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Nasal administration
Nasal administration
Nasal administration
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A medical professional applies nose drops.

Nasal administration, popularly known as snorting, is a route of administration in which drugs are insufflated through the nose. It can be a form of either topical administration or systemic administration, as the drugs thus locally delivered can go on to have either purely local or systemic effects. Nasal sprays are locally acting drugs, such as decongestants for cold and allergy treatment, whose systemic effects are usually minimal. Examples of systemically active drugs available as nasal sprays are migraine drugs, rescue medications for overdose and seizure emergencies, hormone treatments, nicotine nasal spray, and nasal vaccines such as live attenuated influenza vaccine.

Risks

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Nasal septum perforation

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"Cocaine nose" refers to nasal septum perforation from cocaine use (pictured), or to cocaine-induced midline destructive lesions (CIMDL), which may develop as the damage progresses.
Main article: Nasal septum perforation

A nasal septum perforation is a medical condition in which the nasal septum, the bony/cartilaginous wall dividing the nasal cavities, develops a hole or fissure.[1] Nasal administration may cause nasal septum perforation by gradually injuring and ulcerating the epithelium, causing cartilage exposure and necrosis.[2]

Risk factors for shared drug paraphernalia

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Lines of cocaine prepared for snorting. Contaminated currency such as banknotes might serve as a fomite of diseases like hepatitis C[3]

Sharing snorting equipment (nasal spray bottles, straws, banknotes, bullets, etc.) has been linked to the transmission of hepatitis C. In one study, the University of Tennessee Medical Center researchers warned that other blood-borne diseases such as HIV could be transmitted as well.[4]

Advantages

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The nasal cavity is covered by a thin mucosa which is well vascularised.[5] Therefore, a drug molecule can be transferred quickly across the single epithelial cell layer directly to the systemic blood circulation without first-pass hepatic and intestinal metabolism. The effect is often reached within 5 minutes for smaller drug molecules.[6] Nasal administration can therefore be used as an alternative to oral administration, by crushing or grinding tablets or capsules and snorting or sniffing the resulting powder, providing a rapid onset of effects if a fast effect is desired or if the drug is extensively degraded in the gut or liver.[7]

Large-molecule drugs can also be delivered directly to the brain by the intranasal route, the only practical means of doing so, following the olfactory and trigeminal nerves (see section below), for widespread central distribution throughout the central nervous system with little exposure to the blood.[8][9][10][11] This delivery method to the brain was functionally demonstrated in humans in 2006, using insulin, a large peptide hormone that acts as a nerve growth factor in the brain.[12]

Limitations

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Nasal administration is primarily suitable for potent drugs since only a limited volume can be sprayed into the nasal cavity. Drugs for continuous and frequent administration may be less suitable because of the risk of harmful long-term effects on the nasal epithelium.[7] Nasal administration has also been associated with a high variability in the amount of drug absorbed. Upper airway infections may increase the variability as may the extent of sensory irritation of the nasal mucosa, differences in the amount of liquid spray that is swallowed and not kept in the nasal cavity and differences in the spray actuation process.[13] However, the variability in the amount absorbed after nasal administration should be comparable to that after oral administration.[14][15]

Nasal drugs

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The area of intranasal medication delivery provides a huge opportunity for research – both for specifically developed pharmaceutical drugs designed for intranasal treatment, as well as for investigating off-label uses of commonly available generic medications. Steroids, and a large number of inhalational anaesthetic agents are being used commonly. The recent developments in intranasal drug delivery systems are prodigious. Peptide drugs (hormone treatments) are also available as nasal sprays, in this case to avoid drug degradation after oral administration. The peptide analogue desmopressin is, for example, available for both nasal and oral administration, for the treatment of diabetes insipidus. The bioavailability of the commercial tablet is 0.1% while that of the nasal spray is 3-5% according to the SPC (Summary of Product Characteristics).[16] Intranasal calcitonin, calcitonin-salmon, is used to treat hypercalcaemia arising out of malignancy, Paget's disease of bone, post menopausal and steroid induced osteoporosis, phantom limb pain and other metabolic bone abnormalities, available as Rockbone, Fortical and Miacalcin Nasal Spray. GnRH analogues like nafarelin and busurelin are used for the treatment of anovulatory infertility, hypogonadotropic hypogonadism, delayed puberty and cryptorchidism. Other potential drug candidates for nasal administration include anaesthetics, antihistamines (Azelastine), antiemetics (particularly metoclopramide and ondansetron) and sedatives that all benefit from a fast onset of effect.[17] Intranasal midazolam is found to be highly effective in acute episodes of seizures in children. Recently, the upper part of the nasal cavity, as high as the cribriform plate, has been proposed for drug delivery to the brain. This "transcribrial route", published first in 2014, was suggested by the author for drugs to be given for Primary Meningoencephalitis.[18]

Medicines

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Oxytocin

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Oxytocin (brand name Syntocinon) nasal spray is used to increase duration and strength of contractions during labour. Intranasal oxytocin is also being actively investigated for many psychiatric conditions including alcohol withdrawal, anorexia nervosa, PTSD, autism, anxiety disorders, pain sensation and schizophrenia.

Recreational drugs/entheogens

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List of substances that have higher bioavailability when administered intranasally compared to oral administration.

