Seizing child recieving IN treatmentTherapeutic Intranasal Drug Delivery

Needleless treatment options for medical problems

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Intranasal Medications for acute pain:

Table of Contents:

Introduction to nasal opiates for treatment of acute pain (click here)

Advantages of intranasal opiate medications (click here)

Concerns regarding intranasal opiate medications (click here)

Therapeutic threshold, side effect threshold (click here)

Literature overview and discussion

Pediatric pre-operative and post-operative agitation/pain control (click here)

Adult Postoperative pain control (click here)

Intranasal ketorolac (Toradol) in the operating suite (click here)

Acute pain in the Emergency department and prehospital setting (click here)

Intranasal opiates (fentanyl , diamorphine) for painful pediatric injuries (click here)

Intranasal opiates (fentanyl) for adult ambulance patients (click here)

Intranasal opiates (diamorphine, fentanyl) for sickle cell crisis (click here)

Intranasal opiates (fentanyl) for burn dressing changes (click here)

Intranasal Ketamine for acute pain (click here)

Break-Through pain (click here)

Intranasal flumazenil and intranasal naloxone as a reversal agents (click here)

Personal insights from experienced clinicians (click here)

Treatment protocol (click here)

Dosing tables (to assist with volume calculations) (click here)

Teaching materials (click here)

Peer Reviewed Articles (click here)

Bibliography (click here)

Introduction

Intranasal opiate delivery offers one of the most interesting and perhaps broadly useful indications for intranasal medication delivery. Acute pain is an extremely common problem in the outpatient setting (over 40 million emergency room visits in the United States per year for acute pain),[1] as well as in the hospice setting where patients often have acute episodes of breakthrough pain despite long acting opioid use. Due to the sheer volume and variety of patients a large number of treatment options are necessary to meet each patients individual needs.

Intranasal opiates are simply one of many treatment options that may be useful in selected patients. For selected opiate medications, intranasal delivery can result in rapid medication absorption with serum and cerebral spinal fluid (CSF) levels approaching those comparable to intravenous (IV) administration.

Cerebral spinal fluid concentrations of medications following intranasal, sublingual and subcutaneous delivery - the nose brain pathway demonstratedNasal versus intravenous versus oral serum concentrations of drug

 

This delivery method is effective because the enormous surface area (180 cm2) and blood supply of the mucosa allows small molecules to be rapidly transported into the blood stream.[2] For example, dipping a cotton swab tip into sufentanil and applying it to the nasal mucosa of the ferret produces an effect within seconds.[2] Recognition of this rapid opiate analgesic effect has resulted in numerous research publications confirming its effectiveness. Studies investigating treatment of acute pain via opiate delivery across the nasal mucosa note equivalent or superior pain control to IV, IM and subcutaneous delivery methods.[3-6] In the post-operative setting, patient controlled intranasal analgesia (PCINA) systems used to deliver intranasal fentanyl or sufentanil result in equivalent pain control as IV PCA devices and superior pain control to customary ward-delivered pain medication.[7-11] Oncologists are beginning to recognize the advantage of this delivery site and have posted a web site protocol for intranasal fentanyl and sufentanil directed to patients suffering breakthrough cancer pain that is resistant to standard therapy.[7] (click here for link) The U.S. military is even investigating intranasal analgesics (ketamine) as an option for their soldiers to self treat the pain associated with battlefield injuries and possibly self-extract themselves from the situation.[12](click here for slides)

Advantages of intranasal opiate medications :

  1. Rapid onset – intranasal opiates have similar onset of action to intravenous opiates
  2. Ease of delivery / Rapid delivery – because no IV skills and no shots are needed, medication delivery can be undertaken quite rapidly in an EMS, ER or hospice setting. This further reduces the time to onset, improving pain control and patient satisfaction.
  3. Painless administration – since no shot is needed, this delivery method is very attractive to patients, especially pediatric patients and hospice patients.
  4. High medication bioavailability – by bypassing the gastrointestinal tract and the liver, nasal medications do not undergo gastrointestinal degradation or hepatic first pass metabolism. Therefore more medication is available in the blood stream for therapeutic effect.
  5. Special hospice advantages: a) Medications do not have to be swallowed or absorbed through the oral mucosa so they work well even in patients with dry mouths, nausea, vomiting. b) Self administration – If an appropriate delivery device is provided, intranasal medications can easily be administered by the patient or their family

Concerns regarding intranasal opiate medications:

  1. Rapid onset in opiate naïve patient – As with any opiate, concern must exist regarding the potential of over sedation, respiratory depression and hypoxia. This concern is valid, but unfortunately it often leads to under-dosing of the medication and therapeutic failure. Numerous authors have not found this to be an issue when adequate doses of medication are used.[3, 6, 13-17] Please see the excerpt below regarding therapeutic threshold and side effects that addresses this issue. Also realize that IN fentanyl has been used in neonates safely (click here for link to abstract).
  2. Bad taste or nasal burning from the medication: Spraying anything including water up the nose can cause some discomfort in patients. Midazolam is commonly reported to sting by pediatric patients. However, nasal opiates have less reported uncomfortable side effects and tend to be tolerated quite well. In fact a number of studies specifically report little or no discomfort or bad taste when fentanyl is used.[3, 13, 15, 18]
  3. Variations in clinical effect: In some investigations there has been considerable variability in the effect of a standard dose of opiate medication, leading the authors to question how useful intranasal medications are if the dosing is ineffective in many patients. These findings of significant inter-individual variation in pharmacokinetics and clinical effect are likely a result of three factors: Improper volumes and concentrations of drug, inadequate mucosal coverage and the well known inter-individual response to all opiates regardless of method of administration. Much of the published data tends to report the use of low doses of inadequately concentrated formulations with large volumes of medication delivered in various fashions (drops, sprays, atomization, nebulization). Since dilute medications are not very effective when delivered nasally, and delivery methods impact how much is absorbed it is not surprising that there is great variation in efficacy of many studies. Furthermore, opiates often demonstrate interindividual variation in effect regardless of their mode of delivery.[18, 19] Due to this well know inter-individual response opiate medications are generally titrated to effect. Much of the variation seen with intranasal opiate medication delivery can be overcome with standardized spray delivery systems and highly concentrated medication solutions.[6, 13, 18] Finally, because nasal opiates have a rapid onset of action, additional doses of the medication can be administered in a titrated fashion (similar to IV medications) until the desired clinical effect has been achieved.
  4. Inadequately concentrated medications: Some generic IV opiate medications are fairly dilute, making their delivery via the nasal mucosa suboptimal.[18, 20] For example, highly concentrated fentanyl has rapid onset of action without loss out the nostril[13, 15] while less concentrated formulations may require more titrated dosing with more variable onset and peak.[3] Ideally a maximum volume of 0.2 to 0.3 ml per nostril would be administered to obtain the best coverage with little or no runoff from the nostril.[18] Some investigators have solved this by requesting their pharmacies to compound the medications at a more potent concentrations.[13, 15] Other investigators obtain their opiate (diamorphine) in a lyophilized powder form and mix the appropriate dose into a small volume of solution.[6, 21] Perhaps easiest of all for U.S. clinicians would be to simply use adequate doses of a generic, inexpensive and highly concentrated opiate sufentanil.[20] In the future, commercially available prepackaged intranasal opiates may solve these concentration issues.

Therapeutic threshold, side effect threshold:

A common problem with IN medication delivery is that the clinician fails to give an adequate dose of the drug because they are used to using intravenous (IV) medications and are afraid to give a higher dose of "IV" medication via the nose. For example, to treat a child for a painful condition one needs at least 1.5 to 2.0 times the IV dose of fentanyl intranasally to begin seeing an adequate therapeutic effect. This may appear as a seemingly huge dose to the clinician and they will give less. Failure to use adequate dosing will lead to inability to achieve a therapeutic threshold and the patient will not have adequate effect from the medication. To understand the reasoning behind administering such "high" doses one must consider several factors. The first is bioavailability. For oral medications we often give 10 to 100 times higher doses of a medication – because it takes that much to achieve adequate blood levels. For intranasal medications the doses are not as high, but they do need to be more than IV doses to achieve adequate serum levels of medication. How much more will depend on the medication bioavailability. Secondly, the medication is not instantly in the serum when given via the IN route (as is the case with IV medication). It takes several minutes to absorb, often achieving therapeutic effect in 3-5 minutes and peaking at 10-30 minutes. Due to this delayed rise, IN medications given in proper doses will rarely achieve levels high enough to cause clinically important respiratory depression (the exception to this rule is when using sufentanil - it is so potent that inadvertent overdosing or administration to a patient who is already altered can result in respiratory depression and even apnea. For this reason be sure to give properly measured doses and to always monitor these patients). The following figure demonstrates a theoretical dose of intranasal versus intravenous opiate medication, demonstrating that the peak levels of the two methods of administration are far different, leading to less risk of respiratory depression when the IN dose is administered.

