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 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.

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.  Perhaps as important, these two authors as well as a third (Voronov et al) find that 9n 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] 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.

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."

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 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 mg/ml fentanyl is very effective, well tolerated and inexpensive method for treating painful injuries in children.

Intranasal opiates (fentanyl) for adult 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]

Intranasal opiates (diamorphine) 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.  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 15-20 minutes as needed would greatly reduce suffering, expedite patient care and reduced nursing resource utilization.

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.

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]

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

See separate extensive Hospice section as well (click here)

1. Fentanyl, sufentanil or diamorphine are most appropriate for IN delivery to treat pain and cause sedation
   1. Reasonable IN starting dose for painful procedures:
      1. Fentanyl: 2-3 ug/kg (comes in 50 ug/ml, you can ask your pharmacy to concentrate the solution or use sufentanil in larger patients).
      2. Sufentanil: 0.6 to .08 ug/kg
      3. Diamorphine 0.1 mg/kg (not available in USA)
   2. Administer half the dose into each nostril
   3. 1/4 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 5-10 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 – monitor patients with pulse oximetry and close observation whenever using these very powerful opiate medications, be even more careful when used in combination with midazolam.
   5. Titration to pain is often necessary – repeat dosing (1/2 dose) at 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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18. Dale, O., R. Hjortkjaer, and E.D. Kharasch, Nasal administration of opioids for pain management in adults. Acta Anaesthesiol Scand, 2002. 46(7): p. 759-70.

19. Takala, A., et al., Pharmacokinetic comparison of intravenous and intranasal administration of oxycodone. Acta Anaesthesiol Scand, 1997. 41(2): p. 309-12.

20. Wolfe, T., Intranasal fentanyl for acute pain: techniques to enhance efficacy. Ann Emerg Med, 2007. 49(5): p. 721-2.

21. Kendall, J.M. and V.S. Latter, Intranasal diamorphine as an alternative to intramuscular morphine: pharmacokinetic and pharmacodynamic aspects. Clin Pharmacokinet, 2003. 42(6): p. 501-13.

22. Abrams, R., et al., Safety and effectiveness of intranasal administration of sedative medications (ketamine, midazolam, or sufentanil) for urgent brief pediatric dental procedures. Anesth Prog, 1993. 40(3): p. 63-6.

23. Bates, B.A., S.A. Schutzman, and G.R. Fleisher, A comparison of intranasal sufentanil and midazolam to intramuscular meperidine, promethazine, and chlorpromazine for conscious sedation in children. Ann Emerg Med, 1994. 24(4): p. 646-51.

24. Bayrak, F., et al., A comparison of oral midazolam, oral tramadol, and intranasal sufentanil premedication in pediatric patients. J Opioid Manag, 2007. 3(2): p. 74-8.

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27. Vercauteren, M., et al., Intranasal sufentanil for pre-operative sedation. Anaesthesia, 1988. 43(4): p. 270-3.

28. Zedie, N., et al., Comparison of intranasal midazolam and sufentanil premedication in pediatric outpatients. Clin Pharmacol Ther, 1996. 59(3): p. 341-8.

29. Finkel, J.C., et al., The effect of intranasal fentanyl on the emergence characteristics after sevoflurane anesthesia in children undergoing surgery for bilateral myringotomy tube placement. Anesth Analg, 2001. 92(5): p. 1164-8.

30. Galinkin, J.L., et al., Use of intranasal fentanyl in children undergoing myringotomy and tube placement during halothane and sevoflurane anesthesia. Anesthesiology, 2000. 93(6): p. 1378-83.

31. Manjushree, R., et al., Intranasal fentanyl provides adequate postoperative analgesia in pediatric patients. Can J Anaesth, 2002. 49(2): p. 190-3.

32. Roelofse, et al., Intranasal sufentanil/midazolam versus ketamine/midazolam for analgesia/sedation in the pediatric population prior to undergoing multiple dental extractions under general anesthesia: a prospective, double-blind, randomized comparison. Anesth Prog, 2004. 51(4): p. 114-21.

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34. Striebel, W.H., et al., Intranasal meperidine titration for postoperative pain relief. Anesth Analg, 1993. 76(5): p. 1047-51.