Cocaine

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Insufflation of cocaine leads to the longest duration of its effects (60–90 minutes).[19] When insufflating cocaine, absorption through the nasal membranes is approximately 30–60%.[20]

Ketamine

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Ketamine prepared in a spiral for "snorting"

Among the less invasive routes for ketamine, the intranasal route has the highest bioavailability (45–50%).[21][22]

Snuff

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Snuff is a type of smokeless tobacco product made from finely ground or pulverized tobacco leaves.[23] It is snorted or "sniffed" (alternatively sometimes written as "snuffed") into the nasal cavity, delivering nicotine and a flavored scent to the user (especially if flavoring has been blended with the tobacco).[23] Traditionally, it is sniffed or inhaled lightly after a pinch of snuff is either placed onto the back surface of the hand, held pinched between thumb and index finger, or held by a specially made "snuffing" device.

Yopo

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Snuff trays and tubes similar to those commonly used for yopo were found in the central Peruvian coast dating back to 1200 BC, suggesting that insufflation of Anadenanthera beans is a more recent method of use.[24] Archaeological evidence of insufflation use within the period 500-1000 AD, in northern Chile, has been reported.[25]

Research

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Olfactory transfer

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There is about 20 mL capacity in the adult human nasal cavity.[26] The major part of the approximately 150 cm2 surface in the human nasal cavity is covered by respiratory epithelium, across which systemic drug absorption can be achieved. The olfactory epithelium is situated in the upper posterior part and covers approximately 10 cm2 of the human nasal cavity. The nerve cells of the olfactory epithelium project into the olfactory bulb of the brain, which provides a direct connection between the brain and the external environment. The transfer of drugs to the brain from the blood circulation is normally hindered by the blood–brain barrier (BBB), which is virtually impermeable to passive diffusion of all but small, lipophilic substances. However, if drug substances can be transferred along the olfactory nerve cells, they can bypass the BBB and enter the brain directly.[10][11]

The olfactory transfer of drugs into the brain is thought to occur by either slow transport inside the olfactory nerve cells to the olfactory bulb or by faster transfer along the perineural space surrounding the olfactory nerve cells into the cerebrospinal fluid surrounding the olfactory bulbs and the brain.[27][28]

Olfactory transfer could theoretically be used to deliver drugs that have a required effect in the central nervous system such as those for Parkinson's or Alzheimer's diseases. Studies have been presented showing that direct transfer of drugs is achievable.[28][29]

References

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Revisions and contributorsEdit on WikipediaRead on Wikipedia

Nasal administration

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from Grokipedia
Nasal administration is a non-invasive method of delivering medications and therapeutic agents directly to the , where they are absorbed through the highly vascularized to produce local effects within the , achieve systemic circulation, or enable targeted delivery to the via specialized pathways. This route leverages the nose's anatomical proximity to the and its large surface area for absorption, making it suitable for a variety of formulations including sprays, drops, powders, and gels. The relevant anatomy includes the , which has a total surface area of approximately 160 cm² in adults, lined with pseudostratified ciliated columnar and goblet cells that produce . The mucosa is richly vascularized, facilitating rapid absorption, while the olfactory in the upper —covering about 5–10% of the surface—contains connected to the brain via the , enabling direct nose-to-brain transport. The nasal valve and turbinates influence airflow and deposition of administered substances. Absorption occurs primarily through paracellular and transcellular mechanisms across the epithelial barrier, with the olfactory and trigeminal facilitating direct nose-to-brain , bypassing the blood-brain barrier.

Introduction and Basics

Definition and Mechanism

Nasal administration refers to the introduction of therapeutic substances, such as drugs or vaccines, directly into the to achieve either local effects within the or systemic effects throughout the body. This route is distinguished from , which involves gastrointestinal absorption and potential degradation, and from intravenous administration, which requires vascular access and carries risks of infection. The primary mechanism of absorption in nasal administration involves passive diffusion of drug molecules across the nasal epithelium, either through paracellular pathways between epithelial cells or transcellularly via lipid membranes for lipophilic compounds. The nasal mucosa's rich vascularization facilitates rapid entry of absorbed substances into the systemic bloodstream, often within minutes, while bypassing the hepatic first-pass metabolism that reduces in oral routes. Historically, nasal administration traces its origins to indigenous practices in the dating back to the , where finely ground snuff was inhaled for its stimulating effects, highlighting the route's potential for rapid absorption and influencing the development of modern pharmacological applications. These early uses demonstrated the nasal cavity's efficiency in delivering substances without invasive procedures, paving the way for contemporary systems. Key factors influencing in nasal administration include the molecular weight of the , with optimal absorption typically occurring for compounds under 1000 Da, as larger molecules face greater barriers to epithelial . also plays a critical role, enabling lipophilic s to cross cell membranes more readily and achieve near-complete absorption rates.

