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.

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)

Literature overview and discussion

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] McHale presents data essentially demonstrating that IN fentanyl is their standard for all myringotomy cases.[145]

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:

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."

Other post-operative pain situations:

Yenigun et al showed that either IN fentanyl or IN ketamine were effective analgesics for children following tonsillectomy.[146]

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]

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.

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 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."

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.

Adelgais et al retrospectively reviewed 5 years of data comparing IV opiates to intranasal fentanyl using three Institute of Medicine quality indicators (timeliness, safety and effectiveness). 1702 patient encounters were reviewed. This study  is unique in that IN fentanyl  was used not just for orthopedic cases but was used for any patient that needed opiates.  They found that patients receiving IN fentanyl had a shorter time to delivery of pain medications, faster onset of analgesia (39 vs 68 minutes) faster time to discharge from dosing (109 vs 203 minutes), shorter ED length of stay (168 vs 267 minutes) and equal efficacy of pain control. This is yet more data supporting prior studies showing that IN fentanyl is just as good as IV opiates for controlling pain, but results in much faster patient throughput time and less resource utilization. [130]

Hoeffe et al investigated the efficacy of IN fentanyl plus nitrous oxide for pain control during pediatric fracture reduction. They found this combination very effective and well liked by clinicians (96%), parents (97%) and patients (89%).[133]

Reynolds et al conducted a RCT comparing IN ketamine 1 mg/kg to IN fentanyl 1.5 mcg/kg for treating pain in children with suspected extremity fractures. They found both drugs equally effective but had a higher incidence of minor side effects using ketamine. No respiratory depression occurred in either group.  They conclude that IN ketamine deserve more research and may offer an opiate sparing alternative to treating acute severe pain.[135]

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.

Sheier et al found that ketamine 1 mg/kg given 15 minutes prior to difficult IV starts was very effective in reducing pain and anxiety in both children and their parents.[136]

 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.

Nemeth et al published one of the few nasal drug delivery papers coming out of Germany.[137]  As these authors elude, German physicians have been a bit hesitant to adopt this treatment modality until they see more evidence from their own colleagues. Here is a very well done study using adequate doses of IN drugs and an atomizer to deliver the drugs – so the results should be reliable and believable. The authors provide good evidence that IN drug delivery is safe and effective for sedation and pain control when delivered by German clinicians to their patients using the protocols and doses they recommend.

Arnautovic published a study showing that even in an ED with a pediatric pain pathway utilizing IN fentanyl, most physicians are still not very comfortable with the concept and prefer IV morphine despite extensive literature showing the equivalence or superiority of IN fentanyl. Over 40% of cases of pediatric long bone fractures would have been eligible for INF but did not receive it. Obviously there is still a lot of room to expand this treatment modality when an institution that has a pathway still has this much improvement possible.[140]

Fenster randomized 20 children (10 per group) to either IN fentanyl (2 mug/kg) or IV morphine (0.1 mg/kg) prior to incision and drainage of an abscess. They found a 13 point difference in the observational scale of behavioral distress favoring IN fentanyl. Furthermore, more patients preferred IN fentanyl over IV morphine.[141]

Frey et al conducted an RCT comparing IN ketamine (1.5 mg/kg) to IN fentanyl (2 mug/kg) in 90 children with moderate to severe pain from traumatic injuries to the extremity. They found pain reductions at thirty minutes to be equivalent (31 mm vs 32 mm drop in VAS scores no a 100 mm scale). There were more side effects with ketamine. The authors conclude that in this era of concern regarding opioid use, IN ketamine may be an appropriate alternative for treating painful acute extremity injuries.[142]

Quinn et al conducted a small but well designed study demonstrating what most other similar studies have shown: That IN ketamine is a good pain reliever for children with acute pain, though perhaps not quite as good as IN fentanyl and with a higher side effect profile. It does provide a reasonable an alternate to an opiate however.[148]