Therapeutic threshold and side effect threshold demonstrated by initial serum levels achieved using IV versus IN opiate


The exception to this concept occurs with the newer extremely concentrated synthetic intranasal opiates designed for hospice care. These drugs are concentrated to doses as high as several THOUSAND micrograms per ml (generic fentanyl is 50 mcg/ml). Using these very highly concentrated opiates on an opiate naive patient can lead to respiratory compromise and overdose due to the delayed but still very high levels of serum concentration achieved. A case report by Gracia in 2013 demonstrates this.[96]

Literature overview and discussion

Pediatric pre-operative and post-operative agitation/pain control:

Medications are frequently administered to children in the pre-operative setting to reduce separation anxiety and induce sedation. The most commonly used medications are benzodiazepines, however opiates or combinations of both are also frequently used. Numerous studies demonstrate that intranasal benzodiazepines and/or opiates are very effective for this indication.[22-28] Additional discussion of this literature can be found in the sedation section of this web-site. As a general summary of the literature, sufentanil seems to be the most frequently studied intranasal opiate used for sedation, demonstrating very effective sedation with reduced separation. However, the dosing regimens in the literature vary by a factor of 5, with the higher doses (over 2 micrograms per kg) leading to higher incidences of side effects such as respiratory depression, desaturation and prolonged sedation. Careful monitoring is suggested when this medication is used, especially in higher doses.

Myringotomy:

An additional group of studies have specifically investigated the efficacy of intra-nasal fentanyl to improve emergence characteristic of patients following myringotomy (a procedure commonly done without an IV in place).[29,30,61,77,81,83,103,127] Both Finkel et al and Galinkin et al found that intraoperative treatment with intra-nasal fentanyl reduced post-operative agitation. Galinken also noted a reduction in tachycardia, nausea, vomiting and recovery room length of stay in-patient treated with IN fentanyl while Finkel found a slight increase in PONV.  Perhaps as important, these two authors as well as a third (Voronov et al) find that in children undergoing myringotomy (no IV at all) they were able to easily control pain at the end of the case with intranasal fentanyl. [29, 30, 61] In a more recent study Rampersad found IN fentanyl equivalent fro controlling post-operative myringotomy pain to other non-opioid medications, however these authors used a dose (1 mcg/kg) that is probably barely effective when given intranasally so one would not expect much effect on pain.[77] Pestieau compared IN fentanyl to IN dexmedetomidine and placebo for post-operative myringotomy pain and agitation. Both fentanyl and dexmedetomidine resulted in better pain control than placebo. However, the study had to be stopped early due to overly long sedation in the high dose dexmedetomidine group.[81] This is not entirely surprising since the length of action of IN dexmedetomidine is around 60-100 minutes. The authors conclude that IN fentanyl or rectal acetaminophen are very effective and therefore the longer length of time in recovery for IN dexmedetomidine cannot be clinically justified in short operative cases such as myringotomy where the drug effect is so prolonged. Hippard conducted a randomized double blind trial comparing nasal fentanyl to intravenous morphine and intramuscular morphine to assess the immediate postoperative analgesia can behavioral effects of these three routes of administration. They found them all to be equivalent in terms of efficacy and minimal side effects and conclude that establishing an IV in this setting is unnecessary.[83] Dewhirst et al conducted a prospective double blind RCT comparing IN dexmedetomidine (1 mcg/kg) to IN Fentanyl (2 mcg/kg) for postoperative treatment of pain following bilateral myringotomy and tympanostomy tube placement in 100 children. They found equivalent reduction in pain scores postoperatively.[103]

Liang et al describe similar results to these myringotomy trials using IN sufentanil or fentanyl for reducing post-operative agitation in children following eye surgery.[109]

Post-operative abdominal pain:

Heshmati et al found intranasal sufentanil (0.7 mcg/kg) effectively treated the pain of lower abdominal surgery within 10 minutes time in thirty children.[48] They noted only two episodes of nausea and no respiratory compromise, excess sedation, hemodynamic effects or desaturation. They conclude that intranasal sufentanil in this dose range is rapidly effective and safe and suggest that it be considered not only in post-operative care but also as a triage initiated pain medication in the emergency department. Additional investigations note IN opiates are appropriate alternatives for pain treatment in the post-operative pediatric patient.[31, 32]

In a recent review of the drug Sufentanil, Lundeberg and Roelofse tout their experience with over 1000 uses of intranasal sufentanil in pediatric anesthesia practice.[74] Here is what they say:

"At Astrid Lindgren Children’s Hospital, Stockholm, Sweden we have used intranasal sufentanil for reducing procedural pain, and infrequently as premedication for more than a decade, and in over 1000 patients. Our clinical experience is that the dose of sufentanil could substantially be decreased when changing the mode of application from drops to an aerosol. The onset is also faster with the aerosol.

Different devices could be used for creating an aerosol but we favor ...atomization devices, for simplicity and accuracy of dosing. The onset of sufentanil aerosol is about 5–10 min with a maximum sedative and analgesic effect at about 20– 25 min. Depending on the dose used, the effect wears off at about 60 min. Doses used for procedural pain are usually 0.7–1 ug/kg) and very occasionally over 1.5 ug/kg). These doses (<1.5 ug/kg) very seldom give adverse effects like nausea ⁄ vomiting and ventilatory depression. Lower doses of intranasal sufentanil can be used when combined with other drugs such as intranasal s-ketamine or dexmedetomidine."

 

Adult Postoperative pain control:

Pateint control intranasal fentanyl versus IV patient controlled device shows IN is equivelent in pain control

Striebel is the thought leader in adult post-operative pain therapy using intranasal opiates. He and his colleagues have published multiple studies investigating both nurse administered as well as patient administered intranasal fentanyl or intranasal meperidine (pethidine) in patients following surgical procedures.[3, 4, 8-10, 33, 34] These investigators used non-concentrated IV formulations of the opiate medication and overcame the volume issue by administering multiple small doses in a titrated fashion. In all of this groups published data the intranasal formulation was equivalent in onset of action and quality of pain control to the IV delivery route. Furthermore, when the patient was given control of dosing using a patient-controlled intranasal analgesia pump (PCINA) there was improved satisfaction and improved pain control due to the lack of need for a health care worker to respond to the patients pain needs.

Christrup et al confirmed Striebel’s data in a double blind, crossover trail in patients undergoing multiple molar extractions. They found the IN and IV fentanyl were equivalent in quality of pain control and in duration of effect.[35] Other authors have found similar results using various different opiate formulations.[36-39]

Hallett et al noted that intranasal diamorphine (heroin) provided good to complete post-operative pain relief in the majority of patients studied, but the delivery system they used suffered some technical problems, leading the authors to conclude that the concept is valid but the delivery system needed improvement.[40]

Abboud et al noted that intranasal butorphanol was superior to placebo, but of slower onset than IV butorphanol in treating post-cesarean section pain.[41]

Cannon found adequate pain relief with IN butorphanol in about 70% of his post-op head and neck outpatients.[42] A review of additional data on intranasal butorphanol can be found in an article by Gillis and a review by Dale.[18, 43]

Stoker et al compared a modified and concentrated form of intranasal morphine (generic morphine is not lipophilic and does not absorb well so needs to be modified for adequate nasal absorption) to intravenous morphine for treatment of postoperative bunionectomy pain.[38] These authors confirmed others findings that intranasal opiates are equivalent to intravenous opiates in terms of pain control.

Han published an interesting article noting that low doses of intranasal sufentanil if effective at reducing myoclonus seen during etomidate induction (click here for link to abstract).[56] Sufentanil is 5 to 10 times as potent as fentanyl and is probably the opiate of choice for nasal delivery in adults with severe pain based on preliminary data discussed in this web site and in the hospice literature.

A trial by Nave in 2013 sought to define the bioavailability and efficacy of nasal vs buccal fentanyl.[95] The authors used 24 volunteers as their own controls and measured plasma fentanyl levels following delivery of 100 mcg of fentanyl via the nasal cavity or via buccal mucosa using an oral transmucosal fentanyl lozenge (lollipop). At 15 minutes time, plasma levels of fentanyl were 602 vs 29 pg/ml. There were no significant side effects noted.  The conclusion – a single dose of nasal fentanyl provides significantly higher plasma levels and bioavailability than the buccal route.

Editorial note: This is yet another of many trials both in the pain literature and the epilepsy literature (many featured throughout this web site) demonstrating faster onset of therapeutic levels and higher bioavailability of drug when given via the nasal mucosa as opposed to via the buccal mucosa. It seems apparent that if time of onset and patient compliance are an issue – the nasal routes is preferred.

Miscellaneous inpatient uses of nasal pain medications.

Child Birth

Fleet conducted an RCT comparing IN and SC fentanyl to IM pethidine (meperidine, Demerol) in women in labor. They found pain control to be similar, but the IM pethidine group mothers and babies were frequently over sedated, labor was prolonged, and patients were far less satisfied.[112]

 

Intranasal ketorolac (Toradol)

Moodie et al note that intranasal ketorolac (30 mg)given postoperatively results in reduced need for opiate rescue medication, less tachycardia and fewer fevers.[58] It was well tolerated and might be considered as a method of ketorolac delivery in appropriate clinical situations. Other authors confirm the effectiveness of IN ketorolac.[110] It is now available as a prescription prepackaged drug.

 

Acute pain in the Emergency department and prehospital setting:

Graph demonstrating equivelent pain control with nasal fentanyl versus IV morphine in children with extremity fractures

Several well designed randomized controlled trials exist that demonstrate intranasal opiates are clinically equivalent to intravenous morphine and superior to intramuscular morphine for the management of acutely painful conditions in children.