Relevant Anatomy

The is a paired structure within the , extending from the nostrils to the nasopharynx, and is divided into three main s: the nasal vestibule, the respiratory , and the olfactory . The nasal vestibule, located at the anterior entrance, is lined with containing hair follicles, sebaceous glands, and sweat glands, serving as a preliminary filter for inspired air. The respiratory occupies the majority of the cavity and is characterized by pseudostratified ciliated columnar that facilitates air conditioning, humidification, and particle trapping. Projecting from the lateral walls are three turbinates (superior, middle, and inferior conchae), which are scroll-like bony structures covered by mucosa; these increase the internal surface area to approximately 160 cm² in adults, promoting efficient and distribution. The olfactory region is situated in the superior portion of the nasal cavity, primarily on the of the , the superior , and the superior turbinate, comprising about 3-5% of the total nasal surface area. This specialized area houses the , a pseudostratified containing olfactory receptor neurons, supporting cells, and basal cells, which detect odorants and connect directly to the brain via the . The overall features a multilayered structure: the surface includes ciliated cells for propulsion, goblet cells that secrete to trap particulates, and non-ciliated columnar cells; beneath lies the lamina propria submucosa, a layer densely vascularized with capillaries, arterioles, and venules, as well as lymphatic vessels that aid in immune and fluid drainage. Blood supply to the nasal cavity arises primarily from branches of the internal and external carotid arteries: the anterior and posterior ethmoidal arteries from the (internal carotid branch) perfuse the anterior and superior regions, while the sphenopalatine, greater palatine, and posterior lateral nasal arteries from the (external carotid branch) supply the posterior and lateral areas, forming a rich vascular network that supports rapid absorption. Lymphatic drainage from the converges into vessels that empty into the retropharyngeal and upper , facilitating and clearance of antigens. Key barriers to substance absorption in the include the system, where coordinated beating of cilia on epithelial cells propels the layer at a rate of approximately 5-10 mm/min toward the nasopharynx, potentially removing deposited materials within minutes. Additionally, enzymatic degradation occurs via nasal peptidases, such as aminopeptidases and carboxypeptidases present in the mucosa and , which hydrolyze peptides and proteins, limiting their during intranasal administration.

Administration Techniques

Liquid Formulations

formulations represent a primary method for nasal administration, delivering active pharmaceutical ingredients in aqueous or solvent-based solutions directly to the . These formulations are commonly used for both local and systemic effects due to their ease of application and compatibility with the nasal cavity's limited volume capacity. Typical volumes range from 0.05 to 0.2 mL per nostril to avoid overflow and ensure effective contact with the mucosal surface. Nasal drops involve administration through simple droppers or , where the liquid is instilled into the nostril while the patient tilts their head backward. This method offers advantages such as simplicity and low cost, making it suitable for home use, but it suffers from imprecise dosing due to variability in drop size and patient technique, potentially leading to inconsistent . Drops often target posterior deposition in the nasopharynx, covering a larger surface area but resulting in faster compared to other techniques. In contrast, nasal sprays utilize metered-dose pumps or squeeze bottles to generate a fine , providing more uniform distribution across the . These devices ensure consistent particle sizes typically in the range of 10-200 µm, which is crucial for optimal deposition on the mucosal lining influenced by nasal turbinates. For instance, over-the-counter decongestants like nasal sprays employ this approach to deliver precise doses, often 50-100 µL per actuation, promoting anterior deposition for localized effects. To maintain stability and safety, liquid nasal formulations incorporate preservatives such as at concentrations up to 0.1% w/w to prevent microbial growth during multi-dose use. Additionally, is adjusted to a range of 4-6.5 to ensure compatibility with the , minimizing and supporting effective absorption. Deposition patterns vary by device: sprays favor anterior delivery near the nostrils for slower clearance, while drops enable posterior targeting deeper in the cavity. Absorption enhancers, such as surfactants like polysorbates, are sometimes included in liquid formulations to improve mucosal permeability and drug uptake without altering the formulation's overall stability.

Powder Formulations

Powder formulations for nasal administration consist of dry, finely divided particles delivered directly to the nasal mucosa, providing enhanced physicochemical stability and prolonged residence time compared to liquid dosage forms. These formulations leverage the limited fluid volume in the nasal cavity for dissolution, facilitating mucosal absorption without the need for preservatives or cold-chain storage. Unlike liquids, powders eliminate solvent-related instability but require careful engineering to mitigate risks such as particle agglomeration leading to uneven distribution. Insufflation represents a primary technique for powder delivery, involving the manual propulsion of dry powders into the nostrils to achieve localized deposition. Traditional methods employ simple tools like straws or rubber bulbs to blow the powder, a practice historically associated with 18th-century snuff boxes that allowed users to store and dispense finely ground powder for nasal . Particle size optimization is critical for effective , with sizes of 50-100 µm promoting retention in the by minimizing to the lungs while ensuring adequate surface contact for dissolution. Formulation of nasal powders demands precise processes to ensure and patient tolerability. Micronization, often via air jet milling or , reduces particle size to the desired range, enhancing flow properties and dispersibility. Moisture control is equally vital, with strict limits during , , and storage to prevent clumping, agglomeration, or degradation, as excess can compromise powder stability and lead to inconsistent dosing. Specialized devices have advanced beyond manual , particularly for therapeutic applications like vaccines. Nasal powder insufflators, such as the Solovent or OptiNose systems, generate controlled clouds of micronized particles, directing them toward targeted nasal regions while avoiding deep deposition. These breath-actuated or plunger-based devices improve dose uniformity and are evaluated in preclinical studies for dry powder vaccines, offering a needle-free alternative with potential for mass .

