Sumatriptan Iontophoretic Transdermal System: History, Study Results, and Use in Clinical Practice


  • Conflict of Interest: The authors are employees of NuPathe, Inc.

Address all correspondence to M. Pierce, NuPathe, Inc., 227 Washington Street, Suite 200, Conshohocken, PA 19428, USA, email:


Nausea is a common symptom of migraine, and current treatment guidelines recommend non-oral formulations for nauseated or vomiting patients. Transdermal delivery of sumatriptan, a 5-hydroxytryptamine1B1D agonist with established efficacy in patients with migraine, represents a novel approach to acute treatment. The sumatriptan iontophoretic transdermal system circumvents the gastrointestinal tract by using low-level electrical energy to transport sumatriptan across the skin. In multiple well-controlled studies, the sumatriptan transdermal system has shown that it provides consistent drug delivery with low interpatient variability, rapid relief of migraine pain and associated symptoms, and an excellent overall safety profile, with a low incidence of triptan-sensation adverse events. Patients and health care professionals who have used the sumatriptan transdermal system give it high ratings for ease of use/application. The sumatriptan transdermal system will allow a wide range of patients, especially those who experience migraine-related nausea or vomiting, to receive the benefits of migraine-specific therapy.

Migraine is a chronic neurologic disorder that affects about 28 million people in the United States[1] with episodic attacks of head pain and some combination of photophobia, phonophobia, nausea, and/or vomiting.[2] Although migraine frequency, intensity, and symptomatology tend to vary over time, evidence suggests that about half (49.5%) of patients have migraine-related nausea (MRN) with at least half of their attacks.[3] In addition to being a common feature of migraine, frequent MRN has been shown to increase migraine symptom burden and medication-related impairment at home, work, and school, as well as in social and leisure activities,[4] and satisfaction with treatment decreases as the frequency of MRN increases.[3]

Sumatriptan, a serotonin receptor agonist for a vascular 5-hydroxytryptamine1B1D receptor subtype,[5] is the most frequently prescribed migraine therapy in the United States.[6] It has established efficacy for acute treatment of migraine with oral, intranasal, subcutaneous, and, outside the United States, rectal routes of administration.[7-11] While these highly effective medications have improved basic pharmacological understanding of migraine, enhanced clinical practice,[12] and transformed the lives of many migraine patients,[13] they are associated with a number of important therapeutic limitations, particularly for patients with MRN. For example, not only can oral agents cause nauseated patients to delay or avoid acute treatment[14, 15] but oral triptans are associated with treatment-emergent nausea in up to 20% of patients.[16] Current treatment guidelines recommend non-oral formulations for nauseated or vomiting patients.[17]

With the intranasal formulation of sumatriptan, the challenges are nausea and/or vomiting (13.5%), low bioavailability (∼17%), and a bad or unusual taste reported by 25% of patients who use the 20-mg dose,[18] while high proportions of patients treated with subcutaneous sumatriptan have injection site reactions (59%), and atypical and unpleasant sensations (42%), such as paresthesias, and pain and pressure sensations.[19] Taken together, these limitations do as much to explain why dissatisfaction with current medications remains among the most common areas of unmet need for migraineurs[20] as they do to underscore the pressing need for novel approaches to medical treatment for acute migraine.

Transdermal Delivery of Sumatriptan: From Concept to Clinical Reality

Transdermal delivery represents a non-oral treatment alternative that, until recently, has not been attempted in migraine.[21] Well-established in other disease states, this route of administration has a range of benefits that includes avoidance of the gastrointestinal (GI) tract and first-pass metabolism, sustained and controlled delivery, and convenient usage.[22] Many medications, including nicotine, estrogen, and scopolamine, are delivered through the dermis by passive diffusion, but the barrier properties of the stratum corneum limit passive delivery to low-molecular weight drugs that are lipophilic and effective at low doses.[23] Active transdermal systems, on the other hand, use an external energy source to help propel active drug across the skin, which facilitates delivery of smaller, lipophilic molecules and allows larger charged and hydrophilic molecules to be transdermally delivered.[21] Among the various active methods of transdermal delivery, iontophoresis – which uses low-level electrical energy to achieve controlled input kinetics and minimum intersubject variability and maintain a steady-state scenario similar to a continuous intravenous infusion[24] – had previously been used to deliver fentanyl, lidocaine, and acyclovir.[23]

Initial studies with sumatriptan established that it could be delivered transdermally via iontophoresis technology.[25, 26] Research also confirmed that passive delivery of therapeutic quantities of sumatriptan was not feasible without iontophoresis.[27, 28] Based on these initial findings, additional investigations were undertaken to identify the optimal materials, size, current density, and ionic strength for active transdermal delivery of sumatriptan using iontophoresis.[28-31]