Intranasal opiates (fentanyl , diamorphine) for painful pediatric injuries:

Borland et al conducted a randomized, double blind placebo controlled trial comparing atomized intranasal fentanyl (mean dose 1.7 microgram/kg) to intravenous morphine (mean dose .11 mg/kg) in children with acute pain due to long bone fractures.[13] 67 patients were randomized. Visual analog pain scores demonstrated clinically significant reductions in pain scores by 5 minutes that persisted throughout the entire study (out to 30 minutes) for both IN fentanyl and IV morphine (see diagram). Pain score reductions were equivalent for both study drugs. The authors point out that time delays were required to start an IV in the children before they could receive the study drug – a delay that could be eliminated if IN fentanyl were used in a non-blinded fashion. Given the clinical equivalency of these two modalities they conclude that IN fentanyl offers the advantage of a noninvasive, simple painless method for treating acute pain. These advantages suggest that this therapy would be useful not only in the emergency room but also in an EMS setting and at triage to allow more rapid onset of pain control in children suffering severely painful conditions. It could also be used prior to IV establishment, allowing time for topical anesthetics to take effect on the skin.

In a follow-up study to her randomized trial, Borland et al report on the results of clinical experience once IN fentanyl was introduced as a standard treatment in their pediatric emergency room.[50]  She found the average time from triage to administration of opiate medications (Intranasal fentanyl versus IV morphine) dropped from 57 minutes prior to introduction of intranasal fentanyl, to 24 minutes following introduction.  Furthermore, the eventual need for an IV to give further pain control in these cases was reduced from 100% to 42%.  This real world observational report confirms the ability to speed up delivery of care while reducing resource utilization when intranasal medications are implemented for appropriate situations.

In 2011 Dr. Borland and colleagues published additional data regarding atomized intranasal fentanyl - a randomized controlled trial comparing generic 50 mcg/ml fentanyl to more expensive custom concentrated fentanyl (300 mcg/ml) in children (age 3-15 years) with painful extremity fractures.[79] There was substantial improvement in pain at 10, 20 and 30 minutes for both concentrations and there was no statistical difference (or clinical difference) in the reduction in pain scores. More of the heavier children (> 50 kg) required additional acetaminophen or NSAIDS at some point in their care. This data supports the use of inexpensive generic fentanyl for treating painful fractures in children. (Editor note - if you need more concentrated opioids for IN delivery in adults or opioid tolerant patients, sufentanil is also generic and is about 5-8 times more potent than fentanyl - in essence providing you a non-customized readily available opioid for nasal delivery)

Saunders et al conducted a similar trial assessing the efficacy of 2 mcg/kg of IN generic fentanyl (50 mcg/ml) in pain reductions for pediatric orthopedic trauma. They found effective control and high satisfaction scores using this treatment method.[44]

 Kendall et al diagram demonstrating the ease of acceptance of intranasal drug versus intramuscular shot

 

Kendall et al conducted a randomized controlled trail comparing intranasal diamorphine to intramuscular morphine in 404 children and teenagers with extremity fractures.[6] Intranasal therapy provided superior pain control at 5, 10 and 20 minutes while pain control was similar for both study groups by 30 minutes. Treatment acceptability as judged by nurses and parents was 98% and 97% for intranasal therapy versus 32% and 72% for intramuscular therapy (see diagram above demonstrating patients reactions to each type of therapy). The authors conclude: "Nasal diamorphine spray should be the preferred method of pain relief in children and teenagers presenting to emergency departments in acute pain with clinical fractures. The diamorphine spray should be used in place of intramuscular morphine."

A few years later this same author (Kendall) conducted a pharmaceutical safety trial of diamorphine 0.1 mg/kg in children, specifically looking for adverse events. They entered 226 patients with acute pain and found a 26% incidence of mild side effects consisting of nasal irritation. There were no episodes of respiratory depression and 3 episodes of sedation (reduction in GCS). They conclude that despite some expected side effects, there were no safety concerns.[102]

Cole investigated the efficacy of intranasal fentanyl (50 mcg/ml) in children ages 12 to 36 months who were suffering painful injuries in need of more than an oral medication.[62] In a prospective sample of 57 patients these authors found a mean initial pain score of 8/10 with pain reduction to a mean of 2/10 by 10 minutes (93% had control of their pain) and to a mean of 0/10 by 30 minutes (98% had control of their pain). There were no complications and the delivery was well tolerated (nasal fentanyl does not burn nor taste bad). They conclude this is an effective, safe, well-tolerated method of pain control for moderate to severe pain.

Holdgate evaluated the time it took to treat children (ages 1-15 years) with acute pain when IV morphine was the standard, compared to after the introduction of intranasal fentanyl.[63] The study occurred in a mixed setting ED (adult and pediatric emergency department). In the 7 months before study implementation they administered opiates (IV morphine) to 63 children. In the 7 months after study implementation they provided opiates to twice as many children (118 patients). 81 children received intranasal fentanyl while 37 received IV morphine. The median time for delivery of pain control was 32 minutes for nasal fentanyl and 63 minutes for IV morphine. Furthermore, there was a clear trend to provide opiates via the nasal route to younger children (who might otherwise NOT get pain medicine due to the need for an IV). Median age for IN fentanyl was 8.5 years while it was 12 years for IV morphine.  The authors conclude - "This study demonstrates that children treated with IN fentanyl received analgesic medication faster than those treated with IV morphine in a mixed ED. Younger children were more likely to receive opioid analgesia following the introduction of fentanyl."

Crellin 2010 graph demonstrating the efficacy of intranasal fentanyl for treating painful orthopedic injuries

Schacherer et al further confirm that an IN fentanyl pathway results in a significant decrease in time to pain medication administration for long bone fractures. In his study they decreased time to pain medication delivery from 62 minutes (IV morphine) to 37 minutes (IN fentanyl) with equivalent ability to control pain.[114]

Crellin et al evaluated the efficacy of generic IV fentanyl (50 mcg/ml) for treating orthopedic pain in children 5-15 years of age.[64] They found it very effective with pain score reductions from 7 at onset to 5 in 5 minutes and 2 at 30 minutes (see above figure). Mean time from triage to drug delivery was only 20 minutes. They titrated to effect with multiple doses as needed. It was well tolerated and very inexpensive. The authors conclude that generic 50 mcg/ml fentanyl is very effective, well tolerated and inexpensive method for treating painful injuries in children.

Regan found intranasal diamorphine to be equivalent to intravenous morphine in terms of time to administration of the drug in children in his A&E department.[84] However, there was less frequent need for further analgesia using the nasal medication. They conclude that nasal diamorphine remains a preferred agent and note that it has been adopted in 60% of U.K. emergency departments.

Harlos et al have even used nasal fentanyl in newborn babies who are suffering from terminal illnesses in an effort to reduce their pain and suffering.[86] They demonstrated safety and efficacy (as well as possible in this unique setting) and felt this was more compassionate than an injection. Prior to this publication the youngest reported age of nasal atomized fentanyl was 3 months old.

Williams presented data at an international nursing conference detailing the experience in an emergency room in Australia demonstrating that nurse initiated IN fentanyl given at triage significantly improved time to pain control in children  with suspected limb fractures.[101] Hopefully that data will be published as a study soon.

 A nice review of most of these pediatric articles prior to 2011 was published in September 2011.[80] The conclusions are that IN fentanyl is equivalent or superior to morphine administered IV, IM or orally and that it is much faster in onset. Furthermore it is safe and does not require compounding (generic 50 ug/ml is fine for children). Given this efficacy, safety and low cost it offers an approach to improve care, improve satisfaction and reduce resource utilization.

Click here for a table from the article that summarizes all the articles.

Interestingly a 2014 Cochran review on IN fentanyl use in children with acute pain is probably a good idea but concludes that the data is inadequate to draw many conclusions.[105]

Nielsen et al found that a combination IN sufentanil (0.5 mcg/kg) plus ketamine (0.5 mg/kg) was effective at preventing / reducing pain in 78% of children given this combination prior to a painful procedure.[106]

Graudins et al showed that IN ketamine at subdissociative doses (1 mg/kg intranasal) is equivalent to intranasal fentanyl (1.5 mcg/kg) for controlling acute moderate to severe pain in children with limb injuries.[117]

Tsze et al describe a Tetralogy of Fallot case where the baby was suffering an acute hypercyanotic spell (oxygen sats 56%) that failed to respond to knee chest positioning.[108] They successfully reversed the episode using IN fentanyl.  These children are on a physiologic knife edge and if you frighten them or hurt them they can decompensate severely (or die) with an increase in their right to left shunting of blood in the heart. Traditional treatment includes oxygen administration, knee-chest positioning, calming the patient AND administering IV morphine. Obviously IV starts in these situations are both difficult AND not calming to the child. These authors are the first to publish data on using intranasal opiates rather than IV opiates to calm the child – with no need for establishing IV access in the midst of a dangerous hypercyanotic spell. This therapy will never enter the realm of a randomized controlled trial due to the infrequency of the event so these kinds of case reports are all we have and can assist us in changing practice to better care for these complex but rare conditions.

Fenster et al compared IN fentanyl (2 mcg/kg) to IV morphine (1 mg/kg) for pain control during abscess incision and drainage.[124] They found pain control and patient satisfaction was superior with IN fentanyl and required less time and resource utilization. Kurien et al showed that a combination of IN diamorphine plus inhaled nitrous oxide provided adequate pain control to reduce fractures in children. [125]

Murphy et al conducted a prospective study evaluating the efficacy of IN fentanyl to treat severe pain in children cared for by their prehospital providers. They found clinically significant pain reductions in 83% of children with a median pains score reduction from 10 to 5 in ten minutes.[126] There were no adverse events associated with the treatment. They conclude this is a safe and effective treatment and maybe an attractive alternate to oral and IV opiates.