Schoolman-Anderson et al present data relating to triage nurse initiated administration of IN fentanyl in a pediatric ED. They found rapid administration of pain meds (34.5 minutes), higher  utilization of IN fentanyl than pre-protocol (60% vs. 41% prior) and reductions of unneeded IV placement (0% vs. 24%). Patients and parents preferred the IN route for analgesia.[149]

Elitsur and colleagues (2019) utilized a minimal sedation and analgesia protocol to reduce pain and anxiety in patient with juvenile idiopathic arthritis who needed steroid injections in their joints. They were able to combine several agents including intranasal fentanyl into a regimen that resulted in pain scores of 1 for the patients. The result of this protocol change was the reduction of the need for general anesthesia to do this procedure and resultant dramatic drops in hospital charges – (and probably in length of stay.)[150]

Frey et al conducted a prospective randomized trial that compared the efficacy of IN ketamine (1.5 mg/kg) to IN fentanyl (2 ug/kg) in children with extremity injuries. They gave adequate doses of the medications bases on prior research and found that the two treatment modalities resulted in equivalent reductions in pain scores (about 3 out of 10). There were slightly more minor adverse events (dizzy, drowsy, bad taste) in the ketamine group but no serious adverse events.[151]

Guthrie et al did a chart review to evaluate their staff impression and patient outcomes when IN ketamine was used for analgesia or mild anxiolysis/sedation. They found high provider satisfaction and a drop in use of IV medications for analgesia and sedation. Interestingly (but not surprising if you have been paying attention for the last decade and are willing to use the proper does to obtain you clinical effect) the doctors preferred ketamine in the 3-5 mg/kg dose – higher than we see in many studies. Side effects occurred in 6% but were all minor (nausea, dizziness, drowsiness).[152]

Lord et al did a large data base review of pediatric EMS transports and found that once IN fentanyl was introduced they noted a significant increase in children who had clinically relevant reductions in their pain scores during transport.[153]

Miguez found that Orthopedic procedural sedation and pain control using IN fentanyl and nitrous oxide was equally effective as IV ketamine with fewer side effects and shorter lengths of stay. [154]

Williams and colleagues reviewed their experience in a pediatric urgent care and found that intranasal fentanyl and midazolam are safe and effective in this less resource intense setting.[155]

Ku conducted a small retrospective study on 17 neonatal ICU patients and noted that IN midazolam and fentanyl were safe and effective in this population.[165]

Sindhur et al evaluated the safety and efficacy of IN fentanyl in  111 premature infants (2 mcg/kg – a well established effective dose) to assist them in assessing retinopathy of prematurity.[166] They found this treatment significantly reduced pain with NO evidence of respiratory depression.

Editorial comment:Here is data showing IN fentanyl is pretty darn safe. These authors gave this drug to 111 premature children at full dose and found NO issues with respiratory compromise.

Turner investigated IN Ketamine (0.1 to 0.2 mg/kg titrated to effect using up to 5 doses) for treatment of migraine headaches in children, finding it to reduce pain by 66%.[167] They suggest ketamine should be added to your therapeutic options  for migraine treatment.

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.

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.

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.

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).

Graph comparing pain score versus time from Belkouch study

 Click here for the article (open access)

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).

Farnia et al compared IN ketamine 1 mg/kg to IV morphine  (0.1 mg/kg) for treating pain associated with acute renal colic. They found equivalent reductions in pain scores over the first 30 minutes. These findings suggest that ketamine maybe a suitable alternative to opiates for treating renal colic and IN ketamine might be useful to reduce resource e utilization by avoiding IV starts in some of these patients.[131]

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).

Parvizrad et al compared the efficacy of intranasal ketamine (0.4 mg/kg) to intravenous ketamine (0.2 mg/kg) for treating  pain associated with moderate to severe isolated extremity trauma. Despite the IN dose being in the low range (1-4 mg/kg is more typical ketamine dose to treat pain), they found both therapies were equally effective (VAS scores dropped a mean of about 45 mm on a 100 mm scale) and had equally low side effects. They feel that the use of IN ketamine is warranted in situations where venous cannulation is otherwise not needed (isolated extremity trauma for example), especially in a busy or crowded emergency department.[134]

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).