The sumatriptan iontophoretic transdermal system (Zecuity®, sumatriptan TDS, NuPathe, Inc., Conshohocken, PA, USA), which was developed to address the unmet needs of migraine patients, particularly those with MRN, employs iontophoretic technology to deliver sumatriptan, the most widely used treatment for migraine. Sumatriptan TDS, which circumvents the GI tract by using low-level electrical energy to transport sumatriptan across the skin, provides clinical benefits in migraine without the need for oral, intranasal, or subcutaneous administration[32] by relying on proprietary iontophoretic technology. Migraine patients apply sumatriptan TDS to the upper arm or thigh, and the activated system drives ionized sumatriptan into the bloodstream at controlled rates over 4 hours (Fig. 1 —), resulting in a predictable pharmacology and efficacy.

Figure 1 —.

Mechanism of sumatriptan iontophoretic transdermal system delivery. Transdermal sumatriptan is delivered through a single-use patch using iontophoretic technology, which uses low-level electrical energy to facilitate transdermal drug transport. Upon activation of the patch and application of an electrical current, the positively charged drug moves away from the anode, through the patient's skin, and into systemic circulation.

Scientific Support

The pharmacological and clinical profiles of sumatriptan TDS have been characterized in multiple well-controlled studies.


In a single-center, open-label, cross-over study, Pierce and colleagues compared the pharmacokinetic (PK) profiles of the oral (100 mg), intranasal (20 mg), and subcutaneous (6 mg) formulations of sumatriptan with sumatriptan TDS in 25 healthy volunteers aged 21-57 years.[32] The area under the drug concentration-time curve (AUC) for sumatriptan TDS was similar to the subcutaneous formulation, but it had a lower maximum observed drug concentration (Cmax), which decreased the relative risk of triptan-like sensations believed to be attributable to peak plasma concentrations. Moreover, because the transdermal and subcutaneous formulations had lower coefficients of variation than the oral and intranasal formulations (Table 1), they achieved and sustained more predictable target drug levels.[32]

Table 1. Pharmacokinetics of Oral, Subcutaneous, and Intranasal Sumatriptan Compared With the Sumatriptan Iontophoretic Transdermal System[32]
TreatmentAUC0-inf Hour ng/mLCmax ng/mLTmax HourT1/2 HourAUC0-inf CV (%)Cmax CV (%)
  1. AUC0-inf = area under the drug concentration-time curve up to the last measurable concentration extrapolated to infinity; CV = coefficient of variation; T1/2 = terminal elimination half-life; Tmax = time of maximum drug concentration.
Oral, 100 mg tablet (n = 23)
Subcutaneous, 6 mg (n = 23)113.682.
Intranasal, 20 mg (n = 23)50.312.
Sumatriptan Iontophoretic Transdermal System (n = 17)113.524.81.72.924.726.4

Sumatriptan was detected in plasma within 15 minutes after activation of sumatriptan TDS, it reached plasma concentrations of 10 ng/mL by approximately 30 minutes after patch activation, and it maintained concentrations of approximately 20 ng/mL until 4 hours post-activation. Over the 4-hour study period, the mean drug delivery for sumatriptan TDS was approximately 6.1 mg. When drug delivery was stopped at 4 hours post-activation, steady declines in serum concentration for sumatriptan matched the gradual reductions in plasma concentrations following administration of the oral and intranasal formulations.[32]

Other investigations have extended these early findings. For example, in a phase I, open-label, single-dose, 4-way cross-over study (N = 18) comparing the PK of sumatriptan tablets (50 mg) with sumatriptan TDS during a migraine attack and during a non-migraine period (eg, no headache or aura and last headache resolved for at least 72 hours, with no premonitory symptoms for 24 hours) to determine if transdermal delivery of sumatriptan is susceptible to a “migraine effect” – GI disturbances that delay or reduce the absorption of oral formulations during an attack – Wilks et al showed that migraine attacks have a much greater influence on the PK profile of oral formulations than on transdermal sumatriptan.[33]

Among patients who had a migraine effect (n = 7), patients treated with oral sumatriptan experienced large decreases in Cmax, AUC0-4, AUC0-12, and AUC0-inf during an attack compared with a non-migraine period. The changes for patients treated with transdermal sumatriptan were relatively minor, and there was a small increase in AUC0-4. Because the migraine effect on the oral formulation was much greater than the transdermal formulation, Wilks et al concluded that sumatriptan TDS provides a more consistent and predictable means of delivering sumatriptan than oral formulations.[33]

