Seizing child recieving IN treatmentTherapeutic Intranasal Drug Delivery

Needleless treatment options for medical problems

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Intranasal opiates (fentanyl, sufentanil, morphine) and ketamine for the treatment of acute, chronic and breakthrough pain - abstracted references:

(1988). "Sedation, analgesia, and intranasal sufentanil." Lancet 2(8601): 24.

(2003). "Intranasal delivery of morphine may offer better effects." Clin J Oncol Nurs 7(4): 377.

(2006). "Intranasal morphine for postoperative pain." J Pain Palliat Care Pharmacother 20(2): 93-4.

Abdell-Ghaffar, H. and M. A. M. Salem (2012). "Safety and Analgesic efficacy of Pre-emptive Intranasal Ketamine versus Intranasal fentanyl in patients undergoing endoscopic nasal surgery." Journal Am Sci 8(3): 430-436.

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Objectives: No  clinical  studies  investigated nasal mucosal  coverage  and nasal  integrity  as  local causative  factors  for  inter-individual  variation  in  clinical  effects  commonly  reported  with  intranasal  opioid  administration.  Moreover, most of published clinical trails investigated the use of intranasal analgesic medications in extranasal painful  settings. The purpose of this study was to demonstrate safety and analgesic efficacy of pre-emptive intranasal ketamine  (non-opioid)  vs.  intranasal  fentanyl  (opioid)  in  patients  undergoing  endoscopic  nasal  surgery. Methods: 60  adult  normotensive  patients  were  randomly  assigned  to  receive  intranasal  administration  of  either  1.5mg/kg  ketamine  50mg/ml (INK group, n=20) or 1.5µg/kg fentanyl 50µg/ml (INF group, n=20), or saline (placebo group, n=20) 30 min.  before induction of general anesthesia. Assessment parameters included; hemodynamics, postoperative pain, sedation  and adverse effects. Results: Intranasal fentanyl significantly attenuated hemodynamic changes in SBP, DBP and HR at  1,  3,  5  and  7min.  after  intubation.  INK  and  INF  significantly  prolonged  time  to  first  analgesic  request  (253.74±25.01min. P<0.000 vs. 233.80±24.57min, P<0.000), compared with placebo (120.71±24.64min.). Diclofenac  consumption  was  significantly  reduced  in  INK  (85.32±10.31mg)  and  INF  (81.42±8.48mg)  compared  with  placebo  (150.00±0.00mg). VAS scores were significantly lower with INK and INF in first 4h postoperative (P<0.000) with a  trend  towards  lower  values  at  all  recorded  time  points.  Incidence  of  adverse  effects  was  higher  in INK,  While  the  surgeon (P<0.000) and patient (P<0.000) satisfaction indices were higher with INF. Conclusion: Intranasal ketamine or  intranasal  fentanyl  enhanced  postoperative  analgesia  after  endoscopic  nasal  surgery.  Psychomimetic  side  effects  of  ketamine still occur with intranasal administration and the clinical goal of ketamine must be defined.

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

Thirty children presenting to the dental clinic of a pediatric hospital who required brief but urgent dental care, and who could not be satisfactorily examined or treated, were administered one of three medications--ketamine (Ketalar), 3 mg/kg; midazolam (Versed), 0.4 mg/kg; or sufentanil (Sufenta), 1.5 or 1.0 micrograms/kg--intranasally in a randomized, double-blinded protocol. The patients were brought to the day surgery area following appropriate fasting and administered one of the medications diluted in a dose of 0.1 mL/kg normal saline while sitting in a nurse's arms. Cardiorespiratory monitors were applied when tolerated, and the child was placed on the operating room table. Each child was injected locally with up to one dental cartridge of 2% lidocaine with 1:100,000 epinephrine before dental extractions. A sedation score was recorded using a scale where 1 = hysterical/untreatable, 5 = ideal sedation, and 10 = obtunded and desaturated, requiring airway management assistance. Midazolam administration resulted in acceptable sedation (mean score: 4) with no desaturations below 90% as measured by pulse oximetry and a mean recovery room observation time of only 3 +/- 2 min (+/- SD). Ketamine also had a mean sedation score of 4 and a short recovery period (7 +/- 7 min); however, two children experienced brief desaturations. Sufentanil at 1.5 micrograms/kg was noted to produce much more heavily sedated children (mean score 7), with a high incidence of significant oximetry desaturation (80%) and prolonged recovery room duration (58 +/- 40 min). Use of 1.0 microgram/kg sufentanil resulted in no desaturations, less sedation (mean score 4), and a brief recovery time (7 +/- 13 min).(ABSTRACT TRUNCATED AT 250 WORDS)

Adelgais, K. M., A. Brent, et al. (2017). "Intranasal Fentanyl and Quality of Pediatric Acute Care." J Emerg Med.

                BACKGROUND: Changes in the manner in which medications can be delivered can have significant effects on the quality of care in the acute care setting. OBJECTIVE: The objective of this study was to evaluate the change in three Institute of Medicine quality indicators (timeliness, safety, and effectiveness) in the pediatric emergency department (ED) after the introduction of the Mucosal Atomizer Device Nasal (MADn) for opioid analgesia. METHODS: This was a retrospective review of patients receiving opioid analgesia for certain conditions over a 5-year period. We compared patients receiving intravenous opioid (IVO) to those receiving intranasal fentanyl (INF). Timeliness outcomes include time from medication order to administration, time from dose to discharge, overall time to analgesia, and ED length of stay. Effectiveness outcomes include change in pain score and frequency of repeat dosing. Safety outcomes were the frequency of reversal agent administration or a documented oxygen desaturation of < 90%. Sensitivity analyses were performed to evaluate the effect of moderate sedation on all three outcomes. RESULTS: During the study period, 1702 patients received opioid analgesia, 744 before and 958 after MADn introduction, of whom, 233 (24%) received INF. After MADn introduction, patients receiving INF had a shorter time to discharge from dose (109 vs. 203 min; p < 0.05) and shorter ED length of stay (168 vs. 267 min; p < 0.05). There was no difference in pain score reduction; however, repeat dosing was less frequent for patients receiving INF (16% vs. 27%). There was no use of reversal medication and no difference in the frequency of oxygen desaturations. When patients undergoing moderate sedation were removed from the analysis, there was no difference in the direction of findings for all three outcomes. CONCLUSIONS: INF is associated with improved timeliness and equivalent effectiveness and safety when compared to IVO in the setting of the pediatric ED.

Afridi, S. K., N. J. Giffin, et al. (2013). "A randomized controlled trial of intranasal ketamine in migraine with prolonged aura." Neurology 80(7): 642-647.

OBJECTIVE: The aim of our study was to test the hypothesis that ketamine would affect aura in a randomized controlled double-blind trial, and thus to provide direct evidence for the role of glutamatergic transmission in human aura. METHODS: We performed a double-blinded, randomized parallel-group controlled study investigating the effect of 25 mg intranasal ketamine on migraine with prolonged aura in 30 migraineurs using 2 mg intranasal midazolam as an active control. Each subject recorded data from 3 episodes of migraine. RESULTS: Eighteen subjects completed the study. Ketamine reduced the severity (p = 0.032) but not duration of aura in this group, whereas midazolam had no effect. CONCLUSIONS: These data provide translational evidence for the potential importance of glutamatergic mechanisms in migraine aura and offer a pharmacologic parallel between animal experimental work on cortical spreading depression and the clinical problem. CLASSIFICATION OF EVIDENCE: This study provides class III evidence that intranasal ketamine is effective in reducing aura severity in patients with migraine with prolonged aura.

Akinsola B.T., Hagbon R., Zmitrovich A., et al: More rapid delivery of parenteral analgesia by adding intranasal fentanyl to the management of sickle cell disease Vaso-occlusive pain.

Background: Vaso-occlusive episodes (VOE) are the leading cause of hospitalizations & emergency department (ED) visits in sickle cell disease (SCD), & are associated with increased mortality. Intranasal fentanyl (INF) provides rapid & powerful parenteral analgesia, with an onset of action of 5-10 minutes, & peak effect in 30 minutes.  INF is a safe & effective method of pain management for children in the ED & other settings, yet it is underutilized in SCD. Objective: To study the impact of the addition of  INF to standard ED management for SCD VOE on time to parenteral opioid, pain scores, ED length of stay (LOS) & admission rate. Methods: This quality improvement initiative was conducted at a tertiary pediatric ED at Children's Healthcare of Atlanta from November 2013-May 2014. Patients with all genotypes of SCD ages ≥2 years old who presented with VOE & pain score >6/10 were offered INF within 15 minutes of triage. 2 INF doses (1.5mcg/kg/dose; max 100mcg/dose) were given 5 minutes apart. Patients then continued on institutional standard protocol treatment for VOE (±PO hydrocodone, ±IV ketorolac, & ± IV morphine or IV hydromorphone). Pain scores were documented at frequent intervals by nursing staff. Patient/parent satisfaction data were obtained using a satisfaction questionnaire. Outcomes included: Time from arrival to 1st parenteral opioid, pain scores, ED LOS (time from arrival to disposition), admission rates & patient/parent satisfaction. We compared patients in this study to those who did not receive INF during the study period (n=48) & historical controls from Jan-Dec 2012 (n=231) for the 1st three outcomes. Results: 248 visits for VOE met inclusion criteria, of whom 228 received parenteral opioids (92%) & 180/228 (79 %) received INF. Mean age was 11.7±4.5 years. The majority were female (56%), 65% HbSS, 14% HbSC & 21% had other genotype.  48 patients did not receive INF; 36 were not offered INF without explanation for protocol deviation &12 patients refused. They had similar gender & Hb genotype, but were older than INF+ patients (13.5±4.0 years, p=0.01).   The mean time from arrival to 1st parenteral opioid decreased significantly in the INF+ group compared to historical controls, and was remarkably shorter than those not treated with INF. There was minimal difference in LOS between INF+ group & historical controls, but LOS was shorter in the group that did not receive INF. Admission rates were significantly higher in those who did not receive INF when compared to those treated with INF & historical controls.

(See Table 1)

Table 1



(n =180)


(n =48)

Historical Data (n=231)


Time to 1st Parenteral Opioid (minutes)

29 ±15

77 ±44


p < 0.0001

LOS (minutes)

215± 86

197± 67


p = 0.028

Admission Rate (%)




p = 0.004

Mean baseline pain score was 8.5±1.5, 1st reassessment pain score after INF was 7.8±2.4 & last ED pain score prior to disposition was 5.5±3.4. Pain scores were similar in all groups.  98 families completed the patient satisfaction questionnaire, 79 (81%) of whom received INF. 65% of patients who received INF were satisfied & would like to receive the treatment again in the ED. Conclusions: The addition of INF to the management of SCD VOE significantly improved time to receipt of 1st parenteral analgesia & was well tolerated.  Admission rates were significantly higher in patients who did not receive INF during our study period. The associated delay in time to receipt of 1st parenteral analgesia may have contributed to the increased admission rate. However, causality of INF on admission rates cannot be determined without further study. INF did not impact ED LOS compared to historical controls, however rapid admission turn-around time likely decreased LOS in the INF- group.   INF is a safe & effective strategy to provide rapid pain relief in children with SCD & VOE. Disclosures: Off Label Use: Intranasal Fentanyl (INF). Widely accepted as off label use in pediatric ED's and a variety of other clinical settings for the management of pain. It is a synthetic narcotic analgesic with a rapid onset and short duration of action. Current evidence suggests that INF is a safe and effective method of pain management for children in a variety of clinical settings..

Akinsola, B., R. Hagbom, et al. (2018). "Impact of Intranasal Fentanyl in Nurse Initiated Protocols for Sickle Cell Vaso-occlusive Pain Episodes in a Pediatric Emergency Department." Am J Hematol.

 Ali, S. and T. P. Klassen (2007). "Intranasal fentanyl and intravenous morphine did not differ for pain relief in children with closed long-bone fractures." Evid Based Med 12(6): 176.

Andolfatto, G., E. Willman, et al. (2013). "Intranasal Ketamine for Analgesia in the Emergency Department: A Prospective Observational Series." Acad Emerg Med 20(10): 1050-1054.

OBJECTIVES: The objective was to examine the feasibility, effectiveness, and adverse effect profile of intranasal ketamine for analgesia in emergency department (ED) patients. METHODS: This was a prospective observational study examining a convenience sample of patients aged older than 6 years experiencing moderate or severe pain, defined as a visual analog scale (VAS) score of 50 mm or greater. Patients received 0.5 to 0.75 mg/kg intranasal ketamine. Pain scores were recorded on a standard 100-mm VAS by trained investigators at baseline, then every 5 minutes for 30 minutes, and then every 10 minutes for an additional 30 minutes. The primary outcome was the number and proportion of patients experiencing clinically significant reductions in VAS pain scores, defined as VAS reductions of 13 mm or more, within 30 minutes. Secondary outcomes included the median reduction in VAS, the median time required to achieve a 13 mm reduction in VAS, vital sign changes, and adverse events. Continuous data are reported with medians and interquartile ranges (IQRs). The Wilcoxon signed-ranks test was used to assess changes in VAS scores. Adverse effects are reported with proportions and 95% confidence intervals (CIs). RESULTS: Forty patients were enrolled with a median age of 47 years (IQR = 36 to 57 years; range = 11 to 79 years) for primarily orthopedic injuries. A reduction in VAS of 13 mm or more within 30 minutes was achieved in 35 patients (88%). The median change in VAS at 30 minutes was 34 mm (44%). Median time required to achieve a 13 mm VAS reduction was 9.5 minutes (IQR = 5 to 13 minutes; range = 5 to 25 minutes). No serious adverse effects occurred. Minor adverse effects included dizziness (21 patients, 53%; 95% CI = 38% to 67%), feeling of unreality (14 patients, 35%; 95% CI = 22% to 50%), nausea (four patients, 10%; 95% CI = 4% to 23%), mood change (three patients, 8%; 95% CI = 3% to 20%), and changes in hearing (one patient, 3%; 95% CI = 0% to 13%). All adverse effects were transient and none required intervention. There were no changes in vital signs requiring clinical intervention. CONCLUSIONS: Intranasal ketamine reduced VAS pain scores to a clinically significant degree in 88% of ED patients in this series. Adverse effects were minor and transient. Intranasal ketamine may have a role in the provision of effective, expeditious analgesia to ED patients.

Andolfatto, G., K. Innes, et al. (2019). "Prehospital Analgesia With Intranasal Ketamine (PAIN-K): A Randomized Double-Blind Trial in Adults." Ann Emerg Med 74(2): 241-250.