Intranasal opiates for acute pain in adults

Most of the emergency medicine literature relating to intranasal opiates focuses on pediatric cases due to the desire to limit further pain from starting an IV or giving an intramuscular injection. However, intranasal opiates are also very useful in the adult patient (see the EMS and Burn sections below). Many adults with minor acute burns, orthopedic trauma and other painful conditions often get an IV line for  pain control (no resuscitation needed). In this setting nasal opiates are very effective, save nursing time and are well accepted by the patients.

Steenblik published a series of 40 patients with acute orthopedic trauma who were cared for in a ski clinic that confirms the above statement.[82  ] In this non-blinded clinical trial the investigators entered patients that they cared for in a ski clinic who were suffering from moderate to severe pain related to orthopedic trauma. The mean pain score on study entry was 9 (on a 10 point scale). Patient all were administered intranasal sufentanil (chosen rather than fentanyl due to higher potency and smaller weight based volume) at a does of 0.5 mcg/kg.

Pain scores following intranasal sufentanil administration

This treatment was successful in 95% f patients with a mean reduction in pain from 9 to 4.3 at 10 minutes and 3.3 at 20 minutes – a highly clinically significant reduction in pain.  On a 5 point satisfaction scoring they found that “very satisfied” answer in 78% of patients, 83% of nurses and 87% of physicians. There were minimal side effects – dizziness being the most frequently reported. One patient dropped their saturations to less than 92% after a second dose of nasal sufentanil was given due to inadequate pain control. The authors conclude that intranasal sufentanil provides rapid and adequate pain control in austere conditions and can be easily administered with no pain to the patient.

Stephen investigated the efficacy, safety and satisfaction scores when IN sufentanil was used in adults with acute orthopedic trauma.[85] Using a dose of 0.5 micrograms per kg they found pain scores dropped from 7.8 to 3.5 within 30 minutes, that of the 15 patients studies only one had a reduction in their pulse oximetry below 90% (88%) but 46% had some sensation of feeling whoozy. Satisfaction scores for patients, nurses and physicians (5 Point Likert score with 5 being the best) were 4.5, 4.0 and 4.2 respectively.

 Stephen 2012 JOM graph for IN sufentanil in adults

The authors conclude this is an effective, safe method to treat acute pain in adults and sufentanil offers many highly desirable features (volume of administration, potency, therapeutic index, cost) for use in the emergency setting.

Dolatabadi et al conducted a randomized controlled trial directly comparing IN sufentanil (0.3 mcg/kg) to intravenous morphine ( 0.1 mg/kg - gold standard) for severe pain related to extremity trauma in 88 adult patients.[116]  Both therapies provided equivalent pain control with no difference in time to onset after drug delivery. Side effect profiles were similar. They conclude that IN sufentanil is equivalent to IV morphine for quality of pain control and is rapid, efficient and non-invasive.

Etteri et al did a very nice clinical trial that compared IV morphine plus IV ketorolac (5 mg / 30 mg) to intranasal fentanyl (3 mcg/kg of 50 mcg/ml solution) for the treatment of acute renal colic in adults. Not surprisingly, the IV formulation was superior in efficacy. However, it is still quite impressive how the nasal group faired in terms of pain control for such an uncomfortable condition (see the graph). Pain scores on a 10 cm VAS at entry, 30 minute and 60 minutes for the morphine/ketorolac IV arm were 8.6 / 2.3 / 1.1 respectively. For the intranasal fentanyl arm they were 8.8 /4.0 / 2.2 respectively. The authors conclude that for a condition as painful as renal colic, IV morphine and ketorolac is the first choice of therapy, while nasal fentanyl might be appropriate in a less controlled setting such as out of hospital or nurse initiated setting.

Etteri IN fentanyl in renal colic  

Click here for the journals link to the article (free)

Editorial comment: It is not surprising that the IV combination of an opiate plus a NSAID worked better than an opiate alone for 2 reasons. First generic concentrations of fentanyl tend to be a little less effective in adults due to volume issues and second because non-steroidal anti-inflammatories are a mainstay for successful therapy of renal colic. They are in reality the best treatment over time, but take longer to work so we tend to add an opiate to get pain more rapidly in control. I wonder if a combination of concentrated fentanyl or generic sufentanil PLUS an oral or nasal NSAID might not have changed these results. I have no research data to support this opinion but do have personal experience (nasal sufentanil plus oral ibuprofen) suggesting it is very effective. Future investigators should strongly consider these minor protocol changes – the authors actually admit the lack of a NSAID is a limitation to their study design.  I do agree with the investigators that IV therapy is preferred if possible because these patients frequently need multiple doses of drugs and nausea medications and repeat evaluations, need their blood drawn to evaluate renal function (so get a needle stick anyhow), etc. Never the less this is a great study and helps us define the niche (or lack of niche) for nasal drugs in our daily practice.

Belkouch et al conducted a prospective study evaluating the efficacy of generic atomized intranasal fentanyl (1.5 mcg/kg, 50 mcg/ml concentration) for therapy of acute renal colic in adult patients.[115] The patients who did not experience a significant drop in pain by 5 minutes got rescue IV morphine for pain. 23 patients were enrolled. VAS pain scores dropped significantly at all times measures dropping from 85/100 at time zero to 48 (5 min) 35 (15 min) and 8 (30 min) - see graph (power calculations were not provided).

Belkouch table showing pain reduction from nasal fentanyl for renal colic

Graph comparing pain score versus time from Belkouch study

 Click here for the article (free)

There were no adverse events. The authors feel that IN fentanyl at generic concentrations (50 mcg/ml) is very effective, safe, readily available, inexpensive and easily delivered. They conclude that when compared to current practice (IV meds), IN fentanyl “has the potential to improve patient and family satisfaction and could have further implications related to improved cost-effectiveness and quality of care.”  This article provides a possible inexpensive method of treating renal colic deserving of more research:  IN opiate, IN ketorolac, transmucosal antiemetic, No IV started at all (IV fluids do NOT assist in stone expulsion or pain control).

Chew et al showed that adding IN fentanyl (1.5 mcg/kg) to IV tramadol improved pain scores in adults with acute musculoskeletal injury when compared to IV tramadol alone (drop of 29 vs. 19 points on a VAS).[123] They also noted a transient but statistically significant drop in blood pressure (13.35 vs. 7.65 mm Hg less) though it is unclear whether that is a clinically important drop (BP drop might be due to improved pain).

Kerr et al investigated titrated patient controlled intranasal fentanyl for treating pain during child birth.[118] 32 women were studied using a nasal PCA device that delivered 50 mcg of fentanyl every 3 minutes as needed. The average titrated dose over 3.5 hours was 734 mcg. 78% of patients reported satisfactory to excellent pain control and 85% said they would use it again. Perhaps not surprising, when accumulated dosing exceeded 700 mcg there was some neonatal respiratory depression requiring transient bag ventilation (12.5% of births).

Emergency room throughput - can it be influenced by implementing intranasal pain medications?

In 2014 an interesting paper by Sokoloff et al noted that the time to administration of analgesia (but not the adequacy of the analgesia) was highly correlated with shorter length of ED stay.[111] In fact if analgesia was provided within 90 minutes or less, ED lengths of stay were reduced by 2 hours or more. This highly impacts patient flow. The authors suggest efforts should be put into new methods to reduce time to analgesic delivery and cite Australian data (some presented here) showing early delivery of pain medications (Intranasal fentanyl) in the EMS setting and triage setting as a possible approach in the appropriate setting.

Editorial comment: For years we have been using IN fentanyl for most minor pediatric trauma (burns and orthopedic injuries) upon their arrival in the room (we triage straight to the room). This results in pain medication administration within a few minutes of arrival and pain control in 15-20 minutes from arrival. Often they go straight to radiology and can get splinted and discharged in under an hour. Similarly for minor burns they are debrided and dressed very quickly. This dramatically improves throughput and makes the parents very pleased with the rapidity of pain control for their child. [Some of us do the exact same process for adults using either fentanyl titrated or sufentanil. Ketamine would likely also work].

Click here for a PDF of this paper by Sokoloff (open access)

Intranasal opiates for ambulance patients:

Rickard et al conducted a randomized controlled trial comparing intranasal fentanyl to intravenous morphine in a pre-hospital ambulance setting.[16] 227 adult patients with severe pain (mean VAS score 8/10) were randomized to treatment, with pain scores repeated upon hospital arrival. Both methods were clinically equivalent with mean pain scores dropping to 4/10 by hospital arrival. The authors conclude that IN fentanyl is an effective alternate to IV morphine and is particularity valuable in situations where IV cannulation is difficult, unwanted or unnecessary. Other studies comparing intranasal opiates to alternate therapies for acute pain, have routinely found IN therapy to be an effective and acceptable route in the right clinical situation.[5, 14, 20, 21, 44]

McLean studied IN fentanyl (50 mcg/ml) in adult trauma patients seen at a ski clinic.[65] They treated 46 patients, using a mean does of 1.4 mcg/kg and found clinically significant decreases in pain scores by 2 minutes (14 mm VAS decrease), 5 minutes (28 mm VAS decrease) and 10 minutes (28 mm VAS decrease). they conclude this is an effective analgesic in acutely injured adults in whom immediate IV access is complicated by scenario or resource limitations. and feel its potential in search-and-rescue and other austere medical situations is widespread. (Web site Editors note - this is a relatively low dose of medication using a fairly dilute form for adults - yet it was still fairly effective and very inexpensive and safe.) (click here for abstract)

Johnston studied the efficacy of intranasal fentanyl given to over 500 adult ambulance patients for the treatment of non-orthopedic visceral pain (i.e. chest and abdominal pain). They found it effective with a mean pain score reduction of 32 mm on visual analog score.[67]

Middleton did a retrospective analysis of several thousand uses of intranasal fentanyl for acute pain in an ambulance setting.[75] They found it was about 80% effective at reducing pain by >30% during transport – perhaps very slightly less effective than IV morphine (81.8% effective) but that that benefit was likely offset by the need for an IV to deliver the morphine.