In a randomized, open-label, parallel-group, phase I study conducted to identify clinically significant differences in the PK of sumatriptan TDS in elderly vs young adults, elderly subjects treated with sumatriptan TDS had slightly higher, but clinically insignificant, sumatriptan plasma levels (Cmax 104%; AUC0-inf 115%) than in young adults.[34]

The pharmacological profile for sumatriptan TDS was expanded with findings from a phase I, single-center, open-label, randomized, single-dose study comparing the PK of sumatriptan TDS with and without controlled heat.[35] In this study, each of the 12 subjects used sumatriptan TDS twice: once with a 40°C heat wrap placed over the top of the patch for the 4-hour application wear time and once without the heat wrap. The median times to therapeutic sumatriptan levels (10 ng/mL) were 31.8 minutes with heat and 32.7 minutes without heat. With PK parameters well within the range for bioequivalence, these results showed that the addition of heat does not alter drug exposure, a result consistent with the known properties of iontophoresis and distinct from passive transdermal dermal systems, in which heat can cause potentially dangerous increases in exposure.[35]

Efficacy and Safety

The efficacy of sumatriptan TDS was evaluated in a randomized, parallel-group, double-blind, placebo-controlled, phase III trial in 530 generally healthy men and women aged 18-66 years of age who had been diagnosed before age 50 years with migraine with or without aura according to criteria set forth in the International Classification of Headache Disorders.[36] Results showed that a significantly higher proportion of patients who received sumatriptan TDS were headache pain-free 2 hours after patch activation compared with placebo (18% vs 9%, respectively; P = .009); the significant difference from placebo continued for all subsequent time points up to and including 12 hours after patch activation (P ≤ .0357).[36] Significantly more sumatriptan TDS patients than placebo patients had headache pain relief at 2 hours post-dose (52.9% vs 28.6%, respectively; P < .0001), with significant differences vs placebo at all time points from 1 hour through 12 hours after patch activation (P ≤ .0135, Fig. 2 —A).[36]

Figure 2 —.

Percentages of patients reporting headache pain relief and freedom from nausea with the sumatriptan iontophoretic transdermal system and placebo.[36] *P ≤ .05 vs placebo; **P ≤ .001 vs placebo; **P ≤ .01 vs placebo.

As shown in Figure 2 —B, within 1 hour after patch activation, a significantly higher percentage of patients in the sumatriptan TDS group were nausea-free compared with the placebo group (71% vs 58%, respectively; P = .0251).[36] This significant difference was maintained for all subsequent time points up to and including 12 hours after patch activation (P ≤ .01). Compared with placebo-treated patients, a significantly greater proportion of patients treated with sumatriptan TDS were photophobia- and phonophobia-free by 2 hours after patch activation (P ≤ .0028 for all comparisons), significant differences that were maintained for all subsequent time points up to and including 12 hours (P ≤ .0095).[36]

No treatment-emergent serious AEs were attributed to transdermal sumatriptan. Treatment-emergent AEs were reported by 50% of patients who received transdermal sumatriptan and 44% of patients who received placebo. As expected, most AEs with transdermal sumatriptan were application site reactions that resolved within 2 days (Table 2).[36]

Table 2. Sumatriptan iontophoretic transdermal system vs placebo: most common adverse events (N = 530)[36]
Adverse event, n (%)Sumatriptan TDS (n = 234)Placebo (n = 235)
Application-site pain54 (23)34 (15)
Application-site paresthesia28 (12)44 (19)
Application-site pruritus18 (8)16 (7)
Application-site reaction16 (7)13 (6)

Triptan sensation AEs were experienced by 1.7% of the subjects both for atypical sensations, and pain and pressure sensations vs 0% and 0.4% for placebo, respectively.[36]

A post-hoc analysis of the 215 patients who had nausea at baseline confirmed and extended these efficacy findings.[37] At 1 and 2 hours post-activation, more patients with nausea achieved pain relief when treated with sumatriptan TDS than with placebo (22% vs 13% at 1 hour and 54% vs 22% at 2 hours). Similarly, higher proportions were nausea-free at 1 and 2 hours after patch activation when treated with sumatriptan TDS compared with placebo (1 hour, 44% vs 32%, respectively; 2 hours, 68% vs 43%, respectively), as well as photophobia-free (1 hour, 31% vs 26%, respectively; 2 hours, 55% vs 34%, respectively) and phonophobia-free (1 hour, 42% vs 37%, respectively; 2 hours, 64% vs 37%, respectively).[37] In this study, sumatriptan TDS provided rapid relief from migraine pain and associated symptoms, including nausea, suggesting that it may be an attractive alternative to oral formulations among migraineurs who delay or avoid taking oral migraine medications because of nausea.[37]