STUDY OBJECTIVE: We compare intranasal ketamine with intranasal placebo in providing pain reduction at 30 minutes when added to usual paramedic care with nitrous oxide. METHODS: This was a randomized double-blind study of out-of-hospital patients with acute pain who reported a verbal numeric rating scale (VNRS) pain score greater than or equal to 5. Exclusion criteria were younger than 18 years, known ketamine intolerance, nontraumatic chest pain, altered mental status, pregnancy, and nasal occlusion. Patients received usual paramedic care and were randomized to receive either intranasal ketamine or intranasal saline solution at 0.75 mg/kg. The primary outcome was the proportion of patients with VNRS score reduction greater than or equal to 2 at 30 minutes. Secondary outcomes were pain reduction at 15 minutes, patient-reported comfort, satisfaction scores, nitrous oxide consumption, and incidence of adverse events. RESULTS: One hundred twenty subjects were enrolled. Seventy-six percent of intranasal ketamine patients versus 41% of placebo patients reported a greater than or equal to 2-point VNRS reduction at 30 minutes (difference 35%; 95% confidence interval 17% to 51%). Median VNRS reduction at 15 minutes was 2.0 and 1.0 and at 30 minutes was 3.0 and 1.0 for ketamine and placebo, respectively. Improved comfort at 15 and 30 minutes was reported for 75% versus 57% and 61% versus 46% of ketamine and placebo patients, respectively. Sixty-two percent of patients (95% confidence interval 49% to 73%) versus 20% (95% confidence interval 12% to 32%) reported adverse events with ketamine and placebo, respectively. Adverse events were minor, with no patients requiring physical or medical intervention. CONCLUSION: Added to nitrous oxide, intranasal ketamine provides clinically significant pain reduction and improved comfort compared with intranasal placebo, with more minor adverse events.

Arnautovic, T., K. Sommese, et al. (2018). "Evaluating the Implementation Barriers of an Intranasal Fentanyl Pain Pathway for Pediatric Long-Bone Fractures." Pediatr Emerg Care 34(7): 473-478.

OBJECTIVES: This study aimed to assess physician comfort, knowledge, and implementation barriers regarding the use of intranasal fentanyl (INF) for pain management in patients with long-bone fractures in a pediatric emergency department (ED) with an INF pain pathway. METHODS: A retrospective chart review was conducted of patients, 3 to 21 years old, in our ED with an International Classification of Diseases-9th Revision code for a long-bone fracture from September 1, 2013, to August 31, 2015. Patients were divided into 4 groups: (1) received INF on the pathway appropriately; (2) "missed opportunities" to receive INF, defined as either INF was ordered and then subsequently canceled (for pain ratings, >/=6/10), or INF was ordered, cancelled, and intravenous (IV) morphine given, or INF was not ordered and a peripheral IV line was placed to give IV morphine as first-line medication; (3) peripheral IV established upon ED arrival; (4) no pain medication required. Additionally, a survey regarding practice habits for pain management was completed to evaluate physician barriers to utilization of the pathway. RESULTS: A total of 1374 patients met the inclusion criteria. Missed opportunities were identified 41% of the time. Neither younger patient age nor more years of physician experience in the ED were associated with increased rates of missed opportunities. The survey (95% response rate) revealed greater comfort with and preference for IV morphine over INF. CONCLUSIONS: The high rate of missed opportunities, despite the implementation of an INF pain pathway, indicates the need for further exploration of the barriers to utilization of the INF pain pathway.

Banala, S. R., O. K. Khattab, et al. (2020). "Intranasal fentanyl spray versus intravenous opioids for the treatment of severe pain in patients with cancer in the emergency department setting: A randomized controlled trial." PLoS One 15(7): e0235461.

OBJECTIVE: Intranasal fentanyl (INF) quickly and noninvasively relieves severe pain, whereas intravenous hydromorphone (IVH) reliably treats severe cancer pain but requires vascular access. The trial evaluated the efficacy of INF relative to IVH for treating cancer patients with severe pain in an emergency department (ED) setting. METHODS: We randomized 82 patients from a comprehensive cancer center ED to receive INF (n = 42) or IVH (n = 40). Eligible patients reported severe pain at randomization (>/=7, scale: 0 "none" to 10 "worst pain"). We conducted non-inferiority comparisons (non-inferiority margin = 0.9) of pain change from treatment initiation (T0) to one hour later (T60). T0 pain ratings were unavailable; therefore, we estimated T0 pain by comparing 1) T60 ratings, assuming similar group T0 ratings; 2) pain change, estimating T0 pain = randomization ratings, and 3) pain change, with T0 pain = 10 (IVH group) or T0 pain = randomization rating (INF group). RESULTS: At T60, the upper 90% confidence limit (CL) of the mean log-transformed pain ratings for the INF group exceeded the mean IVH group rating by 0.16 points (>pain). Substituting randomization ratings for T0 pain, the lower 90% CL of mean pain change in the INF group extended 0.32 points below (<pain relief) mean change in the IVH group. Finally, assuming all subjects in the IVH group had maximum pain at T0 and that T0 pain for the INF group remained unchanged from randomization, the lower bound of the 90% CL for mean pain decrease in the INF group extended 1.37 points below (<pain relief) mean decrease in the IVH group. Time (minutes) from randomization until T0 was longer for the IVH (Median 23, IQR 12) versus INF (Median 15, IQR 11) group (P<0.001). CONCLUSIONS: Two of three analyses supported non-inferiority of INF versus IVH, while one analysis was inconclusive. Compared to IVH, INF had the advantage of shorter time to administration. TRIAL REGISTRATION: Identifier: NCT02459964.

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

            STUDY OBJECTIVE: To compare intranasal sufentanil and midazolam (IN-SM) with intramuscular meperidine, promethazine, and chlorpromazine (IM-MPC) for sedation in children. DESIGN: Single-blind, randomized, controlled study. SETTING: Urban children's emergency department. PARTICIPANTS: A convenience sample of children aged 1 to 4 years requiring suturing. INTERVENTIONS: IN-SM or IM-MPC. RESULTS: Vital signs, O2 saturation, and anxiety and pain scores were recorded. A 6-point scale was used to assess response to medication, and a 12-point recovery score was used to determine readiness for discharge. Both groups were similar in age and sex distribution. There were no significant adverse effects in either group. Patients tolerated the IN regimen better than the IM regimen. Behavioral scores were lower during repair than at baseline within each group; however, they were not different between groups. Time to discharge was longer and recovery scores were lower (worse) among the IM-MPC group. CONCLUSION: IN-SM is as effective as IM-MPC for sedation in children.

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

            BACKGROUND: This study was designed to evaluate the efficacy and safety of oral midazolam, tramadol drops, and intranasal sufentanil for premedication of pediatric patients. METHODS: Sixty children, three to 10 years of age, who were designated as American Society of Anesthesiologists physical status 1 and who were undergoing adenotonsillectomy as inpatients were randomized to receive a dosage of 0.5 mg/kg (total of 4 ml) midazolam in cherry juice (n=20, Group M), 3 mg/kg tramadol drops (n=20, Group T), or 2 microg/kg intranasal sufentanil (n=20, Group S). Clinical responses (sedation, anxiolysis, cooperation) and adverse effects (respiratory, hemodynamic, etc.) were recorded. Safety was assessed by continuous oxygen saturation monitoring and observation. Vital signs (blood pressure, pulse, oxygen saturation, respiratory rate) were recorded before drug administration (baseline) and then every 10 minutes until the induction of anesthesia. RESULTS: Mean blood pressure decreased significantly after five minutes of intranasal sufentanil administration relative to Groups M (p < 0.01) and T (p < 0.05), whereas heart rate remained unchanged. Oxygen saturation and respiratory rate decreased significantly after 20 and 30 minutes of intranasal sufentanil administration relative to Groups M and T (p < 0.05). Anxiety scores showed rates of 45 percent in Group M, 5 percent in Group T, and 40 percent in Group S. Anxiety scores in Groups M and S were better than those of Group T (p < 0.01). Cooperation scores for face-mask acceptance showed rates of 85 percent in Group M, 45 percent in Group T, and 85 percent in Group S (p < 0.01). CONCLUSION: Intranasal sufentanil and oral midazolam are more appropriate premedication options than tramadol drops in children.

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

                INTRODUCTION: Intranasal fentanyl provides rapid and powerful analgesia which is particularly interesting in patients without intravenous access. We propose to use it for analgesia in adults presenting renal colics. METHODS: A prospective study was conducted from the 2nd January to February 2013 in our emergency department. Patients aged up to 18 years old who presented with renal colic were included in this audit. Patients were excluded if they had loss of consciousness, cognitive impairment, acute or chronic nasal problems. A formal written consent was obtained from patients. The research team was alerted by medical and nursing staff. A member of the research team would check with medical or nursing staff whether administration of Intra nasal (IN) fentanyl was required. It was administered at a pre-calculated dose of 1.5 mg/kg and 50 mg/ml concentration was used. Data was prospectively collected by one of the researchers at various intervals during the patient's presentation and recorded on a pre-formatted data sheet. Pain scores were collected at 5, 15, 30, 45 and 60 minutes following IN fentanyl using a visual analogue scale pain. Observations routinely collected for patients receiving IV opiates and any adverse events were also recorded. RESULTS: 23 eligible patients were enrolled; median age was 51,3 years. 47,8% were women and the mean weight was 73 kg. Median dose of IN fentanyl was 106 mug. Two patients have required morphinic analgesia despite having received adapted dose of IN fentanyl. The initial pain scores before IN fentanyl were high with a median of 82,2 mm (59-100). Five minutes after IN fentanyl administration the median pain score dropped to 48 mm(36-63) and achieved the lowest score of 8mm(0-22) at 30 min. Pain scores were significantly lower at 5 min (P < 0.001) and at all subsequent time points (P < 0.001). No side effects were recorded. CONCLUSION: Intranasal fentanyl seems to be efficient for analgesia in adult patients with renal colic.

Bendall, J. C., P. M. Simpson, et al. (2011). "Effectiveness of Prehospital Morphine, Fentanyl, and Methoxyflurane in Pediatric Patients." Prehosp Emerg Care.

Abstract: Objectives. To compare the effectiveness of intravenous morphine, intranasal (IN) fentanyl, and inhaled methoxyflurane for managing moderate to severe pain in pediatric patients in the out-of-hospital setting. Methods. We conducted a retrospective comparative study of 3,312 pediatric patients aged between 5 and 15 years who had moderate to severe pain (pain score over 5) and who received intravenous morphine, IN fentanyl, or inhaled methoxyflurane, either alone or in combination, between January 1, 2004, and November 30, 2006. Multivariate logistic regression was used to analyze data extracted from a clinical database containing routinely entered information from patient health care records. The primary outcome measure was effective analgesia, defined as a reduction in pain severity of over 30% of initial pain score using an 11-point verbal numeric rating scale. Results. Effective analgesia was achieved in 82.5% of cases overall. All analgesic agents were effective in the majority of patients (87.5%, 89.5%, and 78.3% for morphine, fentanyl, and methoxyflurane, respectively). There was evidence that methoxyflurane was less effective than both morphine (odds ratio [OR] 0.52; 95% confidence interval [CI] 0.36-0.74) and fentanyl (OR 0.43; 95% CI 0.29-0.62; p < 0.0001). There was no clinical or statistical evidence of difference in the effectiveness of fentanyl and morphine in this population (OR 1.22; 95% CI 0.74-2.01). There was no evidence that combination analgesia was better than either fentanyl or morphine alone. Conclusion. Intranasal fentanyl and intravenous morphine are equally effective analgesic agents in pediatric patients with moderate to severe acute pain in the out-of-hospital setting. Methoxyflurane is less effective in comparison with both morphine and fentanyl, but is an effective analgesic in the majority of children.

Benish, T., D. Villalobos, et al. (2019). "The THINK (Treatment of Headache with Intranasal Ketamine) Trial: A Randomized Controlled Trial Comparing Intranasal Ketamine with Intravenous Metoclopramide." J Emerg Med 56(3): 248-257 e241.

BACKGROUND: Headache is a common chief complaint in the emergency department (ED) setting. OBJECTIVES: To compare analgesia with metoclopramide and diphenhydramine vs. intranasal ketamine among ED patients with primary headache. METHODS: We enrolled a convenience sample of adults with a primary headache in a randomized, single-blind, placebo-controlled trial. We randomized patients to either a control arm (intravenous metoclopramide and diphenhydramine) or intranasal ketamine. The primary outcome was change in pain 0-100 mm visual analog scale (VAS) score measured at study start and 30 min post completion of initial medication administration. Secondary outcomes included side effects, hospital admission, and return to care within 48-72 h. RESULTS: All 53 enrolled subjects completed the study, 26 of whom were allocated to the control arm and 27 to intranasal ketamine. The mean change in pain VAS score at 30 min post intervention was 22.2 mm in the control arm vs. 29.0 in the intranasal ketamine arm (effect size difference 6.8 mm, 95% confidence interval -5.8-19.4). The incidence of reported side effects was 65.4% in the control arm vs. 66.7% in the ketamine arm. Three patients (11.5%) allocated to the control arm required admission for headache pain control vs. 1 patient (3.7%) in the intranasal ketamine arm. Three (11.5%) additional patients in the control arm returned to the ED within 48-72 h for headache pain vs. none in the ketamine arm. CONCLUSIONS: In this small randomized study, intranasal ketamine was not superior to standard therapy among ED patients with primary headache syndromes.

Blancher, M., M. Maignan, et al. (2019). "Intranasal sufentanil versus intravenous morphine for acute severe trauma pain: A double-blind randomized non-inferiority study." PLoS Med 16(7): e1002849.

BACKGROUND: Intravenous morphine (IVM) is the most common strong analgesic used in trauma, but is associated with a clear time limitation related to the need to obtain an access route. The intranasal (IN) route provides easy administration with a fast peak action time due to high vascularization and the absence of first-pass metabolism. We aimed to determine whether IN sufentanil (INS) for patients presenting to an emergency department with acute severe traumatic pain results in a reduction in pain intensity non-inferior to IVM. METHODS AND FINDINGS: In a prospective, randomized, multicenter non-inferiority trial conducted in the emergency departments of 6 hospitals across France, patients were randomized 1:1 to INS titration (0.3 mug/kg and additional doses of 0.15 mug/kg at 10 minutes and 20 minutes if numerical pain rating scale [NRS] > 3) and intravenous placebo, or to IVM (0.1 mg/kg and additional doses of 0.05 mg/kg at 10 minutes and 20 minutes if NRS > 3) and IN placebo. Patients, clinical staff, and research staff were blinded to the treatment allocation. The primary endpoint was the total decrease on NRS at 30 minutes after first administration. The prespecified non-inferiority margin was -1.3 on the NRS. The primary outcome was analyzed per protocol. Adverse events were prospectively recorded during 4 hours. Among the 194 patients enrolled in the emergency department cohort between November 4, 2013, and April 10, 2016, 157 were randomized, and the protocol was correctly administered in 136 (69 IVM group, 67 INS group, per protocol population, 76% men, median age 40 [IQR 29 to 54] years). The mean difference between NRS at first administration and NRS at 30 minutes was -4.1 (97.5% CI -4.6 to -3.6) in the IVM group and -5.2 (97.5% CI -5.7 to -4.6) in the INS group. Non-inferiority was demonstrated (p < 0.001 with 1-sided mean-equivalence t test), as the lower 97.5% confidence interval of 0.29 (97.5% CI 0.29 to 1.93) was above the prespecified margin of -1.3. INS was superior to IVM (intention to treat analysis: p = 0.034), but without a clinically significant difference in mean NRS between groups. Six severe adverse events were observed in the INS group and 2 in the IVM group (number needed to harm: 17), including an apparent imbalance for hypoxemia (3 in the INS group versus 1 in the IVM group) and for bradypnea (2 in the INS group versus 0 in the IVM group). The main limitation of the study was that the choice of concomitant analgesics, when they were used, was left to the discretion of the physician in charge, and co-analgesia was more often used in the IVM group. Moreover, the size of the study did not allow us to conclude with certainty about the safety of INS in emergency settings. CONCLUSIONS: We confirm the non-inferiority of INS compared to IVM for pain reduction at 30 minutes after administration in patients with severe traumatic pain presenting to an emergency department. The IN route, with no need to obtain a venous route, may allow early and effective analgesia in emergency settings and in difficult situations. Confirmation of the safety profile of INS will require further larger studies. TRIAL REGISTRATION: NCT02095366. EudraCT 2013-001665-16.