Bendall published another article of many noting that IN fentanyl is just as good as IV morphine for controlling acute pain in children.[76] The authors were allowed to titrate IV and IN drugs to effect allowing customization to the patients needs. The unique feature of this article is the clinical setting of EMS where IV lines in children are even more difficult and time consuming due to a variety of factors. The authors appropriately conclude that in light of the non-invasive route of administration and equivalence to IV morphine, IN fentanyl is the most suitable analgesic agent for managing pediatric patients with moderate to severe pain in the EMS setting.

Ellerton et al describe their mountain rescue experience with opioid drugs for severe pain.[99] They found intravenous opioids most effective (pain score down from 8 to 2) but also most difficult to deliver. Intranasal diamorphine at 5 mg doses, titrate at 15 minutes was found to decrease pain scores from 8 to 4.5 by time of handoff. They felt they needed to further address the proper dose (this is a low dose unless they are treating small adults – more typically we give 0.1 mg/kg) and determine if the cold environment impacted efficacy and if adjusted for could lead to even more effective pain control.

O’Donnell et al introduced IN fentanyl to their EMS system and then looked retrospectively at how this impacted the treatment of pediatric patients in moderate to severe pain.[100] They found little difference in the number of cases who were treated for pain (30% vs 36%). They also noted almost no records showing assessment of severity of pain in these children suggesting the issue to limited pain treatment maybe a misunderstanding of pain assessment rather than effective and simple tools like intranasal fentanyl for treating that pain.

Karlsen prospectively collected data to evaluate the efficacy of IN fentanyl for severe pain in the prehospital setting.[104] A total of 903 adults and children ages 8 or older with severe pain due to orthopedic conditions, abdominal pain or acute coronary syndrome refractory to nitroglycerin were evaluated. The patients received 1-3 doses of IN fentanyl (either 50 or 100 mcg per dose - range 50 to 300 mcg – of highly concentrated fentanyl ) titrated to effect. 7% of cases were less than 18 years old, the remaining 93% were adults. There were no serious adverse events, no respiratory depression and no use of naloxone. Mild adverse reactions (nausea, vomiting, vertigo, mild hypotension) occurred in 4%.  The median initial pain score was 8 and the median pain reduction was 3 points on a 10 point scale. The authors conclude that "out-of-hospital administration of intranasal fentanyl in doses of 50 to 100 mug is safe and appears effective."

Editorial comment: Here is further evidence, in the largest EMS trial published to date, demonstrating both the effectiveness and safety of IN fentanyl for severe acute pain in ambulance patients. The authors demonstrate a high level of understanding of this delivery technique by allowing titration of the drug to effect, a concept that should be mimicked by further researchers. Intranasal medication delivery for painful conditions should be titrated just as IV medications are titrated – the right dose is enough to have clinical effect without significant side effects. They also chose a highly concentrated fentanyl (500-1000 mcg/ml) but data from other studies have demonstrated that this is not required – generic concentrations are adequate and effective especially when titrated.

Another promising concept for prehospital pain control is intranasal ketamine. Ketamine in sub-anesthetic doses (about 10-15 times less than doses used for deep sedation) is an excellent pain killer, yet does not cause dysphoria nor respiratory depression (see details below and in the hospice section). This lack of respiratory depression may make this drug an attractive acute pain treatment modality for both ALS and BLS providers (it is already being used by lay people in the military and hospice setting). Reid et al have published the first report of such use in the EMS setting.[78] They treated a 9 y.o. child who was burned with 0.5 mg/kg (or less due to dead space losses) and within 3 minutes the child's pain and anxiety resolved, he was able to assist in his transfer and he was not sedated. This case report points towards another area of EMS research that is wide open - IN ketamine for acute pain - what is the right dose and is this safe enough for BLS delivery?

Intranasal opiates (diamorphine, fentanyl) for sickle cell crisis

The management of sickle cell crisis is dependent on immediate pain control, often requiring injectable opiates to achieve success. Unfortunately, sickle cell patients present to the emergency room so often in crisis that their veins are often damaged and it is very difficult to obtain rapid IV access - leading to delays in treatment and excessive nursing resources to gain IV access.  An obvious solution given the information presented at this web site is intranasal opiates titrated to effect. Telfer et al report their findings from an observational trial comparing intranasal diamorphine plus IV morphine in 9 patients to intranasal diamorphine plus oral morphine in 13 patients.[49]  By 15 minutes, adequate pain control was achieved in 89% of the IN plus IV group versus 70% of the IN plus oral group. At 30 minutes it was 100% vs. 89% and at 120 minutes it was 89% versus 100%.  Based on this initial trial, this emergency room has instituted immediate intranasal opiate delivery to all patients presenting in sickle cell crisis, followed by oral  opiate medications for longer efficacy. He continues to advocate this humane approach.[107]  They report high patient and caregiver satisfaction using this protocol.  While diamorphine is not available in many countries, fentanyl and sufentanil are often readily available and there is little reason to suspect it would not be just as effective as diamorphine.  Instituting a protocol similar to Telfer's, with the added caveat of allowing titration of repeated IN opiates every 5-20 minutes as needed would greatly reduce suffering, expedite patient care and reduced nursing resource utilization.

Following this publication, a hospital in Ireland was the next to take up the research mantle and they began looking at intranasal fentanyl for treating sickle cell vaso-occlusive crisis.[122] (I found this very curious as I discussed this type of research in the early 2000's with hospitals in the USA where over 50% of their patients were of African descent and they failed to become interested, yet we find a primarily Caucasian country doing the next bit of research in a population with relatively little disease prevalence). They published their proposed protocol in 2012 and presented their data a few years later. The table below tells the story - IN fentanyl was equivalent to IV morphine for adequacy of pain control with rapid onset of effectiveness.

Barret graph of IN fentanyl for Sickle cell crisis 

Click here for the Barrett full slide presentation

In the next few years some USA hospitals jumped on board -  Oakland California, Boston MA, Atlanta GA, Pittsburgh, PA. Data began to emerge from their research in 2014 and 2015:

In October 2015 there was a report from Boston published in the Journal Pediatrics of successful use of IN fentanyl for treating children with acute sickle cell crisis.[119] As with almost every other article that has measured time to pain medication delivery, these authors found IN fentanyl was given in 23 minutes whereas IV opiates took 56 minutes. Time to second dose and to admission or discharge decision was also reduced in the IN group. Finally the  number of admissions dropped from 68% to 52%.

They are now looking at this type of a protocol in adults – I hope given data seen in similar studies and in other authors experiences with IN fentanyl in adults that these authors consider using IN sufentanil as it will work much better in the adult population.

Click here for link    OR here for MS word document OR here for abstract link

Here is an in-depth slide set from Boston medical center discussing the path they used to develop a more rapid method for instituting pain control in acute vaso-occlusive crisis. PDF click here

Here is a condensed version by the same group specifically focusing just on IN fentanyl as the initial approach to reducing those time delays: PDF click here

Here is the current protocols/order sets for you to utilize if you wish:

Another abstract on this same topic was presented by Fein et al at the American academy of Pediatrics in October 2015.[120] They also found more rapid delivery of pain medications and pain control  in these children following introduction of IN fentanyl (2 ug/kg single dose). Both these articles support the idea of using intranasal fentanyl as a bridge therapy allowing more rapid reduction in pain for patients suffering vaso-occlusive crisis while more standard IV interventions are being instituted. In other words – give the patient a dose  of IN fentanyl as soon as you determine they need pain medication, then move on to establishing IV access and beginning more definitive interventions.

Researchers in Atlanta are working on similar protocols, presenting their data at the American society of Hematology meeting in Dec 2014.[121] In a study of close to 200 patients, they too found much faster time to delivery of pain meds in patients receiving IN fentanyl vs. those who did not (29 minutes versus 77 minutes) but with the limited data presented it appears they did not show a reduction in the patients pain scores. When using an opiate for pain this usually implies an erroneous dose. Personally, I think they did not start with a high enough dose and did not repeat it until pain control was significantly improved. Furthermore, as patients size and age increases, I move to a more potent analgesic – sufentanil.  Never the less this is a big study and shows that this concept is feasible and we just need to work out the details and dosing a bit better to improve our ability to quickly relieve the suffering that is occurring.

In summary, it appears that IN opiates are an effective rapidly initiated initial treatment for pain associated with acute sickle cell induced vaso-occlusive crisis. The exact doses, titration time table and appropriate drug (for children, teenagers and adults) are still being determined, but at this time at a minimum intranasal fentanyl at 1.5 to 2.0 mcg/kg, titrated at least once within 5-10 minutes is safe and equivalent to IV morphine, but much more rapidly delivered.

Intranasal medications for Burn dressing changes:

Finn and colleagues compared IN fentanyl to premedication with oral morphine prior to burn wound dressing changes.[45] They found small incremental titrated doses of IN fentanyl equivalent in pain control to pre-medication with oral morphine and felt it was an acceptable alternative that was more easily titratable. Borland et al found similar results with nearly identical conclusions in a population of children requiring burn dressing changes.[46]

Kulbe found low dose intranasal ketamine to be very effective for treating pain associated with burn dressing changes.[59]  Since the dose necessary for pain control is about 10 to 15 times less than that needed for sedation, ketamine is often an appropriate drug in situations where opiates are not effective or their side effects cannot be tolerated.