35. Christrup, L.L., et al., Pharmacokinetics, efficacy, and tolerability of fentanyl following intranasal versus intravenous administration in adults undergoing third-molar extraction: A randomized, double-blind, double-dummy, two-way, crossover study. Clin Ther, 2008. 30(3): p. 469-81.

36. Mathieu, et al., Intranasal sufentanil is effective for postoperative analgesia in adults. Can J Anaesth, 2006. 53(1): p. 60-6.

37. Paech, M.J., et al., A new formulation of nasal fentanyl spray for postoperative analgesia: a pilot study. Anaesthesia, 2003. 58(8): p. 740-4.

38. Stoker, D.G., et al., Analgesic efficacy and safety of morphine-chitosan nasal solution in patients with moderate to severe pain following orthopedic surgery. Pain Med, 2008. 9(1): p. 3-12.

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45. Finn, J., et al., A randomised crossover trial of patient controlled intranasal fentanyl and oral morphine for procedural wound care in adult patients with burns. Burns, 2004. 30(3): p. 262-8.

46. Borland, M.L., et al., Intranasal fentanyl is an equivalent analgesic to oral morphine in paediatric burns patients for dressing changes: a randomised double blind crossover study. Burns, 2005. 31(7): p. 831-7.

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50. Borland, M.L., L.J. Clark, and A. Esson, Comparative review of the clinical use of intranasal fentanyl versus morphine in a paediatric emergency department. Emerg Med Australas, 2008. 20(6): p. 515-20.

51.  Heniff, M.S., et al., Comparison of routes of flumazenil administration to reverse midazolam-induced respiratory depression in a canine model. Acad Emerg Med, 1997. 4(12): p. 1115-8.

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53. Scheepers, L.D., et al., Plasma concentration of flumazenil following intranasal administration in children. Can J Anaesth, 2000. 47(2): p. 120-4.

54. Heard, C., P. Creighton, and J. Lerman, Intranasal flumazenil and naloxone to reverse over-sedation in a child undergoing dental restorations. Paediatr Anaesth, 2009. 19(8): p. 795-7.

55. Good, P., et al., Intranasal sufentanil for cancer-associated breakthrough pain. Palliat Med, 2009. 23(1): p. 54-8.

56. Kress, H.G., et al., Efficacy and tolerability of intranasal fentanyl spray 50 to 200 microg for breakthrough pain in patients with cancer: a phase III, multinational, randomized, double-blind, placebo-controlled, crossover trial with a 10-month, open-label extension treatment period. Clin Ther, 2009. 31(6): p. 1177-91.

57. Huge, V., et al., Effects of low-dose intranasal (S)-ketamine in patients with neuropathic pain. Eur J Pain, 2009.

58. Moodie, J.E., et al., The safety and analgesic efficacy of intranasal ketorolac in patients with postoperative pain. Anesth Analg, 2008. 107(6): p. 2025-31.

59. Kulbe, J., The use of ketamine nasal spray for short-term analgesia. Home Healthc Nurse, 1998. 16(6): p. 367-70.

60. Carr, D.B., et al., Safety and efficacy of intranasal ketamine for the treatment of breakthrough pain in patients with chronic pain: a randomized, double-blind, placebo-controlled, crossover study. Pain, 2004. 108(1-2): p. 17-27

61. Voronov, P., et al., Postoperative pain relief in infants undergoing myringotomy and tube placement: comparison of a novel regional anesthetic block to intranasal fentanyl--a pilot analysis. Paediatr Anaesth, 2008. 18(12): p. 1196-201.

62. Cole, J., M. Shepherd, and P. Young, Intranasal fentanyl in 1-3-year-olds: A prospective study of the effectiveness of intranasal fentanyl as acute analgesia. Emerg Med Australas, 2009. 21(5): p. 395-400.

63. Holdgate, A., A. Cao, and K.M. Lo, The Implementation of Intranasal Fentanyl for Children in a Mixed Adult and Pediatric Emergency Department Reduces Time to Analgesic Administration. Acad Emerg Med, 2010. 17:p1-4.

64. Crellin, D., R.X. Ling, and F.E. Babl, Does the standard intravenous solution of fentanyl (50 microg/mL) administered intranasally have analgesic efficacy? Emerg Med Australas, 2010. 22(1): p. 62-7.