Borland, M., I. Jacobs, et al. (2007). "A randomized controlled trial comparing intranasal fentanyl to intravenous morphine for managing acute pain in children in the emergency department." Ann Emerg Med 49(3): 335-40.

            STUDY OBJECTIVE: We compare the efficacy of intranasal fentanyl versus intravenous morphine in a pediatric population presenting to an emergency department (ED) with acute long-bone fractures. METHODS: We conducted a prospective, randomized, double-blind, placebo-controlled, clinical trial in a tertiary pediatric ED between September 2001 and January 2005. A convenience sample of children aged 7 to 15 years with clinically deformed closed long-bone fractures was included to receive either active intravenous morphine (10 mg/mL) and intranasal placebo or active intranasal concentrated fentanyl (150 microg/mL) and intravenous placebo. Exclusion criteria were narcotic analgesia within 4 hours of arrival, significant head injury, allergy to opiates, nasal blockage, or inability to perform pain scoring. Pain scores were rated by using a 100-mm visual analog scale at 0, 5, 10, 20, and 30 minutes. Routine clinical observations and adverse events were recorded. RESULTS: Sixty-seven children were enrolled (mean age 10.9 years [SD 2.4]). Fractures were radius or ulna 53 (79.1%), humerus 9 (13.4%), tibia or fibula 4 (6.0%), and femur 1 (1.5%). Thirty-four children received intravenous (i.v.) morphine and 33 received intranasal fentanyl. Statistically significant differences in visual analog scale scores were not observed between the 2 treatment arms either preanalgesia or at 5, 10, 20, or 30 minutes postanalgesia (P=.333). At 10 minutes, the difference in mean visual analog scale between the morphine and fentanyl groups was -5 mm (95% confidence interval -16 to 7 mm). Reductions in combined pain scores occurred at 5 minutes (20 mm; P=.000), 10 minutes (4 mm; P=.012), and 20 minutes (8 mm; P=.000) postanalgesia. The mean total INF dose was 1.7 microg/kg, and the mean total i.v. morphine dose was 0.11 mg/kg. There were no serious adverse events. CONCLUSION: Intranasal fentanyl delivered as 150 microg/mL at a dose of 1.7 microg/kg was shown to be an effective analgesic in children aged 7 to 15 years presenting to an ED with an acute fracture when compared to intravenous morphine at 0.1 mg/kg.

Borland, M. L., I. Jacobs, et al. (2002). "Intranasal fentanyl reduces acute pain in children in the emergency department: a safety and efficacy study." Emerg Med (Fremantle) 14(3): 275-80.

            INTRODUCTION: Provision of rapid, painless and effective analgesia to children remains problematic in the prehospital and emergency setting. Intranasal fentanyl has the potential to eliminate many of the problems of narcotic administration in children. The aim of this study, conducted in a tertiary paediatric emergency department was to evaluate the safety and efficacy of intranasal fentanyl in children. METHODS: Children in acute pain aged between three and 12 years inclusive were enrolled on presentation to the emergency department. Routine observations and pain scoring by the child and caregiver was undertaken prior to the child receiving fentanyl (20 micrograms for 3-7 year olds and 40 micrograms for 8-12 year olds) and at intervals of 5 min for 30 min Additional fentanyl at the dose of 20 micrograms was given 5 minutely as required. Caregivers and older children used a visual analogue scale (VAS) and the younger children used the Wong-Baker faces scale (WBS). RESULTS: Forty five children were enrolled with a mean age of 8.0 years. The median dose of fentanyl administered was 1.5 micrograms/kg. Mean pain score in 32 children using the VAS was 62.3 mm (95% confidence interval 53.2-69.4 mm) at presentation and reduced at 10 min to 44.6 mm (95% confidence interval 36.2-53.1 mm). In 16 children using WBS the initial mean reading was 4.0 (95% confidence interval 3.3-4.7) and reduced to 2.2 (95% confidence interval 1.3-3.1) at 10 min. Caregiver pain scores showed a mean preintervention pain score of 64.9 mm (95% confidence interval 57.7-72.2 mm) with a significant reduction at 10 min to 41.7 mm (95% confidence interval 34.7-48.6 mm). There was no significant alteration in pulse rate, respiratory rate, and blood pressure or oxygen saturations. There were no negative side-effects. CONCLUSIONS: Early and significant reduction in pain (compared to baseline assessments) was achieved in children using intranasal fentanyl by 10 min and sustained throughout the 30 min of observations. This raises the possibility of using intranasal fentanyl in children in the prehospital setting as well as a role for this form of analgesia as triage nurse-initiated administration in the emergency department.

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

            OBJECTIVES: Comparison of intranasal fentanyl (INF) and parenteral morphine in children in an ED. Primary objective was to compare time to analgesia from presentation, with secondary objectives to assess patient profiles, specifics of opiate analgesics used plus rate of i.v. access for analgesia alone. SETTING: Tertiary paediatric ED. METHODS: Retrospective review of case notes identified through controlled drug register. Patients who received INF and/or parenteral morphine between 1 January and 31 March 2005 (before introduction of fentanyl) and in corresponding months in 2006 and 2007 were included. RESULTS: A total of 617 patients were included. Geometric mean time to analgesia was statistically different for INF versus morphine in 2006 (31.2 min, SD 2.6 vs 55.6 min, SD 2.4) and in 2007 (23.7 min, SD 2.8 vs 53.1 min, SD 3.1) (both P < 0.000). Mean initial dose of INF in 2007 was 1.46 mg/kg (SD 0.11) compared with 1.32 mg/kg (SD 0.36) in 2006. Mean total dose in 2007 was 2.14 mg/kg (SD 0.93), increased from 1.60 mg/kg (SD 0.56) in 2006. INF was used most commonly for fractures and morphine for abdominal pain. The i.v. access for opiate analgesia decreased from 161/161 (100%) in 2005 to 99/237 (41.8%) in 2007. CONCLUSION: Use of INF in our paediatric ED setting was associated with a significantly reduced time to analgesia for patients requiring immediate analgesia compared with parenteral morphine. Since the introduction of an INF protocol to our department in mid-2005, INF use has increased, with a corresponding decrease in the use of morphine and a reduction in i.v. access for analgesia.

Borland, M., S. Milsom, et al. (2011). "Equivalency of two concentrations of fentanyl administered by the intranasal route for acute analgesia in children in a paediatric emergency department: A randomized controlled trial." Emerg Med Australas 23(2): 202-208.

Objective: Intranasal fentanyl's (INF) effectiveness is established using highly concentrated INF (HINF). Standard concentration INF (SINF) is more widely available. We aimed to illustrate the equivalence of SINF to HINF. Methods: Double-blinded randomized controlled trial was used within a children's hospital ED. Children aged 3-15 years with fractures were randomized to SINF or HINF. Outcome measures included pain scores at time zero and every 10 min until 30 min. Additional analgesic agents were noted. Results: Data in 189 children (91 HINF, 98 SINF) were obtained. Pre-analgesia median VAS was 80.0 mm (interquartile range [IQR] 60.0-95.5) in SINF, 77.5 mm (IQR 60.0-100) in HINF. At 10 min median VAS was 49.5 mm (IQR 26.5-68.5) and 43.0 mm (IQR 15.2-66.0), respectively, at 20 min 27.5 mm (IQR 18.5-56.5) and 35.0 mm (IQR 9.0-57.0) and at 30 min 20.0 mm (IQR 10.0-46.0) and 21.5 mm (IQR 4.75-51.0). Each agent demonstrated significant decrease in pain scores (median decrease 40 mm, P = 0.000). Additional analgesia was given in 67 (42 SINF, 25 HINF) (P = 0.028). The decrease in pain scores between children < and >/=50 kg in SINF was significant both overall (P = 0.005) and between 10 and 20 min (P = 0.003). There was no difference in HINF at any time by weight. Conclusions: The two concentrations of INF were equivalent in reducing pain, with a trend to increased oral additional agents in the more dilute solution. The widespread use of this readily available analgesic in the standard concentration can be supported, particularly in patients <50 kg.

Bouida, W., K. Bel Haj Ali, et al. (2020). "Effect on Opioids Requirement of Early Administration of Intranasal Ketamine for Acute Traumatic Pain." Clin J Pain 36(6): 458-462.

OBJECTIVES: To evaluate the efficacy and safety of early administration of low-dose intranasal ketamine on reducing the need for opioid and nonopioid analgesic agents in emergency department (ED) patients with acute moderate to severe acute limbs' trauma pain. PATIENTS AND METHODS: This is a double-blind, randomized, prospective, controlled study conducted in the ED. The included patients were randomly assigned to intranasal pulverization of ketamine or placebo. Protocol treatment was given at the triage. The primary outcome is the need for opioids during ED stay. Secondary outcome included the requirement of nonopioid analgesic agents and the percentage of patients discharged from the ED with a visual analog scale (VAS) <30. A combined outcome score including the 3 outcome items was constructed. RESULTS: The authors included 1102 patients, 550 patients in the placebo group, and 552 in the intranasal ketamine group. The groups were similar regarding demographics, clinical characteristics, and baseline VAS. The need for opioids was decreased in the intranasal ketamine group compared with the placebo group (17.2% vs. 26.5%; P<0.001). The need for nonopioid analgesics was significantly lower in the intranasal ketamine group compared with the placebo group (31.1% vs. 39.6%; P=0.003). The percentage of patients discharged with a VAS score <30 was significantly higher in the intranasal ketamine group (P<0.001). The mean combined outcome score was 0.97 in the placebo group and 0.67 in the intranasal ketamine group (P<0.001). CONCLUSION: Intranasal ketamine administered early in the triage was associated with a decrease in opioids and nonopioid analgesics need in patients with acute limb trauma-related pain.

Brown, C., J. Moodie, et al. (2009). "Intranasal ketorolac for postoperative pain: a phase 3, double-blind, randomized study." Pain Med 10(6): 1106-1114.

            OBJECTIVE: Analgesic efficacy and tolerability of intranasal (IN) ketorolac was evaluated in postoperative patients in a randomized, double-blind, placebo-controlled study. METHODS: Patients received IN ketorolac (30 mg) or placebo three times daily for up to 5 days, with access to morphine by patient controlled analgesia (PCA). Patients in a single-dose phase were removed from PCA 3 hours prior to the first study dose the day after surgery, and received a single IN ketorolac or placebo dose when visual analog scale scores were > or =40. RESULTS: Three hundred patients (N = 199 ketorolac, N = 101 placebo) were enrolled following primarily hysterectomies (135/300, 45%) and hip replacements (100/300, 33%); 189 (N = 115 ketorolac, N = 74 placebo) entered the single-dose phase. Mean age was 52 years (range 19-81) and 69% of patients were women. The primary efficacy endpoint, the single-dose summed pain intensity difference score at 6 hours, was significantly higher in the ketorolac group compared with placebo (83.3 vs 37.2, P < 0.007), indicating greater pain reduction with ketorolac. Morphine use was reduced by 34% in the ketorolac group compared with the placebo group. The incidence of adverse events ( approximately 98%) was similar in the two groups. The most common adverse events in both groups were nausea and vomiting. There was a trend in the ketorolac group for a lower incidence of opioid-related side effects such as constipation and pruritus. Nasal irritation occurred more frequently with ketorolac vs placebo (24% vs 2%). CONCLUSION: IN ketorolac was well tolerated and effective in treating moderate-to-severe postoperative pain in inpatients; the convenience of IN dosing suggests that its usefulness in the ambulatory care setting should be evaluated.

Carr, D. B., L. C. Goudas, et al. (2004). "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 108(1-2): 17-27.

            Few placebo-controlled trials have investigated the treatment of breakthrough pain (BTP) in patients with chronic pain. We evaluated the efficacy and safety of intranasal ketamine for BTP in a randomized, double-blind, placebo-controlled, crossover trial. Twenty patients with chronic pain and at least two spontaneous BTP episodes daily self-administered up to five doses of intranasal ketamine or placebo at the onset of a spontaneous BTP episode (pain intensity > or =5 on a 0-10 scale). Two BTP episodes at least 48 h apart were treated with either ketamine or placebo. Patients reported significantly lower BTP intensity following intranasal ketamine than after placebo (P < 0.0001) with pain relief within 10 min of dosing and lasting for up to 60 min. No patient in the ketamine group required his/her usual rescue medication to treat the BTP episode, while seven out of 20 (35%) patients in placebo group did (P = 0.0135). Intranasal ketamine was well tolerated with no serious adverse events. After ketamine administration, four patients reported a transient change in taste, one patient reported rhinorrhea, one patient reported nasal passage irritation, and two patients experienced transient elevation in blood pressure. A side effect questionnaire administered 60 min and 24 h after drug or placebo administration elicited no reports of auditory or visual hallucinations. These data suggest that intranasal administration of ketamine provides rapid, safe and effective relief for BTP.

Chew, K. S. and A. H. Shaharudin (2016). "An open-label randomised controlled trial on the efficacy of adding intranasal fentanyl to intravenous tramadol in patients with moderate to severe pain following acute musculoskeletal injuries." Singapore Med J.