Finn literature showing pain scores in burn patients who get Intranasal fentanyl

Intranasal Ketorolac

Intranasal ketorolac is also quite effective for treating painful conditions (and recently gained FDA approval). Initial studies showed peak levels around 30-45 minutes with half life of 5-6 hours and bioavailability over 70%.(68, 69) In postoperative patients, 30 mg of intranasal ketorolac  results in marked decreases in pain scores and over 30% reduction in opiate use.(70-72) Similar findings occur in patients using intranasal ketorolac for post-dental extraction pain.(73)

Intranasal Ketamine for acute pain

Ketamine is labeled as a general anesthetic drug and in anesthetic doses causes a dissociated catatonic state where patients stare into space – seemingly awake, breathing – but they do not react to painful stimuli.  In these doses it can be used for very painful procedures such as joint and bone reduction and other orthopedic and plastic surgical interventions.  However, ketamine is also an analgesic drug and demonstrates analgesic properties at doses 10-15 times less that that required for anesthesia.  Because of this analgesic effect at low doses, patients often remain completely awake and alert while obtaining substantial relief of their pain.  Several studies now confirm the analgesic effect of ketamine in low doses when used to treat painful conditions as well as during dressing changes.[57, 59, 60, 87-91]

The following text reviews currently available literature on this topic:

Kulbe 1996: This short article is really a case report confirming that intranasal ketamine spray can be effective for acute pain control during burn dressing changes. [59] It is interesting but offers little in terms of dosing  - only suggesting this is an area that deserves further research.

Kaube 2000: Kaube tested 25 mg of intranasal ketamine in 11 patients with severe disabling neurologic deficits due to migraine aura finding that about half the time the nasal ketamine was effective in reducing both severity and duration of the symptoms.[87] 

Editorial comment -  Other migraine researchers have found intranasal lidocaine occasionally effective for aborting migraines  – perhaps a combination of lidocaine with ketamine (I suggest 50 mg ketamine) might be an effective first step therapy to abort a migraine patient visiting the emergency room. If this fails, progression to more time consuming and complex therapies can then proceed.

Carr 2004: Carr found doses of up to 50 mg of IN ketamine were effective in many patients with difficult to control breakthrough pain (mean pain score reductions of about 23 mm on a 100 mm VAS).[60] There was some mild dizziness and feeling of unreality. They conclude that IN ketamine is safe and effective for augmenting pain control in this population but that further investigation is necessary.

Christensen 2007: Christensen investigated intranasal ketamine for treating post-operative pain following wisdom tooth removal. [88] Adult patients were randomized to placebo and doses of 10, 30 or 50 mg of intranasal ketamine. They found that “meaningful pain relief was achieved by 14 minutes in 70% of patients receiving the 50 mg dose of IN ketamine.  Peak analgesic effect (44 mm drop on VAS) was at 30 minutes.

Christensen 2007 IN ketamine pain graph

Figure demonstrating rapid reduction in pain scores using 50 mg of IN ketamine in adults.

There was some feeling of unreality and or visual changes side effects noted in about 50% of patients who received the 50 mg dose which tended to resolve within an hour. The authors report prior data showing Ketamine bioavailability of their formulation (0.1 ml = 10 mg) of about 33%.

Huge 2009: This was a small study investigating the pharmacokinetics of low doses of intranasal ketamine as well as its impact on pain control and the resulting side effects.[57] The authors studies 16 patients with chronic neuropathic pain, randomizing them to either 0.2 mg/kg or 0.4 mg/kg of a dilute form of ketamine (25 mg/ml). Measured serum levels of ketamine peaked at 15 minutes indicating rapid absorption. Although the doses were low, a measurable impact on pain control occurred within 15 minutes and peaked at 60 minutes, lasting several hours. Mild to moderate dose dependent side effects were common, consisting of vertigo, concentration difficulty, blurred vision and some sedation, though measured cognitive ability was never impacted.

Reid 2011:  Reid et al report the successful use in intranasal ketamine in a prehospital setting to treat severe pain in a child with a 3% scald burn.[89] They used low dose ketamine (between 0.25 and 0.5 mg/kg) and noted onset within 3 minutes. There was minimal side effects (no dysphoria, some swimmy feeling). They conclude that more investigation is necessary for this promising intervention.

Goudas 2002 abstract: In this RCT patients received either IN ketamine (10 mg per spray up to 50 mg maximum per event) or placebo for breakthrough pain.[90] The group using ketamine had markedly better control of pain within 5 minutes and never needed rescue analgesia. There were no serious side effects though 20% of the ketamine cases reported feelings of unreality.

Kronenburg 2002:  This study is a review of ketamine in a variety of administrative formulations (including nasal) demonstrating that subanesthetic doses result in good pain control without significant side effects. [91] It is a bit dated now but contains a fair amount of interesting data.

Abdel-Ghaffar 2012:  This RCT comparing IN ketamine (1.5 mg/kg) vs. IN fentanyl (1.5 mcg/kg) for controlling postoperative pain following FESS sinus surgery showed equivalent pain control (much better than placebo) with a slight increase in dissociative side effects in the Ketamine group.[93]

Full article here (click)

Afridi 2013: RCT on IN ketamine (25 mg) vs. IN midazolam (2 mg) for migraines showed reduced severity of migraine in the ketamine group.[92]

Yeaman 2013: Yeaman et al conducted a preliminary trail with sub-dissociative doses of intranasal ketamine to determine a safe and effective dose to treat pain related to acute limb injury in children.[94] This prospective dosing trial entered 30 patients weights 10-50 kg who had pain scores of 6 or higher. In an open label fashion they all received an initial dose of about 0.7 mg/kg of ketamine (100 mg/kg diluted to exactly ½ ml – half up each nostril with an atomization device). At 15 minutes their pain was reassessed and at the clinicians discretion another dose of 0.5 mg/kg was administered. Pain scores were obtained at 0, 30 and 60 minutes. Degree of sedation and side effects were also recorded. 28 patients completed the trail, 10 received a second dose of ketamine at 15 minutes. The mean total dose of ketamine given to all patients was 1 mg/kg. Pain scores for the group at entry, 30 and 60 minutes were 74.5, 30 and 25 mm on a 100 mm scale. Minimal sedation occurred in 12 patients at 30 minutes but was gone by 60 minutes. Very mild side effects that did not need treatment and were transient were noted- dizziness in 36%, dysphoria in 14%. No patients suffered dissociation or hallucinations. 83% of patients were satisfied with the degree of pain control. The authors conclude that intranasal ketamine in sub-dissociative doses is effective for moderate to severe pain associated with orthopedic injury, they recommend future studies start with a dose of 1 mg/kg since it is safe and effective. They suggest this therapy be an alternate or a complementary analgesic choice for IN administration in children with acute pain.

Editorial comment: Here is the first study that many readers have been awaiting describing the efficacy of intranasal ketamine for treatment of acute pain. It is a small, preliminary trial but the results are promising and it gives us a starting dose – 1 mg/kg of intranasal ketamine. This drug might be used to complement fentanyl if the initial dose of fentanyl is effective, or vsa versa – given first line and followed with Fentanyl if additional pain medication is required. The study also points out a concept that some clinicians still are not familiar with – the concept of titration of pain medication via the NASAL route just as we all do via the intravenous route. Within 30 minutes, using no IV access, these children had their pain scores down by 44 mm. This is almost identical to that seen with titrated fentanyl in the Borland study from 2007. Here is another tool in our armamentarium for treating acute pain – painlessly.

Johansson 2013 [97]:  This article is a case series of 9 patients describing the experience of the EMS providers using nasal s-ketamine for the treatment of acute trauma patients (orthopedic ski injuries in severe pain) in a remote, cold environment where they failed to obtain IV access after 2 tries. They used relatively dilute ketamine (25 mg/ml) and doses that are appropriate for pain but should not cause sedation  - 0.5 mg/kg titrated with a second dose 2 minutes later, maximum of 0.5 ml per nostril per dose (final dose approximately 1 mg/kg – range 0.45 to 1.25 mg/kg). Median pain scores were reduced from 8.4 to 3 – a reduction that achieved significance even in this small sample size.

Pain scores before and after ketamine

The authors conclude: “To summarize, the opinion of our experienced prehospital staff was that nasal S-ketamine offered a fast, easy, and essentially non-invasive way of reducing acute pain secondary to trauma, without appreciable side effects…. “Further advantages are a relatively low cost of the treatment, a needleless approach that diminish the risk of transmission of blood-borne infections, and supposedly a reduced rescue-time which is particularly valuable in a cold or otherwise dangerous environment.”

Andolfatto 2013: Andolfatto et al prospectively evaluated the effectiveness of IN ketamine as an analgesic (not as a sedative) in 40 patients.[98] This is the first study on this topic in adults in an emergency room. The authors found this treatment (0.5 to 0.75 mg/kg of intranasal ketamine) to  have a clinically significant impact on pain  reduction in 88% of patients. The mean pain score reduction was 34 mm on a 100 mm scale. The median time to onset was just under 10 minutes. Side effects were minor. This suggests a potential use for IN ketamine in the setting of acute severe pain in adults – cheap, fast, safe, relatively effective with minimal side effects.

Nielsen 2014: Nielsen et al combined IN sufentanil (0.5 mcg/kg) plus ketamine (0.5 mg/kg) finding it effective at preventing / reducing pain in 78% of children given this combination prior to a painful procedure.[106] The spray was well accepted and provided rapid onset of analgesia.

