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. Therefor 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

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.
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.

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 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.

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. 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] 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. 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]

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.

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.

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."

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]

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)

  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.

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)

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.

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 Intranasal Diamorphine reconstitution and dosing protocol (click here).

Teaching materials:

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)

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

Bibliography (click here for abstracts)