Advantages

Pharmacokinetic Benefits

Nasal administration facilitates rapid drug absorption directly into the systemic circulation through the extensive vascular network of the , leading to a quick onset of therapeutic effects. Peak plasma concentrations are generally achieved within 5–30 minutes, in contrast to 30–90 minutes for , as demonstrated in pharmacokinetic studies of drugs like where nasal Tmax ranged from 9–15 minutes versus 30–150 minutes orally. This accelerated absorption is attributed to the thin, permeable epithelial barrier and proximity to major blood vessels, such as the ophthalmic and maxillary veins, which drain into the systemic circulation. A key advantage is the circumvention of hepatic first-pass metabolism, which enhances bioavailability for compounds prone to extensive liver degradation, including peptides and proteins. For example, nasal formulations of peptides like desmopressin exhibit bioavailabilities of 10–20%, far surpassing the negligible levels (<1%) obtained orally due to gastrointestinal and hepatic breakdown. Similarly, intranasal insulin achieves relative bioavailabilities of approximately 15–30% compared to subcutaneous injection, enabling effective systemic delivery without invasive methods. The route also supports targeted nose-to-brain delivery via the olfactory and trigeminal nerve pathways, permitting a small fraction (typically below 1–2% without advanced formulations) of the administered dose to reach the central nervous system directly, bypassing the blood-brain barrier. This direct access is particularly beneficial for lipophilic drugs with a positive logarithm of the octanol-water partition coefficient (log P > 0), which readily permeate the lipid-rich nasal epithelium, improving overall distribution efficiency.

Patient Compliance Factors

Nasal administration is highly valued for its non-invasive nature, which eliminates the need for and thereby enhances acceptance, particularly among individuals with and in pediatric populations. This approach avoids the and anxiety associated with injections, making it suitable for self-administration in settings and reducing barriers to compliance in chronic conditions such as or . Portable devices like nasal sprays facilitate easy self-administration without requiring professional oversight, allowing patients to use them at home and thereby decreasing the frequency of clinic visits compared to injectable therapies. Studies on intranasal treatments for indicate that adherence rates range from 28% to 77%, with an average around 56%, often higher than for some oral medications due to the convenience of this route, though forgetfulness remains a common barrier. Linking nasal routines to daily activities further supports sustained use. Sensory experiences with nasal formulations are generally less intrusive than those of oral medications, as they involve minimal direct taste exposure, though can occasionally cause mild bitterness that is often better tolerated than the prolonged flavor of swallowed pills. The procedure itself is rapid, typically taking less than one minute to complete, which contributes to higher patient willingness to incorporate it into routines. Economically, nasal administration lowers training requirements for patients and caregivers, as the straightforward technique reduces the need for extensive instruction or supervision, leading to cost savings in healthcare delivery. Psychologically, it diminishes the stigma associated with visible injection sites or equipment in chronic scenarios, fostering greater confidence and long-term adherence.

Limitations

Physiological Barriers

The nasal cavity presents several inherent physiological barriers that impede effective drug absorption during nasal administration. These barriers include the mechanism, enzymatic degradation, pH-dependent ionization effects, in the , and limitations on administered volume, collectively reducing the of many therapeutic agents. is a primary defensive mechanism in the nasal , where a viscoelastic layer, secreted by goblet cells and submucosal glands, traps deposited substances while ciliated epithelial cells propel the posteriorly toward the nasopharynx at a rate of approximately 5-6 mm per minute. This process typically clears unabsorbed drugs from the within 15-20 minutes in healthy individuals, significantly limiting the residence time available for absorption and thereby reducing drug efficacy unless rapid uptake occurs. Enzymatic metabolism in the further degrades administered drugs, particularly proteins and . The expresses enzymes, which are especially active in the olfactory region and capable of metabolizing a wide range of xenobiotics, as well as various peptidases including exopeptidases and endopeptidases that hydrolyze peptide bonds, leading to pre-systemic breakdown and diminished . The of nasal secretions, ranging from 5.5 to 6.5, creates an acidic microenvironment that influences and . For weakly basic , this promotes the non-ionized form, enhancing passive across the lipid-rich epithelial , whereas acidic may remain ionized, reducing permeability; deviations from this range can cause without improving absorption. Tight junctions, formed by proteins such as claudins and occludins in the pseudostratified ciliated epithelium, seal the paracellular pathway between cells, restricting the transport of hydrophilic molecules and macromolecules. This barrier primarily allows transcellular absorption for lipophilic, small compounds but severely limits paracellular flux, contributing to low permeability for substances that cannot readily cross the cell membranes. The nasal cavity's limited volume capacity imposes practical constraints, with a maximum recommended dose of 0.2-0.3 mL per to prevent overflow, runoff into the , or , which could lead to unintended gastrointestinal absorption or reduced local exposure. Exceeding this volume risks dilution of the drug and activation of clearance mechanisms without proportional gains in delivery efficiency. These barriers disproportionately affect certain drug classes, particularly hydrophilic molecules and those with molecular weights exceeding 1000 Da, which exhibit poor permeability due to restricted paracellular and transcellular routes, often resulting in below 10% without enhancement strategies. In contrast, lipophilic small molecules (<500 Da) can achieve higher absorption rates, highlighting the selectivity of nasal delivery for specific pharmacophores.