Riediger 2015: Riediger et al found IN ketamine/midazolam as effective as IV morphine for treating post-operative pain following spinal surgery. [113]

Graudins 2015: Graudins et al showed that IN ketamine at subdissociative doses (1 mg/kg intranasal) is equivalent to intranasal fentanyl (1.5 mcg/kg) for controlling acute moderate to severe pain in children with limb injuries. [117]

Shrestha 2016: Shrestha et al conducted a cross sectional observational study of patients who were given IN ketamine (0.7 mg/kg initially, 0.3 mg/kg at 15 minutes if pain scores still exceeded 50 mm) for severe pain in the emergency department. They entered 34 patients and found VAS scores reduced from 80 mm to 40 mm (15 min), 20 mm (30 min) and 20 mm (60 minutes). 80% of patients had clinically significant pain score reductions by 15 minutes. The conclude that IN ketamine is an option for pain control in a busy or resource limited ED.[129]

Intranasal ketamine versus intravenous morphine dosing equivalency

The U.S. military may be the group most interested in intranasal ketamine for treating acute pain. This group is looking for a pain medication that can be self administered and relieve a soldiers acute pain related to war injury, yet let him/her still function at a high level and either be able to extricate himself or finish the mission (often saving his/her life and others by being a functional asset rather than a detriment). To date they have funded and conducted numerous studies to find the right dose of IN intranasal ketamine while determining the incidence of side effects.  Looking at the material posted on the internet, they have studied at least 117 subjects with doses ranging from 10 to 50 mg of ketamine finding no serious effects and adequate pain control.  The graph above notes their results in terms of dosing equivalency – finding 50 mg of nasal ketamine as effective or more effective than 7.5 mg of IV morphine without the loss of function seen with morphine. Look for more literature on this topic in the near future. (click here for military report from the internet in 2005)

Click here for a 2009 review of combat pain control

Click here for a slide set 2010 review of ketamine

Summary: While dissociative sedation with Ketamine requires fairly high doses of drug (10 mg/kg to be reliable - see sedation section) it appears that about  1 mg/kg of nasal ketamine (or simply 50 mg in an adult) is quite effective for pain control without substantial sedation. Many patients do feel a bit dysphoric, but their cognitive functions remain intact.  Using the generic formulation of ketamine at 100mg/ml would make nasal volumes ideal for atomization at this dose. It will be interesting to see if further research in the acute setting such as remote clinics, prehospital  setting (where generic fentanyl is a bit dilute for adult pain control), battle field setting and emergency room validate this concept. Especially interesting to those of us in the hospital will be for use in conditions such as migraines and chronic pain situations where treatment with an opiate has significant clinical downsides.

 

Break-Through pain:

See separate extensive Hospice section as well (click here)

This section of the website is no longer updated as these are now mature, FDA approved products (pricy but highly concentrated and effective though a bit more risky due to that high concentration - especially if kids accidently inhale while copying the adult who needs the drug.  Hundreds of articles per year are available on PubMed)

Graph showing the speed with which cancer breakthrough pain is controlled using intranasal fentanyl

 

Break-through pain is a complex problem affecting many patients and is widespread among patients suffering from cancer. Ideally this condition could be treated with a medication that is easy to use by a lay person, has rapid onset and is short in duration. In addition many of these patients have problems with nausea, swallowing and dry oral mucosa making oral and sublingual opiates suboptimal. Not surprisingly, intranasal opiates offer an attractive solution to this complex problem. Their onset is within a few minutes – comparable to intravenous medications, yet they can be easily delivered by a lay person even if the person has dry oral mucosa or is nauseated. Too date, the published literature on the subject is limited but many large trials are ongoing. It is likely that in the near future numerous intranasal opiate formulations will be available commercially. However, generic medications already exist, have been found to be effective in small patient cohorts and can be inexpensively implemented now in the appropriate patient setting.[7, 17, 47] (click here for a link to a palliative pain and dyspnea protocol)

In 2009 two important studies were published investigating the use of intranasal opiates for the treatment of breakthrough cancer pain and a third was published investigating intranasal ketamine for breakthrough neuropathic pain.[55,56,57]

Good et al studied intranasal sufentanil effectiveness for treating breakthrough pain in cancer patients.[55] The investigators first step was to determine the effective and safe dose of nasal sufentanil by incrementally increasing the dose administered until an effective but non-sedation dowse was determined (dose titration phase).  They found the mean effective dose to be about 20 mcg with a range of 9 to 108 micrograms per dose. They then sent the patients home with the delivery device and allowed them to administer intranasal sufentanil as needed for breakthrough pain. The bottom line – 77% found it as effective as prior medications and 94% preferred it as their first line treatment for breakthrough pain.  The authors conclude that intranasal sufentanil “provides acceptable and often preferred breakthrough analgesia for many patients and most importantly, it can provide rapid pain relief. This study also showed that IN sufentanil can be used safely, with a very low incidence of adverse effects, in an inpatient palliative care population. We suggest that IN sufentanil be added to the armamentarium of medication used to treat breakthrough pain with the proviso that it requires an initial dose titration phase.”

Intranasal sufentanil for breakthrough pain

Kress et al conducted a multinational randomized, double blind, placebo controlled trial investigating intranasal fentanyl (compounded into increasingly potent doses) for the management of cancer breakthrough pain.[56] They also conducted  a dose titration phase (to find the proper individual dose) prior to study entry and found intranasal opiates to be effective (see diagram) in cancer breakthrough pain within a few minutes. Nausea and vertigo were the most common side effects noted. No respiratory side effects were noted.

Intranasal fentanyl for breakthrough pain

Finally, Huge et al investigated intranasal ketamine in the treatment of chronic neuropathic pain.[57] The authors used relatively low doses of this medication since they had no desire for sedation, instead simply wanted NMDA receptor antagonism to suppress neuropathic pain. Used doses of 0.2 to 0.4 mg/kg they noted substantial reductions in pain (dose related – see diagram). They conclude that low-dose intranasal ketamine is a feasible method to produce rapid onset analgesia for neuropathic breakthrough pain conditions.

Intranasal low dose ketamine to control neuropathic pain

Intranasal flumazenil and intranasal naloxone as a reversal agents in sedated patients without an IV line

A concern that often comes up regarding administration of sedatives and opiates to patients who are given these powerful drugs via the intranasal route is how they can be reversed should too much sedation develop (since they presumably do not have an intravenous line). The first point that needs to be considered is whether significant respiratory depression requiring intervention beyond oxygen therapy will even occur from intranasal drug delivery. To date it has not been reported for midazolam and it does not  seem common even with very high doses of the extremely powerful drug sufentanil (it does occur with sufentanil at times).  This is probably because the medications absorb via the nasal mucosa are spread out over 10-15 minutes and never achieve peak levels seen with intravenous boluses (see detailed discussion on therapeutic threshold and side effect threshold concept above).  Never the less, antidotes to opiates - i.e. naloxone - work very well  intranasally as well as via subcutaneous and intramuscular routes (see separate section on this topic - click here).  In terms of intranasal flumazenil - the benzodiazepine antagonist - there is limited data but that which exists also suggests that it is effective when administered via the nasal route.  Two animal studies found transmucosal flumazenil delivered via the sublingual route resulted in rapidly measurable serum drug levels that achieved the therapeutic threshold and approached 100% bioavailability.[51,52] One of these studies actually demonstrated reversal of benzodiazepine induced sedation about 4 minutes after drug delivery.[51] Two human studies exist in children using flumazenil intranasally Scheepers found maximal concentrations in the serum were achieved very quickly (2 minutes), again at therapeutic blood levels and concluded that this may offer an alternate delivery route for benzodiazepine antagonist reversal agents.[53]  Heard et al presents a case where and child undergoing a dental procedure was oversedated using intranasal midazolam combined with intranasal sufentanil. [54] The authors responded to this problem by administering 0.4 on intranasal naloxone and 200 mcg of intranasal flumazenil.  Three minutes following antidote administration the pati9ent was fully awake and did not become re-sedated during the next  2.5 hours of observation.

 

Personal insights from experienced clinicians

Pat Crocker, DO, Chief of Emergency Medicine, Dell Children's Medical Center, Austin TX.... We have had great success with IN fentanyl for immediate pain control in children and it is much quicker than waiting for an iv to be established. Giving the fentanyl IN immediately and applying some topical anesthetic cream makes subsequent iv insertion less traumatic for the child as well.

The combination of IN fentanyl and Versed prior to minor procedures and administration of local anesthetic has been quite useful as well. No child has fallen asleep at the suggested doses but generally is quite a bit more tractable for the procedure reducing our need for full sedations some. We have also combined the above with nitrous oxide for children 5 yo and older and get nice results.

Link to 2011 study abstract by Dr. Crocker showing a comprehensive pain management strategy (including IN fentanyl if appropriate) reduces the childs recollection of pain at ED discharge.

Tom Macfarlane, MD, Staff Emergency Physician, Jordan Valley Hospital, Salt Lake City UT …When a patient presents with an acutely painful condition increasingly I am reaching for an intranasal opiate to treat their pain.  In both children and adults with clinical long bone fractures I am able to substantially control their pain within a few minutes of arrival with IN opiates.  Abscesses, burns and joint dislocations are some of the other conditions that respond very well to IN analgesia.  The IN route of administration has several advantages that I feel are very important.  It is very fast.  Onset is typically apparent in less than a minute after administration.  It is painless and this is especially appreciated by children and their families.  The IN route keeps a patient NPO in case they need sedation or need to go to the operating room.  And lastly, it is very effective and titratable.  Overall this is an excellent means to control acute pain in the emergency department.