            INTRODUCTION: The use of intranasal fentanyl as an alternative type of analgesia has been shown to be effective in paediatric populations and prehospital settings. Studies on the use of intranasal fentanyl in adult patients in emergency settings are limited. METHODS: An open-label study was conducted to evaluate the effectiveness of the addition of 1.5 mcg/kg intranasal fentanyl to 2 mg/kg intravenous tramadol (fentanyl + tramadol arm, n = 10) as compared to the administration of 2 mg/kg intravenous tramadol alone (tramadol-only arm, n = 10) in adult patients with moderate to severe pain due to acute musculoskeletal injuries. RESULTS: When analysed using the independent t-test, the difference the between the mean visual analog scale scores pre-intervention and ten-minute post-intervention was 29.8 +/- 8.4 mm in the fentanyl + tramadol arm and 19.6 +/- 9.7 mm in the tramadol-only arm (t[18] = 2.515, p = 0.022, 95% confidence interval 1.68-18.72 mm). A statistically significant, albeit transient, reduction in the ten-minute post-intervention mean arterial pressure was noted in the fentanyl + tramadol arm as compared to the tramadol-only arm (13.35 mmHg vs. 7.65 mmHg; using Mann-Whitney U test with U-value = 21.5, p = 0.029, r = 0.48). There was a higher incidence of transient dizziness ten minutes after intervention among the patients in the fentanyl + tramadol arm. CONCLUSION: Although effective, intranasal fentanyl may not be appropriate for routine use in adult patients as it may result in a significant reduction in blood pressure.

Christensen, K., E. Rogers, et al. (2007). "Safety and efficacy of intranasal ketamine for acute postoperative pain." Acute pain 9: 183-192.

                Background: Subanaesthetic doses of ketamine are analgesic. Intranasal administration offers a non-invasive route for systemic drug delivery. We evaluated the safety and analgesic efficacy of intranasal ketamine in treating moderate-to-severe, acute postoperative pain in the molar extraction model. Methods: Intranasal ketamine (10mg, 30mg, and 50mg) and placebo were evaluated in a randomised, double-blind, single-dose, parallel study in 40 patients undergoing removal of 2—4 impacted third molars. Analgesic efficacy was assessed over a 3 h period following drug administration. Safety was evaluated through adverse event reporting, vital signs, pulse oximetry, nasal assessments, and a standard dissociative side effects questionnaire. Results: Ketamine delivered intranasally was well tolerated. Statistically significant analgesia, superior to placebo, was observed with the highest dose tested, 50mg, over a 3 h period. Rapid onset of analgesia was reported (<10min), and meaningful pain relief was achieved within 15min of the 50mg dose. The majority of adverse events were mild/weak and transient. No untoward effects were observed on vital signs, pulse oximetry, and nasal examination. At the doses tested, no significant dissociative effects were evident using the Side Effects Rating Scale for Dissociative Anaesthetics. Conclusion: Intranasal ketaminemay offer a safe, nonopioid, well-tolerated, needle-free analgesic with efficacy in moderate-to-severe acute pain.

Christrup, L. L., D. Foster, et al. (2008). "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 30(3): 469-81.

            Objective: The aim of this study was to compare the pharmacokinetic profile, as well as the efficacy and tolerability, of IN and IV administration of fentanyl in acute, episodic pain in patients undergoing third-molar extraction. Methods: In this randomized, double-blind, double-dummy, 2-way, crossover study, patients were randomized to receive 1 of 4 doses (75, 100, 150, or 200 mug) by both the IN and IV routes in random order, after each of 2 separate molar extractions (interval, >/=1 week). Venous blood samples were obtained for quantification of plasma fentanyl concentrations before and at 1, 3, 5, 7, 9, 12, 15, 25, 40, 60, 90, 120, and 180 minutes after administration. Pain scores (on an 11-point numeric rating scale) were recorded before and at 15, 30, 45, 60, 75, 90, 105, 120, 150, 180, 210, and 240 minutes. Patients indicated the times at which they perceived meaningful pain relief (onset of action) and at which analgesia ended (duration of effect), after which they were able to use rescue medication (time to rescue medication use). Results: A total of 24 patients were enrolled (in all, 47 extractions) (46% male; mean age, 24.1 years; 94% white, 6% Asian). Mean T(max) values were 12.8 and 6.0 minutes (P < 0.001), times to onset of analgesia were 7 and 2 minutes (P < 0.001), and durations of effect were 56 and 59 minutes after IN and IV administration (P = NS), respectively. Differences in the onsets and durations of analgesia after IN and IV administration of single doses were not significantly different, and neither was the difference in overall analgesia, with pain scores returning to near-predose values at statistically similar times after dosing. Duration of effect was directly related to IN fentanyl dose, with significantly less use of rescue medication after IN than after IV administration (P < 0.005). The IN and IV formulations were both well tolerated, with similar numbers of nasally related adverse events recorded for both routes of administration. Conclusions: Onsets and durations of analgesia were not significantly different between single doses of IN and IV fentanyl in these adults undergoing third-molar extraction. Both IN and IV administration were generally well tolerated.

Cleary, J. F. (1997). "Pharmacokinetic and pharmacodynamic issues in the treatment of breakthrough pain." Semin Oncol 24(5 Suppl 16): S16-13-9.

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

The primary objective of the present study was to determine the effectiveness of intranasal fentanyl analgesia in children aged 1-3 years with acute moderate to severe pain presenting to the ED. We also aimed to gather information on the safety and acceptability of intranasal fentanyl in this age group. Two paediatric ED enrolled children aged 1-3 years, with acute moderate or severe pain. Intranasal fentanyl was administered (1.5 microg/kg) via a mucosal atomiser device using a 50 microg/mL solution of fentanyl. Physiological parameters (heart rate, respiratory rate, oxygen saturations and level of consciousness) were measured at regular intervals. Objective pain assessment was completed using the Faces, Legs, Arms, Cry, Consolability (FLACC) score. Forty-six children presenting with acute moderate to severe pain were included. The median FLACC score before intranasal fentanyl administration was 8 (interquartile range [IQR] 5-10), decreasing to 2 (IQR 0-4) 10 min post fentanyl (P < 0.0001) and 0 (IQR 0-2) 30 min post fentanyl (P < 0.0001). A clinically significant decrease in FLACC scores was seen in 93% of children 10 min post fentanyl administration and 98% of children 30 min post fentanyl. Intranasal fentanyl delivery using a mucosal atomiser was well tolerated by all children. There were no adverse drug reactions or adverse events detected. Intranasal fentanyl is an effective, safe and well-tolerated mode of analgesia for children aged 1-3 years with moderate to severe pain.

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

Background: Intranasal (IN) fentanyl provides rapid and powerful non-parenteral analgesia in the ED. A concentrated solution of fentanyl (300 microg/mL) has been used in prior trials, yet many ED use the standard solution at a concentration of 50 microg/mL, which is widely available and of low cost. We set out to determine if this lower concentration of fentanyl is also efficacious. Methods: Prospective audit in children aged 5-18 years presenting with upper limb injuries. Patients received IN fentanyl (50 microg/mL) at 1.5 microg/kg. Patient assessed pain scores were collected 5, 10, 20, 30 and 60 min following IN fentanyl administration using a visual analogue scale or Bieri Faces - Revised scale. Parental scores were used if patients were unable to provide a score. Results: Of the 59 eligible patients, 36 were enrolled; median age was 6.8 years (range 5-15 years), and 89% (32/36) ultimately required fracture reduction. Median first dose of IN fentanyl was 1.4 microg/kg. Median pain scores dropped from 7 (interquartile range 5-10) pre-fentanyl to 5 (interquartile range 4-8) at 5 min and 2 (interquartile range 1-4) at 30 and 60 min. A total of 21 (58%) children did not require further analgesia in the ED. There were no adverse events. Conclusions: Standard i.v. concentration IN fentanyl (50 microg/mL) appears to have analgesic efficacy in children with upper limb injuries.

Dale, O., R. Hjortkjaer, et al. (2002). "Nasal administration of opioids for pain management in adults." Acta Anaesthesiol Scand 46(7): 759-70.

            BACKGROUND: Nasal administration of opioids may be an alternative route to intravenous, subcutaneous, oral transmucosal, oral or rectal administration in some patients. Key features may be self-administration, combined with rapid onset of action. The aim of this paper is to evaluate the present base of knowledge on this topic. METHODS: The review is based on human studies found in Medline or in the reference list of these papers. The physiology of the nasal mucosa and some pharmaceutical aspects of nasal administration are described. The design of each study is described, but not systematically evaluated. RESULTS: Pharmacokinetic studies in volunteers are reported for fentanyl, alfentanil, sufentanil, butorphanol, oxycodone and buprenorphine. Mean times for achieving maximum serum concentrations vary from 5 to 50 min, while mean figures for bioavailability vary from 46 to 71%. Fentanyl, pethidine and butorphanol have been studied for postoperative pain. Mean onset times vary from 12 to 22 min and times to peak effect from 24 to 60 min. There is considerable interindividual variation in pharmacokinetics and clinical outcome. This may partly be due to lack of optimization of nasal formulations. Patient-controlled nasal analgesia is an effective alternative to intravenous PCA. Adverse effects are mainly those related to the opioids themselves, rather than to nasal administration. Some experience with nasal opioids in outpatients and for chronic pain has also been reported. CONCLUSION: Nasal administration of opioids has promising features, but is still in its infancy. Adequately designed clinical studies are needed. Improvements of nasal sprayer devices and opioid formulations may improve clinical outcome.

Dewhirst, E., G. Fedel, et al. (2014). "Pain management following myringotomy and tube placement: intranasal dexmedetomidine versus intranasal fentanyl." Int J Pediatr Otorhinolaryngol 78(7): 1090-1094.

PURPOSE: Despite the brevity of the procedure, bilateral myringotomy and tympanostomy tube placement (BMT) can result in significant postoperative pain and discomfort. As the procedure is frequently performed without intravenous access, non-parenteral routes of administration are frequently used for analgesia. The current study prospectively compares the efficacy of intranasal (IN) dexmedetomidine with IN fentanyl for children undergoing BMT. METHODS: This prospective, double-blinded, randomized clinical trial included pediatric patients undergoing BMT. The patients were randomized to receive either IN dexmedetomidine (1 mug/kg) or fentanyl (2 mug/kg) after the induction of general anesthesia with sevoflurane. All patients received rectal acetaminophen (40 mg/kg) and the first 50 patients also received premedication with oral midazolam. Postoperative pain and recovery were assessed using pediatric pain and recovery scales, and any adverse effects were monitored for. RESULTS: The study cohort included 100 patients who ranged in age from 1 to 7.7 years and in weight from 8.6 to 37.4 kg. They were divided into 4 groups with 25 patients in each group: (1) midazolam premedication+IN dexmedetomidine; (2) midazolam premedication+IN fentanyl; (3) no premedication+IN dexmedetomidine; and (4) no premedication+IN fentanyl. Pain scores were comparable when comparing groups 2, 3 and 4, but were higher in group 1 (midazolam premedication with IN dexmedetomidine). There was no difference in total time in the post-anesthesia care unit (PACU) or time from arrival in the PACU until hospital discharge between the 4 groups. The heart rate (HR) was significantly lower in group 3 when compared to the other groups at several different times after arrival to the PACU. No clinically significant difference was noted in blood pressure. CONCLUSION: Following BMT, when no premedication is administered, there was no clinical advantage when comparing IN dexmedetomidine (1 mug/kg) to IN fentanyl (2 mug/kg). The addition of oral midazolam as a premedication worsened the outcome measures particularly for children receiving IN dexmedetomidine.

Dolatabadi, A. A., M. Shojaee, et al. (2015). "Intranasal sufentanil versus intravenous morphine sulfate in pain management of patients with extremity trauma." Iranian Journal of Emergency Medicine 3(2): 116-121.

                Introduction: Pain is one of the most common complaints of patients referred to emergency department (ED) and its control is one of the most important responsibilities of the physicians. The present study was designed, aiming to compare the efficiency of intranasal sufentanil and intravenous (IV) morphine sulfate in controlling extremity trauma patients' pain in ED. Methods: In the present clinical trial, extremity trauma cases referred to the ED of Imam Hossein Hospital, Tehran, Iran, from October 2014 to March 2015 were randomly divided into 2 groups treated with intranasal sufentanil (0.3 μg/kg) and IV morphine sulfate (0.1 mg/kg) single-doses. Demographic data and information regarding the quality of pain control such as pain severity before intervention and 15, 30, and 60 minutes after intervention, and probable side effects were gathered using a checklist and compared between the 2 groups. Results: 88 patients with the mean age of 35.5 ± 14.8 years were included in the study (81.8% male). 44 patients received IV morphine sulfate and 44 got intranasal sufentanil. No significant difference was detected between the 2 groups regarding baseline characteristics. In addition, there was no significant difference in the groups regarding pain relief at different studied times (p = 0.12; F = 2.46; df: 1, 86). Success rate of the drugs also did not differ significantly at different studied times (p = 0.52). No significant difference was seen between the groups regarding side effects (p = 0.24). Conclusion: Based on the results of this study, it seems that intranasal sufentanil has a similar effect to IV morphine sulfate in rapid, efficient, and non-invasive pain control in patients with traumatic extremity injuries.

Dooris, B., C. Reid, et al. (2001). "Intranasal diamorphine in adults." Emerg Med J 18(5): 412-3.

Elitsur, R., A. Hollenbeck, et al. (2019). "Efficacy and cost savings with the use of a minimal sedation / anxiolysis protocol for intra-articular corticosteroid injections in children with juvenile idiopathic arthritis: a retrospective review of prospectively collected data." Pediatr Rheumatol Online J 17(1): 11.

BACKGROUND: Intra-articular corticosteroid injections (IACI) are frequently used in the treatment of juvenile idiopathic arthritis. There is a paucity of evidence-based research describing methods of pain and anxiety control for this procedure. IACI were mostly performed under general anesthesia for children younger than 13 years old in our institution as of 2014. We started to integrate sedation services more commonly in our institution with the minimal sedation/anxiolysis (MSA) protocol outlined as an alternative to general anesthesia for IACI in 2015. The purpose of this study was to evaluate the effectiveness and cost savings of a minimal sedation protocol for intra-articular corticosteroid injections in juvenile idiopathic arthritis patients after instituting this protocol at our institution. METHODS: The MSA protocol included nitrous oxide, intranasal fentanyl, a topical numbing agent, acetaminophen, ibuprofen, ondansetron and child life intervention. A retrospective review of prospectively collected data was performed on a total of 80 consecutive patients with juvenile idiopathic arthritis who underwent joint injections using the protocol. RESULTS: The procedure was successfully completed in greater than 95% of the patients. The median pain score (measured on a verbal numeric scale of 0-10) reported by the patient was 1 (IQR 0-2.5), by the parent 1 (IQR 0-2), by the rheumatologist 1 (IQR 0-1), and by the sedationist 1 (IQR 0-1). Degree of motion during the procedure was reported by the rheumatologist and the sedationist as none in 68% of the patients, mild in 36% and moderate in 6%. Patient, parent, rheumatologist and sedationist rated satisfaction as very high in the vast majority (94%). Emesis was reported in only 2 (2.5%) patients, no significant adverse events were reported, and no patients progressed to a deeper level of sedation than intended. Financial analysis revealed a 33% cost reduction compared with the use of general anesthesia in the operating room. CONCLUSIONS: A minimal sedation/anxiolysis protocol (including nitrous oxide, intranasal fentanyl, a topical numbing agent, acetaminophen, ibuprofen, ondansetron and child life intervention), provides safe and effective analgesia for intra-articular corticosteroid injection in a subset of patients with juvenile idiopathic arthritis and offers a lower cost alternative to general anesthesia.