To assess the long-term tolerability and efficacy of sumatriptan TDS, 183 migraineurs who had participated in the randomized, double-blind, phase III study with sumatriptan TDS used sumatriptan TDS for acute treatment of migraine for up to 12 months in an open-label trial.[38] The most common adverse events involved the patch application site (45% of patients). The only non-application site adverse events reported in >2% of patients were nausea (n = 6, 3.3%), upper respiratory tract infection (n = 6, 3.3%), and nasopharyngitis (n = 4, 2.2%). The incidence of triptan-associated adverse events was 1.6%. Across all visits for investigator assessments, the majority of patients (ranging from 74.7% at Month 1 to 92.2% at Month 9) were scored as having no erythema at patch application sites. For patient assessments, the percentage of patch placement sites scored as having no or minimal redness was 38.2% at the time of patch removal and 65.4% 24 hours after patch activation. Two hours after patch activation across all patch treatments over the 12-month study, 23.8% of initial acute migraine episodes were scored as being free from headache pain, 58.2% as having headache pain relief, 78.9% as nausea free, 60.1% as phonophobia free, 53.4% as photophobia free, and 20.7% as migraine free. There was no evidence of waning tolerability or efficacy over the 12-month study period. The authors concluded that sumatriptan TDS demonstrated tolerability and efficacy with successive uses over 12 months in this clinical trial.[38]

In a separate 12-month, repeat-use, open-label study evaluating the safety of sumatriptan TDS (N = 479), 95.5% of application sites showed no, minimal, or moderate erythema at patch removal.[39] Median time to resolution of erythema was 1 day. Treatment-emergent AEs, mostly mild or moderate application site reactions, were experienced by 56.8% of subjects, but the incidence of triptan sensations (0.6%), and possible and probable allergic contact dermatitis (7.7%) was low. Discontinuation because of AEs occurred in 15.4% of subjects. Investigators concluded that sumatriptan TDS was safe and well tolerated, and that AEs were similar to those reported in previous studies.[39]

Use in Clinical Practice

Evidence suggests that the vast majority of “real world” patients are likely to use sumatriptan TDS correctly. A single-center, open-label study (N = 64) validating its ease of assembly, application, and activation among migraineurs trained to use sumatriptan TDS, migraineurs not trained to use sumatriptan TDS, and health care professionals not trained to use sumatriptan TDS found that 100% of subjects assembled, applied, and activated the device successfully, with subjects across all 3 groups rating sumatriptan TDS very high (6.8 out of 7.0) for ease of use/application.[40]

In clinical practice, patient education is a key component of migraine therapy. Once the decision to prescribe sumatriptan TDS has been made, patients should be directed to the Patient Instructions for Use (Fig. 3 —), which are provided with prescribing information and may be downloaded from the product's website ( An in-office demonstration may help to set expectations and avoid uncertainty when the medication is needed to treat a migraine attack. Only patients who are able to understand and follow the instructions should use sumatriptan TDS, and patients should be encouraged to ask questions during – or after – their office visit.

Figure 3 —.

Sumatriptan iontophoretic transdermal system: Patient Instructions for Use. The Patient Instructions for Use for sumatriptan iontophoretic transdermal system are appended to the prescribing information. Patients with access to a computer and an Internet connection may download them from the product's website.

Although sumatriptan TDS clearly answers an unmet clinical need in the treatment of acute migraine, this therapy is not without limitations. For example, because headache is the most common somatic complaint in children and adolescents,[41] the lack of a pediatric indication prevents access for a sizeable subgroup of patients who might benefit from treatment with sumatriptan TDS. In addition, because immersion in water may interfere with iontophoresis, it is recommended that patients avoid bathing or swimming during the 4 hours of patch operation. Patch placement may also be an issue, as it is unknown to what extent, if at all, the presence of scars, lesions, tattoos, and other dermal irregularities may alter drug delivery or tolerability. Finally, although the incidence of allergic contact dermatitis in the 12-month assessment was relatively low and within the accepted range for currently marketed transdermal systems,[39] a small proportion of patients will be affected.


Multiple clinical trials indicate that sumatriptan TDS provides rapid relief of migraine pain and MRN, as well as the constellation of symptoms associated with migraine, with consistent drug delivery and low interpatient variability and efficacy demonstrated over 12 months. Sumatriptan TDS also has an excellent safety profile, with a low incidence of the triptan-sensation AEs commonly associated with triptans. Sumatriptan TDS will allow patients who experience MRN and vomiting to receive the benefits of migraine-specific therapy.