Development of anti-migraine drugs delivered via transdermal iontophoresis may provide relief to chronic migraine sufferers.
Oral delivery of various forms of medications has significantly helped treat acute migraines. However, it’s not effective for many sufferers. And, for approximately three in 10 patients, migraine-associated nausea and vomiting interfere with their ability to take oral medication.1 In addition, nearly all migraine patients experience gastric stasis, which adversely impacts drug absorption, resulting in delayed, inconsistent, or incomplete relief.2
Although non-oral delivery methods—including nasal sprays and injections—are available, patients may elect not to use them due to discomfort, inconvenience, and other side effects.
An optimal treatment for acute migraine would not require oral administration or gastric absorption, and would produce rapid, consistent, and tolerable relief.
Current triptan delivery methods
Triptans are the mainstay of migraine therapy. Fifteen years after their inception, they are still the drug of choice for acute migraines.3 They are an abortive medication, meaning they stop the attack and associated symptoms, rather than preventing the onset of an attack.
The triptan class comprises seven marketed drugs.4 Zolmitriptan, naratriptan, and rizatriptan are considered to be relatively new migraine treatments, only entering the marketplace in 1997.5
Sumatriptan, the first drug created to specifically treat migraines and its associated symptoms,6 was first discovered in 1984.7 It is an agonist that stimulates the 5-HT1B receptor on cranial vascular smooth muscle to produce vasoconstriction, counteracting the vasodilation of these vessels that is associated with headache. Sumatriptan also stimulates the 5-HT1D receptors in the cranial vasculature, inhibiting the release of peptides which can cause pain and inflammation.8
There are currently four main delivery methods for sumatriptan on the market, available in varying strengths and formulations. These include oral tablets, orally-disintegrating tablets, nasal sprays, and injection.9
The most common route of administration is oral, including ingestible and orally- disintegrating tablets, and has been available in tablet form since 1995. Studies have demonstrated that, two hours after receiving the medication, 65 percent of patients reported headache relief.10
However, patients experiencing gastric stasis or migraine-associated nausea or vomiting may encounter unpredictable absorption in the GI tract as well as difficulty ingesting oral medication, thereby making treatment difficult.
A survey of 500 self-reported migraine sufferers found that 30.5 percent of patients who experienced nausea and 42.2 percent who experienced vomiting reported that the symptoms interfered with their ability to take oral medication.11
The study also found that symptoms of nausea and vomiting were among the primary reasons for patients to discontinue a specific migraine medication, concluding that alternative administration methods can be of clinical value.12
Alternative treatments to oral administrations are available today, and include nasal sprays and an injection. Nasal sprays were first approved for use in 1996,13 and are designed for delivery as a single spray in one nostril. The drug solute penetrates the nasal mucus layer in the nostril. Then, cilia in the nostril move the mucus layer through the body—down the throat and to the GI tract.14
Some patients prefer the ease of administration. However, taste disturbances are common—patients described the drug as tasting bad, bitter, unpleasant, or unusual.15 In addition, local irritation has been reported in some patients.
 click to enlarge This figure illustrates the principle behind iontophoretic drug delivery of sumatriptan. (Source: NuPathe) |
In addition, intranasal delivery does not entirely avoid the GI-tract. Studies found that the majority of the drug is still absorbed in the stomach; only a small portion of the total is absorbed immediately after administration.16
Lastly is the self-administered subcutaneous injection, the original method used for the delivery of sumatriptan.17 When sumatriptan is administered, the needle deposits the drug into the layer of tissue between skin and muscle.18
Because the drug is administered parentally, gastric absorption is avoided, and pain relief is rapid. Approximately 80 percent of patients reported relief two hours after injection. In addition, a sumatriptan injection also alleviated other migraine symptoms, including nausea.19 However, patients develop very high blood levels very quickly—which can result in adverse effects.
The injectable drug delivery method, as well other migraine delivery methods containing sumatriptan have been found to produce “triptan sensations” in patients. These side-effects may include warm/hot sensations, tightness, tingling, flushing, or heaviness and pressure.20
Iontophoretic delivery
Research into new delivery mechanisms and increased knowledge of migraine pathology are leading researchers to develop better ways to maximize the efficacy and convenience of migraine drug therapy.
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Iontophoresis consists of applying a low-intensity electrical current to the skin, which then gently carries the drug through the skin. This technology employs the use of two electrodes, with one immersed in a solution containing the drug compound, and the other immersed in a solution containing salt.
Application of a low potential current across the electrodes results in the movement of the ionized drug away from the electrode, carrying the drug through the skin layers and into the patient’s bloodstream.
Iontophoretic drug delivery is gaining popularity. Recent developments of several FDA-approved and marketed treatments include lidocaine and epinephrine to anesthetize pediatric patients for intravenous insertion, and fentanyl to ease cancer pain. Dexamethasone, an anti-inflammatory drug, is routinely used in physical therapy settings.21
Delivery of sumatriptan to treat acute migraines is a new application for iontophoreses. Phase 1 studies were completed on an iontophoretic patch, SmartRelief Transdermal Patch, from NuPathe. Phase 3 studies are scheduled for completion by the end of 2009.
Iontophoretic drug delivery enables sumatriptan to enter the body quickly and predictably.22 A small device embedded in the patch controls the amount and rate of drug delivery. The device is preprogrammed to provide a specific dose; the patient applies the patch and presses a button to initiate treatment.
Because the drug is administered transdermally, patients experiencing migraine-associated nausea and vomiting avoid the difficulties in taking oral medication, and will not need to worry about receiving the correct dosage with each migraine attack. Moreover, transdermal patches may be preferable to alternative delivery methods, such as nasal and injection, due to the side effects associated with those products.23
Unlike injectable sumatriptan, iontophoretic sumatriptan patches do not expose patients to high blood concentrations, reducing the likelihood for chest discomfort and other adverse effects. In addition, transdermal delivery avoids the gastrointestinal (GI) tract, and thereby might provide more consistent delivery of the drug.24
While transdermal delivery using iontophoresis might not produce some of the side- effects seen with other triptan delivery methods or exacerbate other migraine-associated GI symptoms, it can result in local irritation for some patients. This might include itching, erythema, or hyperpigmentation. For these patients, the patch might not be the most appropriate choice.25
Iontophoresis has been described as a convenient, safe, noninvasive route for the administration of many compounds. As a result, the industry has seen a surge in the development of iontophoresis as a drug delivery device in novel treatments.26
About the Author
Mark W. Pierce, MD, PhD, is NuPathe’s Chief Scientific Officer. He graduated from Northwestern University Medical School, trained at The Peter Bent Brigham Hospital and Massachusetts General Hospital, and has served as Pfizer’s Senior Vice President of Clinical Research..
This article was published in Drug Discovery & Development magazine: Vol. 11, No. 3, March, 2008, pp. 36-39.
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Filed Under: Drug Discovery