Fleet et al also noted that birthing women prefer IN fentanyl that they self administer for pain to either IM meperidine or subcutaneous fentanyl.[132]

Two studies in 2019 noted the efficacy on intranasal ketamine for the treatment of migraine headaches both in adults and in children suggesting this treatment modality might play a role in these complex cases. (Bernish, Turner) [156,157]

Blancher et al published one of several 2019 prospective randomized trials comparing IV morphine to intranasal sufentanil in adults with moderate to severe pain. They included trauma patients with pain scores > 6 on a 10 point scale. This study differs from the study by Sin, et al, (also 2019) in that it was done in Europe, it was multicenter and it allowed titration of the medications to effective pain control levels. They found sufentanil to be slightly superior to IV morphine for pain control by 30 minutes (equivalent at 10 and 20 minutes), (though because titration was allowed it seems they simply needed to give more medication should they want lower pain scores.)  They also found a few minor incidences of hypoxemia in both groups but more in the sufentanil group (3 of 67 versus 1 of 69). They conclude that titrating sufentanil via the IN route allows early, safe and effective analgesia in emergency settings and difficult situations.[158]

Graph from Blancher et al showing the reduction in pain scores (NRS – numerical pain reduction score) for IV morphine and IN sufentanil in patients suffering severe pain due to traumatic injuries.

Graph from Blancher et al showing the percentage of patients over time for whom their pain scores become less than 3 on the pain scale. This study allowed titration of IV morphine or IN sufentanil in patients suffering severe pain due to traumatic injuries. The key point being that you can easily and safely titrate pain to whatever level you desire using IN sufentanil.

Lemoel randomized 144 patients suffering severe traumatic limb pain (>6/10) to two cohorts: One got IN sufentanil in triage plus IV multimodal analgesia as needed, the second got only IV multimodal analgesia.  Pain control and patient satisfaction  were the same by ED discharge, however the IN sufentanil group had far high pain control (pain less than3/10) at 30 minutes from arrival than the IV group:  72% versus 52%. One patient in each group required supplemental oxygen.[159]

Mozafari found that a somewhat low dose of nasal ketamine of 1 mg/kg (given the pain severity) effectively reduced pain associated with renal colic from a mean score of 8.7 down to 2.5 in 30 minutes. This was slightly less effective than IV fentanyl (9.7 to 1.3) but did not require an IV.[160]  In a similar study, Nazemian showed that IN fentanyl was as effective as IV fentanyl for reducing renal colic pain in adults when both were combined with ketorolac.[161] Both of these studies (and prior studies by Belkouch 2015 and Farnia 2017)  point to a less resource intense way to treat renal colic: Transmucosal medication delivery o intranasal opiates (fentanyl or sufentanil) or intranasal ketamine. With the availability these analgesic options and of transmucosal antiemetics and intranasal or oral ketorolac/ibuprofen it is possible to treat renal colic with no IV access and with far less resource utilization. 

Nejati et al noted that intranasal ketamine at a single 50 mg dose in adults effectively reduces pain associated with digital nerve blocks. [162]

Sin et al conducted a prospective randomized trial compared IV morphine to IN sufentanil in adults with moderate to severe pain. They found that the two therapies were equivalent (pain scores decreasing from 9/10 to 2/10 for morphine  and from 10/10 to 2/10 for sufentanil in 5 minutes.) There were infrequent adverse events with none being serious.[163]

Banala et al provide yet more data demonstrating equivalent pain control and faster administration of the pain medication when intranasal fentanyl is compared to IV opiates (hydromorphone).[168]

Bouida et al conducted a double blind RCT that looked at the impact on opiate use in the ED in patients with acute limb injury who were randomized to IN ketamine vs placebo delivered at triage. They found that triage delivered IN ketamine led to less opiate and non-opiate analgesic use  and better overall pain scores at discharge.[169]

Nazemian found that renal colic patients treated with IV fentanyl or IN fentanyl (plus IM ketorolac in both groups) had identical significant reductions in pain.[170]

Pouraghaei el al conducted an RCT comparing In ketamine to IV morphine for renal colic patients. They found both treatments were equivalent in terms of pain reductions with no remarkable side effects in the ketamine group.[171]

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?