Ellerton, J. A., M. Greene, et al. (2013). "The use of analgesia in mountain rescue casualties with moderate or severe pain." Emerg Med J.

OBJECTIVES: To assess the effectiveness of analgesia used in mountain rescue (MR) in casualties with moderate or severe pain. To determine if a verbal numeric pain score is practical in this environment. To describe the analgesic strategies used by MR. DESIGN: Prospective, descriptive study. SETTING: Fifty-one MR teams in England and Wales. The study period was 1 September 2008 to 31 August 2010. PARTICIPANTS: 92 MR casualties with a pain score of 4/10 or greater. MAIN OUTCOME: 38% of casualties achieved a pain reduction of 50% or greater in their initial score at 15 min and 60.2% had achieved this at handover. RESULTS: The initial pain score was 8 (median), reducing to 5 at 15 min and 3 at handover. The mean pain reduction was 2.5+/-2.4 at 15 min and 3.9+/-2.5 at handover. 80 casualties (87%) were treated with an opioid and seven had two different opioids administered. Seven main strategies were identified in which the principal agent was entonox, intramuscular opioid, oral analgesia, fentanyl lozenge, intranasal or intravenous opioid. The choice of strategy varied with the skills of the casualty carer. CONCLUSIONS: Pain should be assessed using a pain score. When possible, intravenous opioid is the gold standard to achieve early and continuing pain control in patients with moderate or severe pain. Entonox and oral analgesics, as sole agents, have limited use in moderate or severe pain. Intranasal opioid and fentanyl lozenge are effective, and appropriate in MR. Research priorities include bioavailability in different environmental conditions and patient's satisfaction with their pain management.

Etteri, M. and A. Bellone (2012). "Intranasal Fentanyl for analgesia in adults with acute renal colic." Emergency Care Journal 8(2): 13-18.

Objectives: The usual treatment of pain in acute renal colic is analgesic in intravenous (IV) route. We tried a rapid, non painful, non-invasive route of administration using intranasal fentanyl versus IV standard treatment (non steroidal anti-inflammatory drug (NSAIDs) plus morphine) for the relief of pain in renal colic presenting to an Emergency Department (ED). Methods: We conducted a prospective non-blinded randomized clinical trial. A sample of 63 adult patients with clinical diagnosis of acute renal colic was included to receive either intravenous morphine (5 mg) plus ketorolac (30 mg) or intranasal fentanyl (3 µg/kg). Pain score were rated by using a 10 cm visual analogue scale at 0,30 and 60 minutes after the treatment. Primary outcome was pain reduction. Secondary outcomes were adverse events and rescue treatment. Results: Sixty-three patients were enrolled. Thirty patients received nasal fentanyl and thirty-three received intravenous morphine plus ketorolac. Morphine-ketorolac therapy was statistically significant more effective than nasal fentanyl therapy in visual analog scores at 30 minutes: the difference in mean visual analog scale between the two groups was 1.74 cm (95% confidence interval 0.29 to 3.2; P=0.018) at 30 minutes. There were not statistically significant differences between the two groups at 60 minutes. There were no significant differences between the groups with regard to secondary outcomes (adverse events and rescue treatment). Conclusions: A combination of intravenous morphine plus ketorolac offers pain relief superior to nasal fentanyl treatment for ED patients with acute renal colic

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Eva, G. (2001). "Nasal diamorphine in children with clinical fractures. Patients should be told what to do when analgesia wears off." Bmj 322(7298): 1367-8.

Farnia, M. R., A. Jalali, et al. (2017). "Comparison of intranasal ketamine versus IV morphine in reducing pain in patients with renal colic." Am J Emerg Med 35(3): 434-437.

                BACKGROUND: Various drugs have been used to relieve abdominal pain in patients with renal colic. Ketamine is a popular choice as an analgesic. OBJECTIVE: To compare the effectiveness of intranasal (IN) ketamine versus intravenous (IV) morphine in reducing pain in patients with renal colic. METHODS: A randomized double-blind controlled trial was performed in 53 patients with renal colic recruited from the emergency department (ED) in 2015. Finally, 40 patients were enrolled in this study. Patients in the ketamine group received IN ketamine 1 mg/kg and IV placebo while patients in the control group received IV morphine 0.1mg/kg and IN placebo. Our goal was to assess visual analogue scale (VAS) changes between the 2 groups. Patients' VAS scores were reported before and 5, 15, 30min after drug injection. RESULTS: Before drug administration, the mean+/-SD VAS score was 7.40+/-1.18 in the morphine group (group A) and 8.35+/-1.30 in the ketamine group (group B) (P-value=0.021). After adjustment by the appropriate analysis, the mean+/-SD VAS score in group (A) and (B) at 5min were (6.07+/-0.47 vs 6.87+/-0.47; mean difference -0.79, 95% confidence interval (CI) -1.48 to -1.04) (P-value=0.025), at 15 and 30min, the mean+/-SD VAS score in group (A) and (B) were (5.24+/-0.49 vs 5.60+/-0.49; mean difference -0.36, 95% CI -1.08 to 0.34) and (4.02+/-0.59 vs 4.17+/-0.59; mean difference -0.15, 95% CI -1.02 to 0.71) (P-value=0.304 and 0.719) respectively. CONCLUSIONS: IN ketamine may be effective in decreasing pain in renal colic.

Fein D.M., Scharbach K., Manwani D., et al: Intranasal fentanyl for initial treatment of a Vaso-occlusive crisis: A Randomized, Double blind, placebo controlled trial. Abstract at AAP October 2015.

Purpose:     A painful vaso-occlusive crisis (VOC) is the most common indication for patients with sickle cell disease (SSD) to seek emergency care. The mainstay of treatment for VOC is aggressive intravenous analgesia with opiates and hydration. However, there is often a delay in establishing intravenous access and providing initial analgesia to these patients. Intranasal fentanyl (INF) has been shown to be safe and effective in providing prompt analgesia to children with other painful conditions in the ED and prehospital setting. Our objective was to determine if children with a VOC who receive initial treatment with INF compared to placebo achieve a greater decrease in pain score 20 minutes after study drug administration. Methods:   This was a randomized, double-blind, placebo-controlled trial. Children with SSD ages 3-20 years not taking daily opiates were eligible for the study and were pre-consented for inclusion at a previous healthcare encounter. Upon presentation to the ED, consented subjects with a pain score ≥6 were randomized to receive a single 2ug/kg (max 100ug) dose of INF or an equivalent volume of intranasal saline. Pain scores were obtained using the Wong-Baker FACES pain scale prior to study drug administration and at 10, 20 and 30 minutes afterwards. Additional analgesic medication was given per standard ED care. Demographic data, information related to the ED visit and adverse events were collected. Pain scores were analyzed using medians with interquartile ranges and the Mann-Whitney U test was used to compare changes in pain scores between groups. Results:     Forty-nine patients completed the study (24 INF, 25 placebo). The two groups were similar with respect to mean age and median initial pain score [INF 10 (IQR 8-10), placebo 9 (IQR 8-10) p=0.38). A greater percentage of subjects who received INF were female (54% vs 24%, (<0.05)]. Patients who received INF had a statistically significant decrease in median pain score at 20 minutes compared to placebo [2 (IQR 0.5-4) vs. 1 (IQR 0-2), p=0.048], but not at 10 or 30 minutes.  Except for one subject in the placebo group, no other subjects received any additional analgesics prior to 20 minutes. There was no difference in the percentage of subjects who received additional analgesics prior to 30 minutes. There was no difference in admission rate between groups. There were no serious adverse events in either group. Conclusion:    Children who received INF had a statistically significant greater decrease in pain score at 20 minutes compared to those who received placebo. Further studies should evaluate how to best incorporate intranasal fentanyl into the emergency care of a child with a painful VOC.

Fein, D. M., J. R. Avner, et al. (2017). "Intranasal fentanyl for initial treatment of vaso-occlusive crisis in sickle cell disease." Pediatr Blood Cancer 64(6).

                BACKGROUND: Analgesia administration for children with vaso-occlusive crises is often delayed in the emergency department. Intranasal fentanyl (INF) has been shown to be safe and effective in providing rapid analgesia for other painful conditions. Our objective was to determine if children with a vaso-occlusive crisis (VOC) who received initial treatment with INF compared to placebo achieved a greater decrease in pain score after 20 min. PROCEDURE: This was a randomized, double-blind, placebo-controlled trial. Children with sickle cell disease, 3-20 years old, not taking daily opiates were eligible for the study. Subjects who presented to the emergency department with a pain score >/=6 were randomized to either a single dose of INF (2 mug/kg, maximum 100 mug) or an equivalent volume of intranasal saline. Pain scores were obtained using a modified Wong-Baker FACES pain scale prior to the administration of study drug and at 10, 20, and 30 min afterward. Additional analgesic medication was given per standard protocol. RESULTS: Forty-nine subjects completed the study (24 fentanyl and 25 placebo). Subjects who received INF had a greater decrease in median pain score at 20 min compared to placebo (2 [interquartile range, (IQR) 0.5-4] vs. 1 [IQR 0-2], P = 0.048), but not at 10 or 30 min. There were no serious adverse events in either group. CONCLUSION: Children who received INF had a greater decrease in pain score at 20 min compared to those who received placebo. Further studies should evaluate how to best incorporate INF into the emergency care of a child with a VOC.

Fenster, D. B., P. S. Dayan, et al. (2018). "Randomized Trial of Intranasal Fentanyl Versus Intravenous Morphine for Abscess Incision and Drainage." Pediatr Emerg Care 34(9): 607-612.

            OBJECTIVES: Abscess incision and drainage (I&D) are painful and distressing procedures in children. Intranasal (IN) fentanyl is an effective analgesic for reducing symptomatic pain associate with fractures and burns but has not been studied for reducing procedural pain during abscess I&D. Our objective was to compare the analgesic efficacy of IN fentanyl with intravenous (IV) morphine for abscess I&D in children. METHODS: We performed a randomized noninferiority trial in children aged 4 to 18 years undergoing abscess I&D in a pediatric emergency department. Patients received IN fentanyl (2 mug/kg; maximum, 100 mug) or IV morphine (0.1 mg/kg; maximum, 8 mg). The primary outcome, determined independently by blinded assessors, was the Observational Scale of Behavioral Distress-Revised (OSBD-R). The prestated margin of noninferiority (Delta) was 1.80. Secondary outcomes included self-reported pain, treatment failure, and patient and parental satisfaction. RESULTS: We enrolled 20 children (median age, 15.4 years), 10 in each group. The difference between total OSBD-R scores was -13.45 (95% confidence interval, -24.24 to -2.67), favoring IN fentanyl.There was less self-reported pain in patients who received IN fentanyl immediately after the procedure. Four patients (40%) receiving IV morphine had treatment failures and required moderate sedation or had the procedure terminated. More patients who received IN fentanyl were satisfied with the analgesic administered compared with those who received IV morphine. CONCLUSIONS: In a small sample of children aged 4 to 18 years undergoing abscess I&D, IN fentanyl was noninferior, and potentially superior, to IV morphine for reducing procedural pain and distress.

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

            Children undergoing placement of bilateral myringotomy tubes (BMT) often exhibit pain-related behavior (agitation) in the postanesthesia care unit. We compared the emergence and recovery profiles of pediatric patients who received sevoflurane with or without supplementary intranasal fentanyl for BMT surgery. By using a prospective, double-blinded design, 150 children 6 mo to 5 yr of age, scheduled for routine BMT surgery, were anesthetized with sevoflurane (2%-3%) in a 60% N(2)O/O(2) gas mixture. Patients were randomized to receive equal volumes of intranasal saline (Control), 1 microg/kg fentanyl or 2 microg/kg fentanyl. A blinded observer evaluated each patient using a previously described 4-point agitation scale and the Steward recovery scale. Response to parental presence was observed after a score of six (full recovery) was achieved on the Steward recovery scale. There were no significant differences among the three groups regarding age, weight, surgeon, duration of anesthesia, or ear condition. Recovery times and emergence characteristic scores were not statistically different. Agitation scores were significantly reduced in the 2-microg/kg Fentanyl group as compared with the Control group (P = 0.012). Fentanyl 2 microg/kg is recommended to reduce the incidence of agitation seen in these patients. IMPLICATIONS: We examined the use of nasally administered fentanyl for the relief of agitation or discomfort after placement of bilateral myringotomy tubes in 150 children ages 6 mo to 5 yr using a prospective, double-blinded design. Fentanyl 2 microg/kg was found to reduce the incidence of agitation in these patients.

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

            This study sought to compare the analgesic efficacy and safety of patient controlled intra-nasal (PCIN) fentanyl with oral morphine for procedural wound care in burns patients. A randomised double-blind placebo controlled, two period, two-treatment crossover trial was conducted within the Burns Unit of a major teaching hospital in Perth, Western Australia. Patients requiring identical wound care procedures on two consecutive mornings (and not prescribed intravenous analgesia) were randomised to receive either PCIN fentanyl with oral placebo or oral morphine with intranasal placebo on 1 day, followed by the alternate active drug on the following day. Twenty-six patients (22 males), aged between 18 and 69 years (35.5 +/- 12.4 years), with total body surface burns (TBSA) range 1-25% (6.9 +/- 4.5), indicated their level of pain on a 10 point (0-10) numeric scale at various time periods before, during and after the procedure. A mean total dose of 1.48 +/- 0.57 microg/kg of PCIN fentanyl and 0.35 +/- 0.12 mg/kg of oral morphine was administered. No statistically significant difference was found between the pain scores recorded for patients during the procedure with PCIN fentanyl compared to that with oral morphine (mean difference = -0.75, 95% CI = -1.97 to 0.47, P = 0.22). Two patients experienced hypotension during the procedure--both had received active oral morphine. No patients experienced respiratory depression or a significant drop in oxygen saturation. There were four episodes (in three patients) where 'rescue analgesia' for severe pain was required--two episodes involving oral morphine and two involving PCIN fentanyl. It was concluded that PCIN fentanyl is similar in efficacy and safety to oral morphine for relief of procedural wound care pain in burns patients.

Fleet, J., I. Belan, et al. (2015). "A comparison of fentanyl with pethidine for pain relief during childbirth: a randomised controlled trial." BJOG 122(7): 983-992.