 

Treatment protocol

Indications:

  1. Adult and pediatric minor painful injuries or procedures:
    • Orthopedic trauma not requiring an IV (or prior to starting an IV)
    • Anytime pain control is needed but oral medication is too slow
    • Burn dressing changes
    • Re-packing wounds such as abscesses
    • Any time you consider an IM shot for pain control (IN works as well or better with faster onset and no pain on delivery)
    • Titration of opiates is often needed - repeat another half to full dose every 15 minutes to until desired effect is obtained
    • The single biggest reason for failure of intranasal opiates is the clinician gives an in-appropriate dose (too low) similar to an IV dose which will simply fail in most situations.

Dosing and method:

  1. Fentanyl, sufentanil or diamorphine are most appropriate for IN delivery to treat pain
    1. Reasonable IN starting dose for painful procedures:
      1. Fentanyl: 2 ug/kg (comes in 50 ug/ml, you can ask your pharmacy to concentrate the solution or use sufentanil in larger patients).
      2. Sufentanil: 0.5 to 0.7 ug/kg (0.5 for elderly, 0.7 for young)
      3. Diamorphine 0.1 mg/kg (not available in USA)
    2. Administer half the dose into each nostril
    3. 1/3 to ½ ml per nostril is ideal but can push up to 1 ml per nostril though some will run off. If you need more than 2 ml total, consider titration with second dose in 5 minutes or use sufentanil. If you have diamorphine you can simply solubilize it within the appropriate volume of liquid so you deliver 1/3 ml per nostril.
    4. Be Wary of respiratory depression with sufentanil – monitor patients with pulse oximetry and close observation whenever using this powerful opiate.
    5. Titration to pain is often necessary – repeat dosing (1/2 to full dose) every 15 minutes until desired effect is achieved.

Strongly consider administering an oral pain medication at the same time as the nasal medication. This way as the effect of the nasal drug wanes, the effect of the oral medication begins to have an effect.

Naloxone is effective intranasally if you need a reversal agent

Be aware that there is often a "dead space" within the delivery device you use - this leads to some of the drug remaining within the device and not being delivered to the patient.  Be certain to draw up that extra volume into the syringe to account for the dead space that will remain.

Dosing tables (to assist with volume calculations)

Generic Fentanyl dosing table

Fentanyl (generic) is most appropriate for children since it becomes too dilute as the child's weight (and therefore the volume delivered) increases.

Dosing Plan: Fentanyl concentration -  0.1ml = 5 mcg (50 mcg/ml)

Comment: A very simple way to calculate the dose is as follows:

Dose in ml = kg weight x 4/100 plus 0.1 ml dead space

or simply Dose in ml  = kg weight x .04 plus the 0.1 ml dead space

Patient weight

Fentanyl dose in micrograms (at 2 mcg/kg)

Fentanyl volume (including extra 0.1 ml for dead space)*

3-5 kg

10 mcg

0.2 + 0.1 ml

6-10 kg

20 mcg

0.4 + 0.1 ml

11-15 kg 

30 mcg

0.6 + 0.1 ml

16-20 kg 

40 mcg

0.8 + 0.1 ml

21-25 kg 

50 mcg

1.0 + 0.1 ml

26-30 kg 

60 mcg

1.2 + 0.1 ml**

31-35 kg 

70 mcg

1.4 + 0.1 ml**

36-40 kg 

80 mcg

1.6 + 0.1 ml**

41-45 kg

90 mcg

1.8 + 0.1 ml**

46-50 kg

100 mcg

2.0 ml**

51-55 kg

110 mcg

2.2 + 0.1 ml#

56-60 kg

120 mcg

2.4 + 0.1 ml#

61-70 kg

140 mcg

2.8 + 0.1 ml#

71-80 kg

160 mcg

3.2 + 0.1 ml#

81-90 kg

180 mcg

3.6 + 0.1 ml#

91-100 kg

200 mcg

4.0 ml#

  You should draw up the additional appropriate dead space of the delivery device you choose. In this table the 0.1 ml represents a typical dead space in a 1 ml syringe connected to a syringe driven atomizer.

**If the volume exceeds 1 ml you might want to consider using sufentanil instead.

# Volumes in this range should be divided in half and administered 10 minutes apart to reduce runoff. It would likely be more appropriate to use sufentanil if that is available.

Generic Sufentanil dosing table

Sufentanil is more appropriate for adult patients because it is so concentrated that it is difficult to measure for small children.  It comes in 50 mcg/1 ml vials. Occasionally you will need two vials for adequate dosing.

Dosing Plan: Sufentanil concentration -  0.1ml = 5 mcg (50 mcg/ml)

Patient weight

Sufentanil dose in micrograms (at 0.70 mcg/kg)

Sufentanil volume (including extra 0.1 ml for dead space)*

3-5 kg

--use fentanyl--

--use fentanyl--

6-10 kg

--use fentanyl--

--use fentanyl--

11-15 kg 

--use fentanyl--

--use fentanyl--

16-20 kg 

14 mcg

0.3 +0.1 ml

21-25 kg 

18 mcg

0.35 + 0.1 ml

26-30 kg 

21 mcg

0.40 + 0.1 ml

31-35 kg 

25 mcg

0.5 + 0.1 ml

36-40 kg 

28 mcg

055 + 0.1 ml

41-45 kg

32 mcg

0.65 + 0.1 ml

46-50 kg

35 mcg

0.70 + 0.1 ml

51-55 kg

39 mcg

0.8 + 0.1 ml

56-60 kg

42 mcg

0.85 + 0.1 ml

61-70 kg

49 mcg

1.0 + 0.1 ml **

71-80 kg

56 mcg

1.1 + 0.1 ml **

81-90 kg

63 mcg

1.3 + 0.1 ml **

91-100 kg

70 mcg

1.4 + 0.1 ml **


*The volumes are rounded up to the nearest 0.05 ml and you should draw up the additional appropriate dead space of the delivery device you choose. In this table the 0.1 ml represents a typical dead space in a 1 ml syringe connected to a syringe driven atomizer.

It is best to use a 1 ml syringe to draw up this drug so you get accurate measurements.

**If the volume exceeds 1 ml, you will need to simply administer a lower mcg/kg dose (just give the entire 50 mcg vial) and re-assess in 10 -12 minutes at which point you can administer additional medication from a second vial. You may also simply obtain a second vial and a second syringe (or draw it up in a 3 ml syringe) at the outset and administer the entire volume at once– you can switch a nasal atomizer from one syringe to the second syringe.

Small Children should probably have fentanyl used rather than sufentanil to simplify the dosing volumes.

Dosing tables in Non-English language

Deutsch / German language

Deutsch 1

Deutsch 2 (Editors note: the doses are too low for fentanyl and morphine - double the dose these chart recommends for better effect that is still safe - see above literature)

Italia / Italian  language

Italian 1

Italian 2

Diamorphine dosing table

Diamorphine is supplied as a powder and needs to be re-concentrated in a diluent prior to administration.  The following link will connect you to a web site that provides directions for reconstitution. Be aware that this link assumes you will be administering the drug to one nostril and that you will use a dropper to administer the medication. If you use an atomizer you must add the additional dead space of the device or you risk under dosing the patient

Leeds Hospital IN diamorphine protocol (click here)

NHS intranasal diamorphine protocol for UK (click here)

Teaching materials:

Intranasal sufentanil delivery photo guide (click here) - Word document

Intranasal sufentanil delivery photo guide (click here) - PDF document

Intranasal fentanyl delivery photo guide (click here) - Word document

Intranasal fentanyl delivery photo guide (click here) - PDF document

What's new in pediatric emergency rooms - IN fentanyl for pain (click here) - Dr. Malcolm Higgins - PDF document of Power Point Slides

Intranasal fentanyl in pediatric emergency rooms (click here) -  Sally Britnell, RN presentation - PDF of Power Point slides

EMS and ER protocol for Intranasal fentanyl

Peer Reviewed articles:

Intranasal Morphine for pain

Fitzgibbon, Nasal Morphine for breakthrough pain, Pain  2003 (click here) - PDF 0.15 MB

Intranasal Fentanyl for pain

Borland, A randomized controlled trial comparing intranasal fentanyl to intravenous morphine for managing acute pain in children in the emergency department, Ann Emerg Med 2007 (click here for web site link)

Rickard, A randomized controlled trial of intranasal fentanyl vs intravenous morphine for analgesia in the prehospital setting, 2007 (click here for web site link)

Belkouch, A., S. Zidouh, et al. (2015). "Does intranasal fentanyl provide efficient analgesia for renal colic in adults?" Pan Afr Med J 20: 407.

Intranasal Sufentanil for pain

Heshmati, Intranasal sufentanil for postoperative pain control in lower abdominal pediatric surgery, IJPT 2006 (click here) - PDF 0.14 MB

Matheiu, Intranasal sufentanil is effective for postoperative analgesia in adults, Can J Anaesthesia 2006 (click here) - PDF 0.32 MB

Intranasal Diamorphine for pain

Kendall, Multicenter RCT of nasal diamorphine for analgesia in children and teenagers with clinical fractures, BMJ 2001 (click here) - PDF 0.28 MB

Intranasal ketamine for pain

Abdel-Ghaffar, IN ketamine vs. IN fentanyl for postoperative pain control following FESS, J AM Sci 2012

Nose brain pathway delivery of pain medications:

 Westin, Olfactory transfer of analgesic drugs after nasal administration, 2007

 

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