In 2019 Andolfatto et al published a well designed RCT in the EMS setting comparing IN ketamine to placebo in patients with pain scores over 5. IN ketamine was not just used in trauma patients like most pain studies, instead they included a variety of different causes of pain making it applicable to a broader EMS population. Using a relatively low dose of IN ketamine (0.75 mg/kg) they found clinically significant decreases in pain scores in 76% of cases (compared to 41% in placebo arm). The medics who administered this drug were not the advanced practice paramedics in the system. [164]

Editorial commentary: I think this is a really important paper in EMS for three major reasons. First it was on all comers (chest pain excluded) not just trauma cases so it demonstrates the broad utility of IN pain medications in EMS.  Second it used a non-sedating drug that does not cause respiratory depression - eliminating the opiate respiratory depression concern, potentially improving safety, at the least reducing opiate usage. I can envision this becoming a therapy that non-paramedic providers will safely and effectively administer in the not too distant future (as was the case in this study where it was delivered by non-paramedic EMTs). Finally, part of the problem with IN medications for pain control in adults has been that IN fentanyl (great in kids) is too dilute to be reliably effective in larger adults – especially those who have any experience with drugs. Sufentanil works great in these cases but is so potent that it probably will not ever be an EMS drug due to risk of death if it is stolen. So finally we have an effective drug for IN pain control in adults with EMS data to support it (and a lot of ER data to support it as well).

Tanguay et al noted nasal fentanyl to be an effective, safe and superior delivery technique compared to subcutaneous fentanyl  for pain management in adults over 70 years of age in the EMS system.[172]

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.

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:

• Oakland children's hospital order set for treating acute Vaso-occlusive crisis

• Oaklands recruitment tool for study on the concept (click here)

• Boston MC children's hospital order set for treating acute Vaso-occlusive crisis

Another abstract on this same topic was presented by Fein et al at the American academy of Pediatrics in October 2015 and then published in 2017.[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). Their study had significant design flaws (no titration, placebo arm got IV opiates, low doses of drug - but still showed promise for IN fetanyl. 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.

• https://aap.confex.com/aap/2015/webprogrampress/Paper29918.html

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.

Akinsola et al describe their experience with instituting a nurse initiated IN fentanyl pathway for sickle cell vaso-occlusive pain episodes. They found it resulted in reductions to first dose of pain medication compared to those who did not get IN fentanyl (29 vs. 77  minutes) and high patient/parent and nurse satisfaction with no negative side effects in approximately 200 patients they treated. Following this QI project they instituted the protocol across three large pediatric emergency departments.[138]  (Open access - click her for paper)

Kelly et al retrospectively reviewed 487 ED visits for sickle cell vaso-occlusive crisis, comparing clinical results of patients who were given IN fentanyl (376 children) with those given traditional IV medications (111 patients). Those given IN fentanyl had a shorter time to pain medication administration (29 vs. 78 minutes), higher percentage getting pain medication within 30 minutes (67% vs. 5%), reduced time to disposition decision (237 vs. 276 minutes) and reduced LOS (316 vs. 363 min). The retrospective nature of the study limits definitive conclusions but mirrors those results found for pediatric extremity injuries in randomized trials.[139]

Myrich et al noted that following the introduction of intranasal fentanyl to their outpatient sickle cell clinic they were able to deliver the first dose of opiates more rapidly, they used less morphine and they admitted fewer patients to the hospital.[173]

Paquin et al introduced nasal fentanyl as first line treatment for sickle cell crisis in their emergency room. They found a 41 minute decrease in time to first opiate dose and a 49% reduction in the need for IV line insertions. They did not see any impact on hospitalization rates.[174]

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.

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.

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)

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.

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.

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]

2017 and beyond: IN ketamine references are common and included in general text now or just listed here as references if not particularly important.[143-144]

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.

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)

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.

Treatment protocol

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.

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.

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