Formulation Challenges

Formulating nasal drug products presents significant pharmaceutical challenges due to the need to balance efficacy, safety, and manufacturability within the constraints of the nasal environment. One primary issue is drug stability, particularly in aqueous spray formulations where active pharmaceutical ingredients (APIs) are prone to degradation from hydrolysis, oxidation, or pH shifts during storage. To mitigate this, buffers are often incorporated to maintain a stable pH, while for sensitive compounds, lyophilization is employed to produce dry powders that enhance shelf-life by removing water and reducing chemical reactivity. Powder formulations, however, introduce their own stability concerns, such as hygroscopicity leading to agglomeration upon exposure to humidity, necessitating careful selection of excipients like mannitol or leucine for moisture protection. Achieving precise dosing remains a critical hurdle, as variability in spray plume —defined by the angle, width, and length of the cloud—can lead to inconsistent deposition patterns, with portions of the delivered dose potentially lost to the due to improper plume characteristics or administration techniques such as excessive head tilt or forceful . Regulatory agencies like the FDA mandate rigorous testing to address this, including characterization of plume via high-speed imaging at distances of 2-7 cm and spray pattern analysis using impaction methods to ensure uniformity, with acceptance criteria requiring ovality ratios close to 1.0 and minimal variation in plume dimensions across multiple actuations. is similarly scrutinized, with cascade impaction recommended for suspensions to verify that 90% of particles fall within 10-100 µm to optimize nasal retention while minimizing penetration, as deviations can exacerbate dosing variability. Excipient compatibility poses another formulation obstacle, as components like must prevent microbial growth without compromising mucosal integrity; for instance, , a common in multi-dose sprays, has been shown to induce ciliotoxicity by impairing ciliary beat frequency, potentially disrupting even at concentrations as low as 0.01%. Strategies to avoid this include using alternative like or developing preservative-free single-dose systems, though these require validation of efficacy through microbial challenge testing per FDA guidelines. Scalability in manufacturing further complicates nasal product development, particularly for powder formulations where producing uniform particles (typically 10–150 µm) demands precise control over milling or spray-drying processes to prevent agglomeration and ensure content uniformity. Batch-to-batch variability in particle morphology can arise from equipment scaling, such as differences in atomization efficiency during spray drying, leading to inconsistent aerosolization and bioavailability; thus, process analytical technology (PAT) is increasingly adopted to monitor real-time particle size and moisture content during upscale production.

Risks and Complications

Local Effects

Nasal administration of medications, particularly through sprays containing vasoconstrictors or corticosteroids, frequently leads to local and of the . Common manifestations include burning, stinging, dryness, and , with epistaxis occurring due to vascular fragility induced by these agents. These effects are reported in 5-10% of patients using intranasal corticosteroids or decongestants. Overuse of topical nasal decongestants, such as or , can result in , a form of rebound characterized by worsening congestion, erythematous and granular mucosa, and progressive with crusting. This condition arises from prolonged exposure beyond 7-10 days, with an incidence ranging from 1% to 9% among otolaryngology clinic visits. Septal perforation represents a more severe local complication, involving erosion of the due to chronic exposure to caustic substances delivered via nasal sprays or powder . Risk factors include high dosage frequency and extended duration of use, with intranasal steroids and decongestants implicated in up to 28% of recent cases, though overall incidence remains below 1%. Histological examination in cases of chronic nasal administration reveals changes such as of the , , and mucosal , particularly in , reflecting adaptive responses to ongoing irritation and inflammation. Monitoring for these local effects involves assessing symptoms like nasal crusting, recurrent epistaxis, and whistling breath sounds during inspiration, which may indicate septal or advanced .

Infectious and Systemic Hazards

Nasal administration carries risks of transmitting blood-borne infections when devices such as straws or nasal applicators are shared, particularly among recreational drug users snorting substances like . This occurs because micro-trauma to the can introduce blood into the , facilitating the transfer of pathogens like (HCV). A study of non-injecting users found that those infected with HCV were twice as likely to have shared straws for snorting, even after adjusting for other factors. Intranasal transmission of HCV has been documented in cases involving repeated , with virological showing the virus's viability in nasal secretions contaminated with blood. While transmission via shared nasal devices is theoretically possible through blood exposure, it remains undocumented and considered low risk compared to injection routes. Epidemiological data indicate higher rates of sexually transmitted infections (STIs) among recreational nasal drug users, often linked to associated risky sexual behaviors rather than direct transmission. Systemic hazards from nasal administration stem primarily from the route's rapid absorption, which can lead to unexpectedly high levels and overdose potential, especially for potent substances like opioids or stimulants. This quick onset—often within minutes—bypasses first-pass , resulting in peak plasma concentrations that heighten the risk of . For example, nasal of produces intense and cardiovascular strain due to sympathomimetic effects, increasing the likelihood of , arrhythmias, or . Similarly, nasal delivery of opioids such as can cause respiratory depression and overdose if doses are miscalculated, with illicit forms posing particular dangers due to variable potency. Additional systemic concerns include allergic reactions to formulation excipients, such as preservatives or in nasal sprays, which can trigger or in susceptible individuals. Dependency risks are elevated for drugs with high abuse potential when administered nasally, as the rapid reinforcement promotes compulsive use patterns. Rare but serious complications, like (CSF) leak, can arise from trauma during forceful , eroding the and allowing brain fluid to escape into the . Such events have been reported in chronic snorters, potentially leading to if untreated. Recent developments highlight additional risks from emerging intranasal formulations. Compounded nasal sprays, used off-label for psychiatric conditions, carry increased potential for misuse, , and adverse events due to inconsistent dosing and lack of standardization, as noted in FDA alerts as of 2022. Similarly, intranasal epinephrine (neffy, approved 2023) poses heightened cardiovascular risks, such as hypertensive emergencies, particularly in patients taking beta-blockers. To mitigate these infectious and systemic hazards, employing sterile techniques and single-use devices is essential in both medical and non-medical contexts. Guidelines recommend disposable nasal applicators for pharmaceuticals to prevent cross-contamination, while programs advocate for personal paraphernalia to reduce sharing among users.