OBJECTIVE: To compare the efficacy of fentanyl administered via the subcutaneous (s.c.) or intranasal (i.n.) route with intramuscular (i.m.) pethidine in labouring women requesting analgesia. DESIGN: A randomised controlled trial three-armed, parallel-design. SETTING: A regional hospital and the largest tertiary maternity centre in South Australia. SAMPLE: One hundred and fifty-six healthy parturients birthing at term. METHODS: Women were randomised to receive s.c. fentanyl (n = 53), i.n. fentanyl (n = 52), or i.m. pethidine (n = 51). The outcomes were analysed by intention-to-treat. MAIN OUTCOME MEASURES: Pain scores measured before and 30 minutes after opioid administration. RESULTS: All groups reported clinically significant reductions in pain scores (mean range 1.2-1.6; P < 0.001), with no significant differences between groups. Significantly more women in the fentanyl groups reported satisfaction with using the study drug again, compared with women receiving i.m. pethidine (82.9% i.n. fentanyl, 80.6% s.c. fentanyl, and 44.0% i.m. pethidine; P < 0.01). Women in the fentanyl groups experienced less sedation (i.n. fentanyl 7.3%, s.c. fentanyl 2.9%, i.m. pethidine 44%; P </= 0.03), shorter labours by at least 2 hours (P < 0.05), and fewer difficulties establishing breastfeeding (78.8% i.m. pethidine, 39.4% i.n. fentanyl, and 44.0% s.c. fentanyl; P < 0.01). Neonates in the pethidine group were more likely to require nursery admission (P < 0.02). CONCLUSIONS: Fentanyl administered by s.c. and i.n. routes is as efficacious in relieving labour pain as i.m. pethidine, but resulted in greater satisfaction, less sedation, shorter labour, fewer nursery admissions, and fewer difficulties in establishing breastfeeding. Fentanyl appears to be a suitable alternative to pethidine when providing parenteral pain relief to labouring women.

Fleet, J. A., M. Jones, et al. (2017). "Taking the alternative route: Women's experience of intranasal fentanyl, subcutaneous fentanyl or intramuscular pethidine for labour analgesia." Midwifery 53: 15-19.

                OBJECTIVE: To compare women's experience of receiving either intranasal fentanyl, subcutaneous fentanyl or intramuscular pethidine for labour analgesia. DESIGN: A content analysis was undertaken as part of the third phase of a larger randomised controlled trial, using the per-protocol dataset to examine women's experiences of treatment received. Healthy women birthing at term, who received intranasal fentanyl (n=41), subcutaneous fentanyl (n=37) and/or intramuscular pethidine (n=38) for labour analgesia, were contacted at 6 weeks postpartum to complete a phone questionnaire. SETTING: A tertiary and regional maternity unit in South Australia. FINDINGS: Over 80% of women who received intranasal or subcutaneous fentanyl reported that they would use the treatment again compared to 44.8% of women who had received pethidine (self-administered intranasal fentanyl provided more expressive responses emphasising the route provided a strong sense of control and enablement. KEY CONCLUSIONS: Route of administration influenced the women's experience, more women who self-administered intranasal fentanyl reported positive emotional responses, with women reporting increased autonomy and satisfaction. Whereas, women who relied on the midwife to administer subcutaneous fentanyl or intramuscular pethidine, were more often focused on the physical effect of the drug. Pethidine was the least preferred option due to adverse effects. IMPLICATIONS FOR PRACTICE: For women requesting parenteral analgesia, fentanyl administered by less invasive routes offers women additional options that may better meet their emotional, cognitive and physical needs than the current practice of administering intramuscular pethidine.

Flood, P. and D. Daniel (2004). "Intranasal nicotine for postoperative pain treatment." Anesthesiology 101(6): 1417-21.

            BACKGROUND: Despite pharmacological treatment, 70-80% of patients report moderate to severe pain after surgery. Because nicotine has been reported to have analgesic properties in animal and human volunteer studies, the authors assessed the analgesic efficacy of a single 3 mg dose of nicotine nasal spray administered before emergence from general anesthesia. METHODS: The authors conducted a randomized, double blind, placebo controlled trial of 20 healthy women (mean age 45 (SD 8) yr) who were to undergo uterine surgery through a low transverse incision. After the conclusion of surgery but before emergence from general anesthesia, the anesthesiologist administered either nicotine nasal spray or a placebo. Numerical analog pain score and morphine utilization and hemodynamic values were measured for 24 h. RESULTS: The patients treated with nicotine reported lower pain scores during the first hour after surgery (peak numerical analog score, 7.6 (SD 1.4) versus 5.3 (SD 1.6); P < 0.001) and used half the amount of morphine as the control group (12 (SD 6) versus 6 (SD 5) mg; P < 0.05). Patients who received nicotine still reported less pain than those in the control group 24 h after surgery (1.5 (SD 0.5) versus 4.9 (SD 1.4); P < 0.01). Systolic blood pressure was lower in the group that received nicotine (105 (SD 3) versus 122 (SD 3); P < 0.001), but there was no difference in diastolic blood pressure or heart rate. CONCLUSIONS: Treatment with a single dose of nicotine immediately before emergence from anesthesia was associated with significantly lower reported pain scores during the first day after surgery. The decreased pain was associated with a reduction in morphine utilization and the analgesic effect of nicotine was not associated with hypertension or tachycardia.

Frey, T. M., T. A. Florin, et al. (2019). "Effect of Intranasal Ketamine vs Fentanyl on Pain Reduction for Extremity Injuries in Children: The PRIME Randomized Clinical Trial." JAMA Pediatr 173(2): 140-146.

Importance: Timely analgesia is critical for children with injuries presenting to the emergency department, yet pain control efforts are often inadequate. Intranasal administration of pain medications provides rapid analgesia with minimal discomfort. Opioids are historically used for significant pain from traumatic injuries but have concerning adverse effects. Intranasal ketamine may provide an effective alternative. Objective: To determine whether intranasal ketamine is noninferior to intranasal fentanyl for pain reduction in children presenting with acute extremity injuries. Design, Setting, and Participants: The Pain Reduction With Intranasal Medications for Extremity Injuries (PRIME) trial was a double-blind, randomized, active-control, noninferiority trial in a pediatric, tertiary, level 1 trauma center. Participants were children aged 8 to 17 years presenting to the emergency department with moderate to severe pain due to traumatic limb injuries between March 2016 and February 2017. Analyses were intention to treat and began in May 2017. Interventions: Intranasal ketamine (1.5 mg/kg) or intranasal fentanyl (2 microg/kg). Main Outcomes and Measures: The primary outcome was reduction in visual analog scale pain score 30 minutes after intervention. The noninferiority margin for this outcome was 10. Results: Of 90 children enrolled, 45 (50%) were allocated to ketamine (mean [SD] age, 11.8 [2.6] years; 26 boys [59%]) and 45 (50%) to fentanyl (mean [SD] age, 12.2 [2.3] years; 31 boys [74%]). Thirty minutes after medication, the mean visual analog scale reduction was 30.6 mm (95% CI, 25.4-35.8) for ketamine and 31.9 mm (95% CI, 26.6-37.2) for fentanyl. Ketamine was noninferior to fentanyl for pain reduction based on a 1-sided test of group difference less than the noninferiority margin, as the CIs crossed 0 but did not cross the prespecified noninferiority margin (difference in mean pain reduction between groups, 1.3; 90% CI, -6.2 to 8.7). The risk of adverse events was higher in the ketamine group (relative risk, 2.5; 95% CI, 1.5-4.0), but all events were minor and transient. Rescue analgesia was similar between groups (relative risk, 0.89; 95% CI, 0.5-1.6). Conclusions and Relevance: Ketamine provides effective analgesia that is noninferior to fentanyl, although participants who received ketamine had an increase in adverse events that were minor and transient. Intranasal ketamine may be an appropriate alternative to intranasal fentanyl for pain associated with acute extremity injuries. Ketamine should be considered for pediatric pain management in the emergency setting, especially when opioids are associated with increased risk. Trial Registration: Identifier: NCT02778880.

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

            BACKGROUND: Many children are restless, disoriented, and inconsolable immediately after bilateral myringotomy and tympanosotomy tube placement (BMT). Rapid emergence from sevoflurane anesthesia and postoperative pain may increase emergence agitation. The authors first determined serum fentanyl concentrations in a two-phase study of intranasal fentanyl. The second phase was a prospective, placebo-controlled, double-blind study to determine the efficacy of intranasal fentanyl in reducing emergence agitation after sevoflurane or halothane anesthesia. METHODS: In phase 1, 26 children with American Society of Anesthesiologists (ASA) physical status I or II who were scheduled for BMT received intranasal fentanyl, 2 microg/kg, during a standardized anesthetic. Serum fentanyl concentrations in blood samples drawn at emergence and at postanesthesia care unit (PACU) discharge were determined by radioimmunoassay. In phase 2, 265 children with ASA physical status I or II were randomized to receive sevoflurane or halothane anesthesia along with either intranasal fentanyl (2 microg/kg) or saline. Postoperative agitation, Children's Hospital of Eastern Ontario Pain Scale (CHEOPS) scores, and satisfaction of PACU nurses and parents with the anesthetic technique were evaluated. RESULTS: In phase 1, the mean fentanyl concentrations at 10 +/- 4 min (mean +/- SD) and 34 +/- 9 min after administering intranasal fentanyl were 0.80 +/- 0.28 and 0.64 +/- 0.25 ng/ml, respectively. In phase 2, the incidence of severe agitation, highest CHEOPS scores, and heart rate in the PACU were decreased with intranasal fentanyl. There were no differences between sevoflurane and halothane in these measures and in times to hospital discharge. The incidence of postoperative vomiting, hypoxemia, and slow respiratory rates were not increased with fentanyl. CONCLUSIONS: Serum fentanyl concentrations after intranasal administration exceed the minimum effective steady state concentration for analgesia in adults. The use of intranasal fentanyl during halothane or sevoflurane anesthesia for BMT is associated with diminished postoperative agitation without an increase in vomiting, hypoxemia, or discharge times.

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

            The objective of this study was to demonstrate the efficacy, safety and patient acceptability of the use of intranasal sufentanil for cancer-associated breakthrough pain. This was a prospective, open label, observational study of patients in three inpatient palliative care units in Australia. Patients on opioids with cancer-associated breakthrough pain and clinical evidence of opioid responsiveness to their breakthrough pain were given intranasal (IN) Sufentanil via a GO Medical patient controlled IN analgesia device. The main outcome measures were pain scores, need to revert to previous breakthrough opioid after 30 min, number of patients who chose to continue using IN sufentanil, and adverse effects. There were 64 episodes of use of IN sufentanil for breakthrough pain in 30 patients. There was a significant reduction in pain scores at 15 (P < 0.0001) and 30 min (P < 0.0001). In only 4/64 (6%) episodes of breakthrough pain did the participants choose to revert to their prestudy breakthrough medication. Twenty-three patients (77%) rated IN sufentanil as better than their prestudy breakthrough medication. The incidence of adverse effects was low and most were mild. Our study showed that IN sufentanil can provide relatively rapid onset, intense but relatively short lasting analgesia and in the palliative care setting it is an effective, practical, and safe option for breakthrough pain.

Goudas, L. C., D. B. Carr, et al. (2002). "Efficacy and safety of intranasal ketamine for the management of breakthrough pain in chronic pain. A randomized, double-blind, placebo-controlled, cross-over trial." American Society of Clinical Oncology Meeting Abstract No:    450.

                Breakthrough Pain (BTP) is common (prevalence: 19% to 93%) among chronic pain patients, however few placebo-controlled trials have investigated BTP in these patients. Breakthrough pain management typically involves dosage increases of round-the-clock opioids and/or supplemental rescue doses of short-acting opioids or fixed-dose mixtures with NSAIDs. These medications have a relatively slow onset of action, rendering them inadequate in treating severe, paroxysmal BTP. The large surface area and local vascularity of the nasal mucosa offers an ideal route for rapid delivery of drugs into the systemic circulation. To evaluate the efficacy and safety of intranasal ketamine HCl, we performed a randomized, double-blind, placebo-controlled, cross-over trial in 20 patients suffering from chronic pain. Patients experiencing at least 2 BTP episodes daily were randomized to receive ketamine and placebo intranasally. Patients self-administered up to 5 fixed doses (10 mg each, up to 50 mg per episode) of drug or placebo at the onset of BTP (intensity of BTP > 5 on a 0 to 10 numeric scale). Two BTP episodes, each on a separate day, were treated with either ketamine or placebo. Patients reported significantly lower intensity of their BTP episode following intranasal ketamine as compared to placebo (p<0.0001). Onset of pain relief occurred within 5 minutes of dosing with ketamine and lasted up to 60 minutes. No patient in the ketamine group required his/her regular rescue medication, while 7/20 (35%) in the placebo group did (p=0.0135). Intranasal ketamine was well-tolerated with no serious adverse events reported. In the ketamine group, there were 4 reports of change in taste (20%), and one report each of rhinorrhea (5%), throat irritation (5%), and nasal irritation (5%). Some patients (20%) reported varying degrees of dizziness and a feeling of unreality, resolving within 60 minutes. No patients reported hallucinations. These data suggest that intranasal ketamine provides rapid, safe, and effective relief for breakthrough pain that may reduce the need for short-acting opioids.

Grant, G. M. and D. R. Mehlisch (2010). "Intranasal ketorolac for pain secondary to third molar impaction surgery: a randomized, double-blind, placebo-controlled trial." J Oral Maxillofac Surg 68(5): 1025-1031.

            PURPOSE: This randomized, double-blind, placebo-controlled study evaluated the efficacy and safety of intranasal (IN) ketorolac in patients who had third molar extraction surgery with bony impactions. MATERIALS AND METHODS: After surgery, patients were randomly assigned to receive IN ketorolac 31.5 mg (n = 40) or IN placebo (n = 40). Safety was assessed from spontaneously reported adverse events and measurement of vital signs. Efficacy assessments included pain intensity, which was measured on a 0- to 100-mm visual analog scale, total pain relief, and global pain evaluation up to 8 hours after dosing or until patients required rescue analgesia. The primary efficacy variable was the summed pain intensity difference score over the first 8 hours after dosing. RESULTS: Summed pain intensity difference values +/- SE were significantly higher (indicating better analgesia) in the ketorolac group compared with placebo (136.7 +/- 33.0 vs -105.2 +/- 29.1, P < .001). Total pain relief scores were significantly higher (P < .001) in the ketorolac group compared with placebo at all times. A larger proportion of subjects in the ketorolac group reported good, very good, or excellent pain control compared with the control group (60% vs 13%). Times to perceptible (21.5 minutes) and meaningful (66.0 minutes) pain relief were significantly shorter and the time to rescue analgesic use was significantly longer in the ketorolac group (P < .001). Eight patients in the placebo group and 3 in the ketorolac group had adverse events, none of which was serious. The 3 events in the ketorolac group were reports of mild headache. CONCLUSION: A single IN ketorolac 31.5 mg dose was well tolerated and provided rapid and effective pain relief in oral surgery patients for a period up to 8 hours.

Graudins, A., R. Meek, et al. (2015). "The PICHFORK (Pain in Children Fentanyl or Ketamine) trial: a randomized controlled trial comparing intranasal ketamine and fentanyl for the relief of moderate to severe pain in children with limb injuries." Ann Emerg Med 65(3): 248-254 e241.

