumatriptan [4].

Allodynia, the sine qua non of central sensitization, is likewise seen as an indicator of triptan resistance, and might direct the clinician to utilize a nontriptan medication, such as inhaled dihydroergotamine, NSAIDs, antiemetics (neuroleptic or antihistamine) or a combination of a triptan with an NSAID or antinauseant. Allodynia generally occurs later in a migraine attack, again suggesting that a non-oral delivery option will probably be more efficacious at that stage [5].

Acute stimulators may be an attractive option in the future for patients with contraindications or aversions to acute medications. Transcranial magnetic stimulation appears to work for migraine with aura, although so far it has not worked in migraine without aura [6]. There is also interest in the development of a sphenopalatine ganglion stimulator for treating acute migraine [7].

Finally, there are variables in patient care that defy any expertise in pharmacokinetics, individual drug properties or neuromodulation, and these cannot be overlooked. If deliberately ignored, they will invariably arise to haunt the well-meaning clinician. These include drug cost, insurance coverage, pharmacy availability, patient concerns or phobias, and patient reliability in self-administration.

In spite of all the above advances, analgesia frequently eludes the best made intentions. Consider the accuracy of diagnosis first. Then, stratify the therapy to the characteristics of the attack and of the patient, taking into account patient preference [8]. Rapid attack onset, nausea and vomiting all favor a non-oral treatment. The presence of allodynia furthers the recommendation of nontriptans or combinations of triptans and other medication classes. Failure of, or contraindication to, acute medications may in the future lead to the use of neurostimulator devices. In the end, the most effective approach will always be the treatment tailored to best suit the needs of an individual patient.

Financial & competing interests disclosure

SJ Tepper is a consultant, or on the scientific advisory board or speaker’s bureau, for: Allergan, GSK, Helsinn, MAP, Merck, Nautilus, NuPathe and Zogenix. He has received research grants from ATI, Allergan, BristolMyerSquibb, GSK, MAP, Merck, NuPathe and Zogenix (no personal compensation). MJ Stillman is on the speaker’s bureaus for GlaxoSmithKline, Pfizer and Merck pharmaceutical companies. He has received consulting fees from Capnea Inc. MJ Stillman and members of his center, the Cleveland Clinic Headache Center, received financial support for research activities from the following pharmaceutical companies: ATI, Allergan, Bristol-Myers Squibb, GSK, MAP, Merck, NuPathe and Zogenix (no personal compensation). The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

No writing assistance was utilized in the production of this manuscript.