Medical Applications

Respiratory and Allergic Treatments

Nasal administration plays a key role in treating respiratory conditions and allergies by delivering medications directly to the , targeting , congestion, and allergic responses in the upper airways. This route allows for rapid onset and localized effects, minimizing exposure to other body systems. Common applications include decongestants, corticosteroids, antihistamines, and for conditions like and prevention. Decongestants such as nasal sprays are widely used for acute symptoms, acting through alpha-adrenergic agonism to induce of nasal blood vessels, thereby reducing mucosal swelling and congestion. These sprays provide symptomatic relief lasting up to 12 hours per dose, making them suitable for short-term management of nasal obstruction in allergic or non-allergic . However, guidelines recommend limiting use to no more than 3-5 days to prevent rebound congestion, known as . Intranasal corticosteroids, exemplified by fluticasone propionate or furoate, are first-line therapies for , exerting anti-inflammatory effects by inhibiting mediator release and reducing nasal and . Clinical studies demonstrate their efficacy, with up to 65% of patients achieving well-controlled symptoms after two weeks of once-daily use, significantly outperforming in alleviating sneezing, itching, and congestion. These agents offer sustained relief over weeks to months when used regularly, with minimal systemic absorption due to high topical potency and first-pass metabolism, resulting in fewer adverse effects compared to oral alternatives. Intranasal antihistamines like provide rapid symptom control in by blocking H1 receptors and exhibiting additional anti-inflammatory properties, such as inhibiting mediator release from mast cells. Administered as sprays, they effectively reduce nasal itching, sneezing, and , often with onset within 15-30 minutes and effects lasting 12 hours. When combined with corticosteroids, they enhance overall efficacy for moderate-to-severe cases. Nasal administration extends to vaccines, notably the (LAIV), such as FluMist, approved by the FDA in 2003 for intranasal delivery to induce mucosal immunity against seasonal without needles. In September 2024, the FDA approved FluMist for self- or caregiver-administration, including home delivery options for the 2025-2026 season. This approach stimulates local IgA production in the upper , offering protection comparable to injectable vaccines in eligible populations aged 2-49 years. According to the and its Impact on () guidelines, a WHO collaborative initiative, intranasal corticosteroids are recommended as the cornerstone for persistent , with decongestants reserved for episodic congestion and antihistamines as adjuncts for rapid relief. These treatments prioritize local action, with systemic absorption typically below 1% for corticosteroids and antihistamines, preserving efficacy while limiting risks like hypothalamic-pituitary-adrenal suppression.

Systemic and Neurological Therapies

Nasal administration facilitates systemic delivery of therapeutic agents by enabling rapid absorption through the into the bloodstream, bypassing hepatic first-pass metabolism and offering advantages for peptides that are prone to gastrointestinal degradation. This route is particularly valuable for hormonal therapies, where consistent is essential for managing endocrine disorders. For instance, , a synthetic analog of antidiuretic , is administered nasally to treat by increasing water reabsorption in the kidneys, with of approximately 3.3-4.1%. Similarly, intranasal salmon calcitonin, a that inhibits activity, demonstrated in a 2000 trial efficacy in postmenopausal by reducing vertebral risk by approximately 33% at a daily dose of 200 IU, while also providing effects for associated ; however, as of 2025, due to a potential increased risk of (e.g., higher incidence in meta-analyses), it is not recommended as first-line and is reserved for patients who cannot tolerate other treatments per current guidelines. In neurological applications, nasal delivery leverages the nose-to-brain pathway for direct access, enhancing treatment for conditions requiring swift intervention. Oxytocin , a , has been investigated in clinical trials since the 2010s for improving in individuals with autism spectrum disorders, showing enhanced emotion recognition and reduced repetitive behaviors after repeated dosing. As of 2025, trials continue to show promise in enhancing social-emotional reciprocity, though results are mixed and it remains investigational. For acute management, (Nayzilam) was FDA-approved in 2019 for patients aged 12 and older experiencing clusters, providing rapid termination within 10 minutes in up to 70% of episodes due to its quick absorption and onset. Nasal formulations also excel in emergency neurological scenarios, such as reversal with , which is FDA-approved for layperson use and reverses respiratory depression within 2-3 minutes by competitively binding opioid receptors, thereby restoring normal breathing without needles. For migraines, offers pain relief with an onset as early as 15 minutes, achieving response rates of over 50% at 2 hours post-dose, attributed to its swift systemic uptake and ability to constrict cranial blood vessels. Additionally, nasal insulin delivery in phase II trials for has shown cognitive improvements, such as better delayed memory recall, alongside reductions in markers of neurodegeneration, by directly influencing insulin signaling without peripheral risks. As of 2025, phase 2A/B trials, including combinations with empagliflozin, continue to show cognitive improvements. These applications underscore nasal administration's role in delivering peptides and small molecules for both hormonal balance and neurological modulation, prioritizing speed and in clinical settings.