                STUDY OBJECTIVE: We compare the analgesic effectiveness of intranasal fentanyl and ketamine in children. METHODS: This was a double-blind, randomized, controlled trial comparing fentanyl at 1.5 mug/kg with ketamine at 1 mg/kg in children aged 3 to 13 years and weighing less than 50 kg, with isolated limb injury and pain of more than 6 of 10 at triage. The sample size was 40 in each arm. Subjects were coadministered oral ibuprofen at 10 mg/kg. The primary outcome was median pain rating reduction at 30 minutes. Secondary outcomes were pain rating reduction at 15 and 60 minutes, subjective improvement and satisfaction, University of Michigan Sedation Score, adverse events, and rescue analgesia. RESULTS: Eighty children enrolled, and 73 were available for analysis: 37 fentanyl and 36 ketamine. Median age was 8 years; 63% were male children; median baseline pain rating was 80 mm. At 30 minutes, median reductions for ketamine and fentanyl were 45 and 40 mm, respectively (difference 5 mm; 95% confidence interval [CI] -10 to 20 mm). Reductions exceeded 20 mm for ketamine and fentanyl in 82% and 79% of patients, respectively (difference 3%; 95% CI -22% to 16%). Pain rating reduction was maintained to 60 minutes in both groups. Satisfaction was reported for ketamine and fentanyl by 83% and 72% of patients, respectively (difference 11%; 95% CI -9% to 30%). Adverse events, mainly mild, were reported for ketamine and fentanyl by 78% and 40% of patients, respectively (difference 38%; 95% CI -58% to 16%). Three ketamine patients had a moderate degree of sedation by University of Michigan Sedation Score. CONCLUSION: Intranasal fentanyl and ketamine were associated with similar pain reduction in children with moderate to severe pain from limb injury. Ketamine was associated with more minor adverse events.

Guthrie, A. M., R. A. Baum, et al. (2019). "Use of Intranasal Ketamine in Pediatric Patients in the Emergency Department." Pediatr Emerg Care.

OBJECTIVES: Ketamine is a safe and widely used sedative and analgesic in the pediatric emergency department (ED). The use of intranasal (IN) ketamine in exchange for the administration of intravenous sedatives or analgesics for procedural sedation in pediatric patients is not commonplace. The goal of this study was to evaluate provider perceptions and patient outcomes at varying doses of IN ketamine for anxiolysis, agitation, or analgesia. METHODS: From January 2018 to May 2018, we performed a prospective survey and chart review of pediatric patients receiving IN ketamine. The primary outcome was to determine provider satisfaction with using IN ketamine. Secondary objectives included comparing outcomes stratified by dose, adverse events, assessing for treatment failure, and ED length of stay (LOS). As a secondary comparison, patients receiving IN ketamine whom otherwise would have required procedural sedation with intravenous sedatives or analgesics were placed into a subgroup. This subgroup of patients was compared with a cohort who received intravenous sedatives or analgesics for procedural sedation during a similar period the preceding year (January 2017 to June 2017). RESULTS: Of the 196 cases, 100% of the providers were comfortable using IN ketamine. The median overall provider satisfaction was 90 out of 100, the perception of patient comfort was 75 out of 100, and perceived patient comfort was maximized when using doses between 3 and 5 mg/kg. There were 15 (7.7%) patients who experienced ketamine treatment failure. Overall, the rate of adverse events was 6%, but were considered minor [nausea (n = 3; 1.5%), dizziness (n = 2; 1%), and drowsiness (n = 2; 1%)]. No patients required respiratory support or intubation. The mean LOS was 237.9 minutes, compared with those who underwent procedural sedation with an LOS of 332.4 minutes (P < 0.001). CONCLUSIONS: This study demonstrates that IN ketamine was able to provide safe and successful analgesia and anxiolysis in pediatric patients in an ED setting. In addition, providers expressed a high degree of satisfaction with using IN ketamine (90 out of 100) in addition to a high degree of patient comfort during the procedure (75 out of 100). Intranasal ketamine provides an alternative to intravenous medication normally requiring more resource-intensive monitoring. Procedural sedations are resource and time intensive activities that increase ED LOS. Intranasal ketamine used for anxiolysis and analgesia offers the benefits of freeing up resources of staff and monitoring while enhancing overall throughput through a pediatric ED.

Hallas, P. and J. Cordtz (2017). "Fracture reduction in the ED and intranasal fentanyl 50mcg/ml in children." Am J Emerg Med.

Hallett, A., F. O'Higgins, et al. (2000). "Patient-controlled intranasal diamorphine for postoperative pain: an acceptability study." Anaesthesia 55(6): 532-9.

            A patient acceptability study was conducted using patient-controlled intranasal diamorphine. Patients undergoing nonemergency orthopaedic or gynaecological surgery self-administered intranasal diamorphine for 24 h postoperatively. Pain, pain relief, sedation, respiratory rate, nausea and vomiting were assessed regularly. After 24 h, patients and their attending nurses completed a questionnaire assessing satisfaction and practical aspects of the technique. Satisfaction was reported as good or complete by 69% of patients and 69% of nurses. Pain relief was assessed as better than expected by 45% of patients and better than normal by 50% of nurses. Seventy-nine per cent of patients would be pleased to use patient-controlled intranasal diamorphine again and 89% of nurses would be happy for their patients to use it again. Sedation was uncommon and mild and there were no episodes of significant respiratory depression. Fifty-three per cent of patients reported no nausea and 74% did not vomit at any stage. There were seven withdrawals, four due to problems with the device and three due to therapeutic problems. The nasal spray may need modification to improve reliability. However, we found patient-controlled intranasal analgesia an effective technique, which was well tolerated by patients and nurses and was without unpleasant side-effects. Further work to determine how it performs compared with intramuscular or intravenous analgesia is now needed.

Han, M., H. Wang, et al. (2009). "Intranasal instillation of sufentanil reduces myoclonus induced by etomidate." Anhui Medical and Pharm J.

            Aim To investigate the effects of intranasal sufentanil reducing myoclonus induced by etomidate. Methods Eighty ASA class I or Ⅱ patients aged 32 to 70 years weighing 50 to 85 kg without neuromuscular disorders who were undergoing elective surgery were randomly divided into two groups: Group A received intranasal instillation of sufentanil 0.2 μg·kg-1,which was diluted to 1 ml. Group B received intranasal instillation of normal saline l ml, After 2 min, two groups were injected etomidate 0.3 mg·kg-1.MBP,HR,SPO2 and RR were recorded before intranasal instillation of sufentanil(T0),at 1 min(T1) and 2 min(T2)after intranasal instillation of sufentanil. Myoclonus was observed and graded. Results The incidence of myoclonus was significantly lower in group A than that in group B(P0.01).There was no significant difference in MBP, HR, SPO2 and RR at all time points between group A and group B. Conclusion Intranasal instillation of sufentanil 0.2 μg·kg-1 can reduce myoclonus induced by etomidate.

Harlos, M. (2002). "Palliative Care Incident Pain and Incident Dyspnea Protocol." Internet public domain protocol:

            This is a protocol for transmucosal (sublingual and intranasal) fentanyl and sufentanil to treat pain and dyspnea in hospice setting.

Harlos, M. S., S. Stenekes, et al. (2012). "Intranasal Fentanyl in the Palliative Care of Newborns and Infants." J Pain Symptom Manage.

CONTEXT: Perinatal palliative care is an area of increasing focus among clinicians supporting newborns and their families. Although not every newborn will survive the neonatal period, assuring their comfort and quality of life remains an imperative for their care providers. It can be challenging to administer medications such as opioids in a minimally invasive yet effective manner. OBJECTIVES: To describe the experience using intranasal (IN) fentanyl in the management of distress in a case series of 11 dying neonates. METHODS: A retrospective chart review was undertaken of 58 consecutive referrals of newborns and infants aged six months or younger between November 2006 and July 2010 to the Winnipeg Regional Health Authority Pediatric Palliative Care Service to determine how often IN fentanyl was used and review documented responses after the medication. RESULTS: Of 58 referrals, IN fentanyl was used in 11 patients, in all cases for concerns regarding respiratory distress. Chart documentation indicated that fentanyl was tolerated well, with no circumstances of drug-related apnea and no occurrences of chest wall rigidity. In most cases, labored breathing and restlessness settled after medication administration. The average time from administration of the last dose of fentanyl until death was 61 minutes. CONCLUSION: We found IN fentanyl, which can be administered in a variety of care settings, to be a minimally invasive means of palliating distress in dying newborns and infants. No adverse events related to its use were noted.

Haynes, G., N. H. Brahen, et al. (1993). "Plasma sufentanil concentration after intranasal administration to paediatric outpatients." Can J Anaesth 40(3): 286.

Heard, C., P. Creighton, et al. (2009). "Intranasal flumazenil and naloxone to reverse over-sedation in a child undergoing dental restorations." Paediatr Anaesth 19(8): 795-7; discussion 798-9.

            We describe a 3-year-old child who became over-sedated after receiving intranasal (IN) midazolam (0.53 and IN sufentanil (1 for dental restorations in the dental office. Desaturation was attributed to laryngospasm, which was managed with positive pressure ventilation and oxygen. The sedation was reversed with a combination of IN flumazenil and naloxone.

Helmers, J. H., H. Noorduin, et al. (1989). "Comparison of intravenous and intranasal sufentanil absorption and sedation." Can J Anaesth 36(5): 494-7.

            The absorption and sedation following an intranasal dose of sufentanil were evaluated and compared with those of the same dose given intravenously. Sixteen adult patients scheduled for elective surgery were randomly allocated to receive as premedication 15 micrograms sufentanil either intravenously or intranasally. Before administration and at fixed time intervals thereafter, the degree of sedation was assessed, vital signs were recorded and venous blood samples were taken for the determination of sufentanil plasma concentrations. Peroperative sedation of rapid onset and limited duration was seen in both groups. However, the onset of sedation was more rapid after intravenous injection. At 10 min, all patients in the IV group were sedated versus only two in the intranasal group (P less than 0.01). No significant intergroup differences in sedation were seen at 20 to 60 min. This clinical effect is in agreement with the measured plasma levels, which were significantly lower after intranasal application at 5 and 10 min, being 36 and 56 per cent of those after IV dosing, respectively. From 30 min, plasma concentrations were virtually identical for the two routes of administration. The AUC0-120 min after intranasal dosing was 78 per cent of that after intravenous injection. Intranasal dosing induced no clinically significant changes in vital signs, whereas after IV sufentanil, a clinically significant decrease in PaO2 was seen at 5 min. The results of this study show that sufentanil, when administered intranasally, is rapidly and effectively absorbed from the human nasal mucosa, so that this route may be an attractive alternative for a premedicant, avoiding the discomfort of an intravenous or intramuscular injection.

Henderson, J. M., D. A. Brodsky, et al. (1988). "Pre-induction of anesthesia in pediatric patients with nasally administered sufentanil." Anesthesiology 68(5): 671-5.

            To evaluate nasally administered sufentanil, 1.5-4.5 micrograms/kg, for pre-induction (i.e., pre-medication/induction) of anesthesia in pediatric patients, the authors studied ASA PS 1 or 2 patients scheduled for elective surgery. Eighty children, ages 6 months to 7 yr, were randomized to receive sufentanil (1.5, 3.0, or 4.5 micrograms/kg) or placebo (normal saline, 0.03 ml/kg) nasally over 15-20 s. Induction of anesthesia was completed with 5% halothane and O2 via facemask. After tracheal intubation, anesthesia was maintained with N2O (60-70%) and halothane, as clinically indicated. A blinded observer remained with the child from prior to drug administration until discharge from the recovery room. Patients given sufentanil were more likely to separate willingly from their parents and be judged as calm at or before 10 min compared to those given saline. Ventilatory compliance during induction of anesthesia decreased markedly in 25% of subjects given sufentanil, 4.5 micrograms/kg. Subjects given sufentanil moved or coughed less during tracheal intubation and required less halothane compared to those given placebo. During recovery, patients given sufentanil cried less and fewer needed analgesics; recovery times were similar for all groups. However, patients given sufentanil, 4.5 micrograms/kg, had a higher incidence of vomiting in the recovery room and during the first postoperative day. The authors conclude that nasally administered sufentanil, 1.5 or 3.0 micrograms/kg, facilitates separation of children from parents, has minimal side effects, may improve intubating conditions, and can provide postoperative analgesia.

Henderson, J. M. and D. M. Fisher (1990). "Intranasal sufentanil." Can J Anaesth 37(3): 387.

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

            OBJECTIVE: To determine whether flumazenil, a drug used to reverse benzodiazepine-induced respiratory depression and approved only for i.v. use, is effective by alternative routes. METHODS: A randomized, controlled, nonblinded, crossover canine trial was performed to evaluate reversal of midazolam-induced respiratory depression by flumazenil when administered by alternative routes. Mongrel dogs were sedated with thiopental 19 mg/kg i.v., then tracheally intubated. With the dogs spontaneously breathing, tidal volume, end-tidal CO2, and O2 saturation were observed until a stable baseline was achieved. Incremental doses of midazolam were administered until respiratory depression (30% decline in tidal volume, 10% decrease in O2 saturation, and 15% increase in end-tidal CO2) occurred. Flumazenil was administered by a randomly selected route [0.2 mg followed 1 minute later by 0.3 mg i.v., sublingual (s.l.) or intramuscular (i.m.); or 1 mg followed 1 minute later by 1.5 mg per rectum (PR)]. Time to return to baseline respiratory functions was recorded ("time to reversal"). Each of 10 dogs was studied using all 4 routes of flumazenil administration with a washout period of at least 7 days. An additional dog served as a control (no flumazenil). RESULTS: The control time to reversal was 1,620 seconds. The i.v. route was significantly faster (mean 120 +/- 24.5 sec) than the other 3 routes (p < 0.005). The SL route was the second fastest (mean 262 +/- 94.5 sec), the IM route was the third fastest (mean 310 +/- 133.7 sec) and the PR route was the s;owest (mean 342 +/- 84.4 sec). The SL, IM, and PR routes did not differ significantly from one another. CONCLUSIONS: Flumazenil administered by all 4 routes reversed midazolam-induced respiratory depression in a dog model. For the selected dosages used, the i.v. route was significantly faster than all 3 other routes, and SL was the second fastest.

Hippard, H. K., K. Govindan, et al. (2012). "Postoperative analgesic and behavioral effects of intranasal fentanyl, intravenous morphine, and intramuscular morphine in pediatric patients undergoing bilateral myringotomy and placement of ventilating tubes." Anesth Analg 115(2): 356-363.

