Nasal Delivery of Acute Medications for Migraine: The Upper Versus Lower Nasal Space

Abstract

The acute treatment of migraine requires effective drugs that are well tolerated and provide rapid and consistent pain relief. Oral tablets are the most commonly used acute treatment for migraine; however, their effectiveness is limited by the rate of gastrointestinal (GI) tract absorption and first-pass hepatic metabolism, and they may not be ideal for patients experiencing GI motility issues. Nasal delivery is an attractive alternative route as it may circumvent GI tract absorption, avoid first-pass metabolism in the liver, and potentially reduce the frequency of GI adverse events. The large surface area and high vascularity within the nose may permit rapid absorption of therapeutics into the systemic circulation, allowing for rapid onset of action. However, the site of drug deposition (upper versus lower nasal cavity) may influence drug pharmacokinetics. Most approved nasal migraine therapies target the lower nasal space where the epithelium is less permeable, and they may be quickly cleared away due to increased ciliary function or dripping from the nose or swallowing, resulting in variable absorption and limited bioavailability. Together with its abundant vascularization, relative mucosal thickness stability, and low clearance rates, the upper nasal space harnesses the benefits of nasal delivery to potentially maximize drug efficacy.

The Pharmacokinetics of Drug Delivery to the Upper Nasal Space: A Review of INP105 Development

“…8 Nasal drug delivery offers many benefits for these applications, including its noninvasiveness, absence of potential needlestick injury, rapid delivery of drug without requiring sterile technique, and a nonoral option that carries a lower risk for systemic side effects. 7,8,11,20,21 Nasal delivery of drugs can be especially advantageous in many challenging clinical scenarios. For example, these drugs can be self-administered or given by a caregiver in multiple settings, including less controlled situations, such as emergency departments, acute crisis, or urgent psychiatric situations where it may be difficult or unsafe to administer an injection.…”

“…7,11,22 Importantly, nasal delivery is typically associated with a low risk for GI side effects and these medications do not need to be taken separate from, or with, meals (as is the case with some oral medications). 16,20,23 Nasal delivery results in absorption across the nasal mucosa into the bloodstream and avoids first-pass hepatic metabolism, which can result in higher bioavailability than most oral methods, facilitating rapid absorption and onset of action. 8,21 An important feature of nasal drug delivery is the site of drug deposition within the nose, which can differ in epithelia type, mucociliary function, and vascular supply, and can affect drug pharmacokinetics.…”

“…8,21 An important feature of nasal drug delivery is the site of drug deposition within the nose, which can differ in epithelia type, mucociliary function, and vascular supply, and can affect drug pharmacokinetics. 8,20,[23][24][25][26][27] The nose can be divided into the upper and lower nasal space. The lower nasal space includes structures such as the vestibule, which is lined with a nonciliated squamous epithelium that is not well suited for effective drug absorption and includes a narrow, constricted region called the nasal valve.…”

“…The nasal turbinates within the lower nasal space are covered by ciliated pseudostratified cuboidal-columnar respiratory epithelium and are coated with mucus that along with the motile cilia, can lead to rapid drug clearance. 8,16,20,27,28 The upper nasal space is partially lined with olfactory epithelium, which may be more permeable than the respiratory epithelium in the lower nasal space, and nonmotile cilia that greatly reduce mucociliary clearance. These allow drugs to enter the bloodstream more effectively via the rich vascular supply to this part of the nose.…”

“…These allow drugs to enter the bloodstream more effectively via the rich vascular supply to this part of the nose. 20,23,24,27,[29][30][31] Although these attributes make the upper nasal space an attractive target for drug delivery, reaching the upper nasal space is challenging because of its complex architecture, 23 which includes navigating the narrow nasal valve.…”