Non-Medical Uses

Recreational Substances

Nasal administration of recreational substances, particularly through of powdered forms, allows for rapid absorption via the , leading to quick onset of psychoactive effects but also heightened risks of local tissue damage and systemic . This route is commonly employed for illicit drugs seeking euphoric, , or highs, often in social settings like parties or clubs, where users prioritize immediacy over safety. Common substances include , , amphetamines, , and misused formulations, each carrying unique pharmacological profiles and health consequences. Cocaine, derived from leaves, has been insufflated for its potent stimulant effects since the late , initially in tonics and nasal sprays marketed as remedies for ailments like congestion and . By the , companies like Burroughs, & Co. produced portable nasal sprays for everyday use, contributing to its widespread adoption before regulatory restrictions in the early . As a local anesthetic and vasoconstrictor, intranasal narrows blood vessels in the nasal passages and beyond, providing a brief euphoric rush but causing immediate irritation and long-term damage such as septal perforation. Its high potential stems from reuptake inhibition, fostering and compulsive use, classifying it as a Schedule II substance with significant misuse liability. Street purity has increased in recent years, averaging 80-90% in samples as of 2023, though adulterants like (an ) remain prevalent, mimicking 's appearance in purity tests while triggering immune-mediated and upon . Ketamine, a dissociative , produces trance-like states and hallucinations via antagonism when insufflated recreationally, with effects onsetting within minutes due to its 25-50% nasal . This route bypasses first-pass more effectively than oral ingestion (8-20% ), enabling doses of 30-75 mg to induce the sought-after "K-hole" detachment. Recreational use surged in club and scenes post-2000, following a decline after its 1990s peak alongside ; by the 2010s, it reemerged at festivals and nightlife venues, with poison center reports showing increased exposures from 2016-2019, and continued growth into the 2020s, including a 40% rise in past-year use from 2021 to 2022 and further increases through 2024, often co-occurring with other club drugs. Chronic insufflation risks include damage and "ketamine bladder" from systemic effects, compounded by its variable purity in illicit markets. Amphetamines, such as , and (3,4-methylenedioxymethamphetamine) are also commonly snorted for their empathogenic and stimulant properties, with yielding faster than oral routes by direct mucosal absorption. For amphetamines, nasal delivery heightens cardiovascular strain, including and , while —often as powdered "Molly"—intensifies serotonin release for enhanced sociability but risks severe , , and nasal ulceration from repeated exposure. Misuse of nasal opioid formulations, like sprays originally for breakthrough pain, contributes to the opioid crisis; while specific nasal misuse data is limited, broader CDC surveillance indicates opioids were involved in nearly 80,000 overdose deaths in 2023, with intranasal routes accelerating respiratory depression in non-medical contexts, though provisional data as of 2024 indicates a decline in overall opioid-involved deaths. Social aspects of nasal recreational use include specialized paraphernalia like "snuff bullets"—small, discreet dispensers typically made of metal or plastic that hold and release measured doses of powder directly into the , facilitating covert consumption at social gatherings. These devices, often marketed ambiguously for snuff, are prevalent for and but increase overdose risks by enabling precise yet unchecked dosing without dilution.

Traditional and Cultural Practices

Nasal snuff, a finely ground form of , has deep roots in traditional practices across and . Introduced to in the following Christopher Columbus's encounters with indigenous American uses of powdered , it quickly gained favor among the Spanish and French aristocracy. By 1566, French diplomat promoted it as a remedy for migraines, sending samples to , which contributed to the naming of after him. In , snuff was inhaled nasally for its stimulating effects, with absorbed rapidly through the due to the preparation's alkaline pH, achieving blood levels comparable to smoking. traditions adopted snuff by the early 17th century, particularly in where Zulu communities incorporated charred stems into dry nasal preparations for medicinal and ritual purposes. In South American indigenous cultures, nasal administration of psychoactive snuffs predates European contact, with yopo—derived from the seeds of —serving as a cornerstone of shamanic rituals for over 4,000 years. Pre-Columbian groups in the , , and , such as the , prepared yopo by roasting green seeds, mixing them with alkaline plant ashes to form a paste, drying it into a biscuit, and grinding it into a fine powder for nasal inhalation using V-shaped tubes or self-applicators. This method facilitated visionary experiences attributed to bufotenine and other tryptamines, used by shamans for , , and spiritual communion. Archaeological evidence, including snuff tubes and seeds from tombs dating to 1000 BCE in northern and , underscores its entheogenic role in magic-religious ceremonies. Rapé, an Amazonian tobacco-based nasal snuff, exemplifies ongoing indigenous health and spiritual rituals among tribes like the Katukina, Huni Kuin, and Yanomami. Prepared by blending Nicotiana rustica or N. tabacum with sacred ashes from tree bark and other plants, rapé is blown into the nostrils during ceremonies to clear energy blockages, enhance focus, and invoke protection, often as part of initiation rites, healing sessions, or communal festivals. Ethnobotanical studies document its use for respiratory ailments, fever reduction, and spiritual purification, with the nasal route prized for direct absorption and immediate effects. In broader Native American contexts, including North American tribes like the Ojibwe, tobacco snuffs featured in 20th-century documented health rituals for warding off illness and facilitating prayers, as recorded in ethnobotanical surveys emphasizing holistic wellness. Contemporary interest has spurred a revival of these practices, distinguishing ceremonial nasal snuffs—prepared with traditional intentions for spiritual and communal healing—from commercial products that prioritize mass production and profit over cultural authenticity. Indigenous-led initiatives and ethnobotanical documentation in the late 20th and early 21st centuries have helped preserve and adapt these rituals, ensuring their role in cultural identity amid globalization.

Research Directions

Enhanced Delivery Methods

Ongoing research into enhanced delivery methods for nasal administration focuses on overcoming barriers such as rapid and limited epithelial permeability to improve drug and efficacy. Innovations in formulations and devices aim to extend , enhance absorption, and ensure precise dosing, particularly for peptides, , and other challenging therapeutics. These advancements build on the inherent advantages of the nasal route while addressing challenges like enzymatic degradation. Nanoparticles and liposomes represent key strategies for enhancing nasal permeability. Chitosan nanoparticles, derived from a biocompatible , interact with negatively charged mucosal surfaces to open tight junctions, thereby increasing paracellular transport and drug absorption. For instance, -based formulations have demonstrated increased bioavailability for in preclinical nasal delivery studies. Liposomes, vesicles, encapsulate drugs to protect them from degradation and facilitate fusion with mucosal membranes, further modified with coatings to boost mucoadhesion and stability; such systems have shown improved retention and permeability in preclinical models. Dry powder inhalers (DPIs) offer advanced alternatives to liquid formulations, particularly for and controlled-release applications. These systems deliver finely milled powders that deposit on the , avoiding preservatives and enabling room-temperature stability for biologics. Preclinical studies have validated nasal DPIs for , where mucoadhesive excipients like extend residence time and promote sustained release, enhancing immune responses without needles. Controlled-release variants incorporate polymers to modulate drug , improving therapeutic profiles for chronic conditions. Mucoadhesive polymers, such as carbopol (a cross-linked ), play a central role in prolonging contact between formulations and the nasal . These polymers form viscous gels upon hydration, resisting clearance and increasing absorption windows; carbopol-based systems have exhibited strong mucoadhesion in evaluations. Clinical exploration includes nasal glucagon-like peptide-1 (GLP-1) agonists for , where intranasal delivery in an exploratory trial led to rapid plasma GLP-1 elevation and glycemic control in type 2 diabetic patients, suggesting potential for non-invasive therapies. Device innovations further refine nasal delivery precision. Smart nasal sprays integrate electronic dose counters and digital displays to track usage and provide adherence reminders, as seen in add-on concepts like Nemera's electronic nasal device, which enhances patient compliance through integrated instructions and feedback. These developments collectively advance nasal administration toward more reliable, user-friendly systems.

Targeted Therapeutic Advances

Targeted therapeutic advances in nasal administration have primarily focused on enhancing drug delivery to the central nervous system (CNS) via the nose-to-brain pathway, bypassing the blood-brain barrier (BBB) to treat neurodegenerative diseases such as Alzheimer's disease (AD) and Parkinson's disease (PD). This approach leverages the olfactory and trigeminal nerve pathways in the nasal cavity to achieve direct CNS targeting, improving bioavailability and reducing systemic side effects compared to oral or intravenous routes. Recent developments emphasize the use of nanocarriers and biomaterials to optimize mucosal penetration, residence time, and specificity, with preclinical and early clinical studies demonstrating increased brain drug concentrations. Nanocarrier systems represent a cornerstone of these advances, including polymeric nanoparticles (e.g., chitosan-based) and lipid-based formulations (e.g., solid lipid nanoparticles and liposomes), which encapsulate therapeutics to protect them from enzymatic degradation and facilitate transport across nasal epithelium. For instance, chitosan nanoparticles have shown enhanced brain uptake and AChE inhibition in rodent models of AD compared to free drug. Similarly, lipid nanocapsules delivering curcumin for PD have demonstrated neuroprotective effects by reducing oxidative stress markers in preclinical studies. These systems often incorporate penetration enhancers like cyclodextrins or cell-penetrating peptides to improve paracellular transport, with recent formulations achieving improved drug permeation efficiency in ex vivo nasal mucosa models. Biomaterials such as mucoadhesive polymers (e.g., hydroxypropyl methylcellulose) and PEGylated nanoparticles have further refined targeting by extending nasal to 4-6 hours and minimizing ciliary clearance, enabling sustained release for chronic conditions. In clinical applications, intranasal insulin has been tested in phase II/III trials for and , with some studies reporting improvements in cognitive scores on the scale. For PD, intranasal glial cell-derived neurotrophic factor (GDNF) nanoparticles have shown preliminary of neurons in preclinical models. Additionally, the FDA approval of intranasal (Spravato) in 2019 for has spurred research into similar derivatives for broader CNS targeting, with ongoing studies reporting rapid antidepressant effects within 24 hours via olfactory pathway activation. These innovations underscore a shift toward personalized, non-invasive therapies, though challenges like variable inter-individual absorption persist. Recent 2025 advances include lactoferrin-functionalized lipid nanoparticles for nose-to-brain delivery in and PD, demonstrating targeted CNS uptake in preclinical models, and cell-penetrating peptide-modified liposomes and nanopolymers enhancing mucosal penetration for broader neurodegenerative applications.

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