          BACKGROUND: Bilateral myringotomy and placement of ventilating tubes (BMT) is one of the most common pediatric surgical procedures in the United States. Many children who undergo BMT develop behavioral changes in the postanesthesia care unit (PACU) and require rescue pain medication. The incidence of these changes is lower in children receiving intraoperative opioids by the nasal, IM, or IV route compared with placebo. However, there are no data to indicate which route of administration is better. Our study was designed to compare the immediate postoperative analgesic and behavioral effects of 3 frequently used intraoperative techniques of postoperative pain control for patients undergoing BMT under general anesthesia. METHODS: One hundred seventy-one ASA physical status I and II children scheduled for BMT were randomized into 1 of 3 groups: group 1-nasal fentanyl 2 mug/kg with IV and IM saline placebo; group 2-IV morphine 0.1 mg/kg with nasal and IM placebo; or group 3-IM morphine 0.1 mg/kg with nasal and IV placebo. All subjects received a standardized general anesthetic with sevoflurane, N(2)O, and O(2) and similar postoperative care. The primary end point of the study was the pain scores measured by the Faces, Legs, Activity, Cry, and Consolability (FLACC) scale in the PACU. RESULTS: There were no significant differences in peak FLACC pain among the 3 groups (mean [95% CI] 2.0 [1.2-2.8] for intranasal fentanyl, 2.7 [1.7-3.6] for IV morphine, and 2.9 [2.1-3.7] for IM morphine, respectively). There were no differences in the scores on the Pediatric Anesthesia Emergence Delirium (PAED) scale, incidence of postoperative emergence delirium (PAED score >/=12), emesis, perioperative hypoxemia, or need for airway intervention, and postoperative rescue analgesia. There were also no differences in the duration of PACU stay or parental satisfaction among the groups. CONCLUSION: In this double-blind, double-dummy study, there was no difference in the efficacy of intranasal fentanyl, IM and IV morphine in controlling postoperative pain and emergence delirium in children undergoing BMT placement. The IM route is the simplest and avoids the potential for delays to establish vascular access for IV therapy and the risks of laryngospasm if intranasal drugs pass through the posterior nasopharynx and irritate the vocal cords.

Hoeffe, J., E. Doyon Trottier, et al. (2017). "Intranasal fentanyl and inhaled nitrous oxide for fracture reduction: The FAN observational study." Am J Emerg Med 35(5): 710-715.

                INTRODUCTION: Procedural sedation and analgesia (PSA) are frequently used for fracture reduction in pediatric emergency departments (ED). Combining intranasal (IN) fentanyl with inhalation of nitrous oxide (N2O) allow for short recovery time and obviates painful and time-consuming IV access insertions. METHODS: We performed a bicentric, prospective, observational cohort study. Patients aged 4-18years were included if they received combined PSA with IN fentanyl and N2O for the reduction of mildly/moderately displaced fracture or of dislocation. Facial Pain Scale Revised (FPS-R) and Face, Leg, Activity, Cry, Consolability (FLACC) scores were used to evaluate pain and anxiety before, during and after procedure. University of Michigan Sedation Score (UMSS), adverse events, detailed side effects and satisfaction of patients, parents and medical staff were recorded at discharge. A follow up telephone call was made after 24-72h. RESULTS: 90 patients were included. There was no difference in FPS-R during the procedure (median score 2 versus 2), but the FLACC score was significantly higher as compared to before (median score 4 versus 0, Delta 2, 95% CI 0, 2). Median UMSS was 1 (95% CI 1, 2). We recorded no serious adverse events. Rate of vomiting was 12% (11/84). Satisfaction was high among participants responding to this question 85/88 (97%) of parents, 74/83 (89%) of patients and 82/85 (96%) of physicians would want the same sedation again. CONCLUSION: PSA with IN fentanyl and N2O is effective and safe for the reduction of mildly/moderately displaced fracture or dislocation, and has a high satisfaction rate.

Holdgate, A., A. Cao, et al. "The Implementation of Intranasal Fentanyl for Children in a Mixed Adult and Pediatric Emergency Department Reduces Time to Analgesic Administration." Acad Emerg Med, 2010; 17:1-4.

ACADEMIC EMERGENCY MEDICINE 2010; 17:1-4 (c) 2010 by the Society for Academic Emergency Medicine Abstract Objectives: The objective was to determine whether the introduction of intranasal (IN) fentanyl for children with acute pain would reduce the time to analgesic administration in a mixed adult and pediatric emergency department (ED). Methods: A protocol for IN fentanyl (1.5 mug/kg) for children age 1-15 years presenting with acute pain was introduced to the department. All children who received intravenous (IV) morphine in the 7 months prior to the introduction of the protocol and either IV morphine or IN fentanyl in the 7 months after the introduction of the protocol were identified from drug registers. Time to analgesic administration, time to see a doctor, and the ages of patients were compared between the periods before and after the introduction of IN fentanyl. Results: Following implementation, 81 patients received IN fentanyl and 37 received IV morphine, compared to 63 patients receiving morphine in the previous 7 months. The median time to analgesic administration for IN fentanyl was significantly shorter than for morphine (32 minutes vs. 63 minutes, p = 0.001). Children receiving fentanyl were significantly younger than those receiving morphine (median = 8.5 years vs. 12 years, p < 0.001). Conclusions: 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.

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

            BACKGROUND: NMDA receptors are involved in the development and maintenance of neuropathic pain. We evaluated the efficacy and safety of intranasal (S)-ketamine, one of the most potent clinically available NMDA receptor antagonists. METHODS: Sixteen patients with neuropathic pain of various origins were randomized into two treatment groups: (S)-ketamine 0.2mg/kg (group 1); (S)-ketamine 0.4mg/kg (group 2). Plasma concentrations of (S)-ketamine and (S)-norketamine were measured over 6h by High Performance Liquid Chromatography combined with mass spectrometry. Quantitative sensory testing (QST) was conducted before, during and after treatment. Side effects and amount of pain reduction were recorded. RESULTS: Intranasal (S)-ketamine administration lead to peak plasma concentrations of 27.7+/-5.9ng/ml at 10+/-6.3min (group 1) and 34.3+/-22.2ng/ml at 13.8+/-4.8min after application (group 2). Maximal plasma concentrations of (S)-norketamine were 18.3+/-14.9ng/ml at 81+/-59min (group 1) and 34.3+/-5.5ng/ml at 75+/-40min (group 2). Pain scores decreased significantly in both groups with minimal pain at 60min after drug administration (70+/-10% and 61+/-13% of initial pain in groups 1 and 2). The time course of pain decrease was significantly correlated with plasma concentrations of (S)-ketamine and (S)-norketamine (partial correlations: (S)-norketamine: -0.90 and -0.86; (S)-ketamine: -0.72 and -0.71 for group 1 and group 2, respectively). Higher dosing elicited significantly more side effects. Intranasal (S)-ketamine had no significant impact on thermal or mechanical detection and pain thresholds in normal or symptomatic skin areas. CONCLUSIONS: Intranasal administration of low dose (S)-ketamine rapidly induces adequate plasma concentrations of (S)-ketamine and subsequently of its metabolite (S)-norketamine. The time course of analgesia correlated with plasma concentrations.

Illum, L., S. S. Davis, et al. (1996). "Nasal administration of morphine-6-glucuronide in sheep--a pharmacokinetic study." Biopharm Drug Dispos 17(8): 717-24.

            The pharmacokinetics of morphine-6-glucuronide (M6G) after both intravenous dosing and nasal administration were studied in sheep. The nasal formulation consisted of M6G in combination with an absorption promoting delivery system in the form of chitosan. The mean half-life of M6G after intravenous administration was 51.0 +/- 8.2 min and that after intranasal dosing was 45.0 +/- 5.5 min. M6G clearance and volume of distribution were 5.4 +/- 1.5 mL min-1 kg-1 and 0.4 +/- 0.1 L kg-1 respectively. The plasma profile after nasal administration demonstrated rapid absorption of M6G. The bioavailability of M6G in the chitosan formulation was found to be 31.4%. These results suggest that M6G administered in combination with the chitosan delivery system may be considered as a suitable non-parenteral means of administering this analgesic.

Illum, L., P. Watts, et al. (2002). "Intranasal delivery of morphine." J Pharmacol Exp Ther 301(1): 391-400.

            Morphine administered nasally to humans as a simple solution is only absorbed to a limited degree, with a bioavailability of the order of 10% compared with intravenous administration. This article describes the development of novel nasal morphine formulations based on chitosan, which, in the sheep model, provide a highly increased absorption with a 5- to 6-fold increase in bioavailability over simple morphine solutions. The chitosan-morphine nasal formulations have been tested in healthy volunteers in comparison with a slow i.v. infusion (over 30 min) of morphine. The results show that the nasal formulation was rapidly absorbed with a T(max) of 15 min or less and a bioavailability of nearly 60%. The shape of the plasma profile for nasal delivery of the chitosan-morphine formulation was similar to the one obtained for the slow i.v. administration of morphine. Furthermore, the metabolite profile obtained after the nasal administration of the chitosan- morphine nasal formulation was essentially identical to the one obtained for morphine administered by the intravenous route. The levels of both morphine-6-glucuronide and morphine-3-glucuronide were only about 25% of that found after oral administration of morphine. It is concluded that a properly designed nasal morphine formulation (such as one with chitosan) can result in a non-injectable opioid product capable of offering patients rapid and efficient pain relief.

Jackson, K., M. Ashby, et al. (2002). "Pilot dose finding study of intranasal sufentanil for breakthrough and incident cancer-associated pain." J Pain Symptom Manage 23(6): 450-2.

Jacobs, I. (2002). "A pilot study of prehospital intranasal fentanyl." Prehosp Emerg Care 6(6): 157-158 (abstract #47).

Johansson, J., J. Sjoberg, et al. (2013). "Prehospital analgesia using nasal administration of S-ketamine--a case series." Scand J Trauma Resusc Emerg Med 21: 38.

Pain is a problem that often has to be addressed in the prehospital setting. The delivery of analgesia may sometimes prove challenging due to problems establishing intravenous access or a harsh winter environment. To solve the problem of intravenous access, intranasal administration of drugs is used in some settings. In cases where vascular access was foreseen or proved hard to establish (one or two missed attempts) on the scene of the accident we use nasally administered S-Ketamine for prehospital analgesia. Here we describe the use of nasally administered S-Ketamine in 9 cases. The doses used were in the range of 0,45-1,25 mg/kg. 8 patients were treated in outdoor winter-conditions in Sweden. 1 patient was treated indoor. VAS-score decreased from a median of 10 (interquartile range 8-10) to 3 (interquartile range 2-4). Nasally administered S-Ketamine offers a possible last resource to be used in cases where establishing vascular access is difficult or impossible. Side-effects in these 9 cases were few and non serious. Nasally administered drugs offer a needleless approach that is advantageous for the patient as well as for health personnel in especially challenging selected cases. Nasal as opposed to intravenous analgesia may reduce the time spent on the scene of the accident and most likely reduces the need to expose the patient to the environment in especially challenging cases of prehospital analgesia. Nasal administration of S-ketamine is off label and as such we only use it as a last resource and propose that the effect and safety of the treatment should be further studied.

Johnston, S., G. J. Wilkes, et al. (2010). "Inhaled methoxyflurane and intranasal fentanyl for prehospital management of visceral pain in an Australian ambulance service." Emerg Med J.

Objective This study analysed the analgesic effect and changes in vital signs associated with administration of inhaled Methoxyflurane (MTX) and/or intranasal Fentanyl (INF) for prehospital management of visceral pain. Method A retrospective, observational study reviewing 1024 randomly selected records of patients with presumed visceral pain administered MTX (465), INF (397) or both (162) by the Western Australian Ambulance Service between January 2004 and February 2006. Clinical variables assessed included systolic blood pressure, pulse rate, respiration rate and Glasgow Coma Scale score. Pain was assessed utilising Visual/Verbal Analogue Scale pain scores. Results Overall effects on vital signs appeared favourable 5 min after use and at hospital arrival with either agent alone or in combination. As sole agents, MTX produced the greatest initial pain scores reduction (2.0 (1.7 to 2.2) vs 1.6 (1.4 to 1.8)) (mean (95% CI), and INF provided greater pain reduction by hospital arrival (3.2 (2.9 to 3.5) vs 2.5 (2.1 to 2.9)). While both agents were effective, INF provided a greater pain score reduction for cardiac (3.0 (2.6 to 3.4) vs 2.3 (1.8 to 2.8)), female (3.4 (2.9 to 4.0) v 2.5 (2.0 to 3.0)) and age 75+ patients (3.2 (2.5 to 3.8) vs 1.8 (1.0 to 2.5)). Combined use of agents was not advantageous. Conclusions MTX and INF are effective agents for providing visceral pain analgesia in the prehospital setting. While MTX provided a more rapid onset of pain relief, INF provided superior analgesia after subsequent doses and in female, cardiac and older patients.

Karl, H. W., A. T. Keifer, et al. (1992). "Comparison of the safety and efficacy of intranasal midazolam or sufentanil for preinduction of anesthesia in pediatric patients." Anesthesiology 76(2): 209-15.

            Nasal administration of sufentanil or midazolam is effective for preinduction of pediatric patients, but there are no data on which to base a choice between them. This blinded randomized study compares behavioral and physiologic responses to sedation with one of these medications followed by inhalation or intravenous induction. Ninety-five patients aged 0.5-10 yr scheduled for elective surgery were stratified by age: 30 infants 0.5-2 yr, 38 preschoolers 2.1-5 yr, and 27 school-age children 5.1-10 yr. They were randomized to receive 0.04 ml/kg of midazolam (0.2 mg/kg) or sufentanil (2 micrograms/kg). Hemoglobin oxygen saturation by pulse oximetry (SpO2) and sedation score were recorded prior to drug administration, at 2.5-min intervals for 10 min, at separation, and during induction with graded halothane in oxygen. Intubation was performed under deep halothane or 3 mg/kg of thiopental and 0.1 mg/kg of pancuronium. Chest wall compliance was assessed qualitatively in all patients prior to intubation. To assess the effects of a mild standardized stress on unpremedicated patients, 75 of the children with parents present were scored before and after oximeter probe placement: of these, in 63% the sedation score did not change; 33% appeared more anxious; and only 4% seemed reassured. Children of all ages reacted negatively to physicians, and 23% were crying prior to administration of drugs. Sufentanil appeared less unpleasant to receive than midazolam: children cried 46 +/- 100 versus 76 +/- 73 s (P less than 0.05), respectively, but by 7.5 min, no child was crying. Median behavior scores at maximum anxiolysis were not different, but response to sufentanil was more variable.(ABSTRACT TRUNCATED AT 250 WORDS)

Karlsen, A. P., D. M. Pedersen, et al. (2014). "Safety of intranasal fentanyl in the out-of-hospital setting: a prospective observational study." Ann Emerg Med 63(6): 699-703.

STUDY OBJECTIVE: Initial out-of-hospital analgesia is sometimes hampered by difficulties in achieving intravenous access or lack of skills in administering intravenous opioids. We study the safety profile and apparent analgesic effect of intranasal fentanyl in the out-of-hospital setting. METHODS: In this prospective observational study, we administered intranasal fentanyl in the out-of-hospital setting to adults and children older than 8 years with severe pain resulting from orthopedic conditions, abdominal pain, or acute coronary syndrome refractory to nitroglycerin spray. Patients received 1 to 3 doses of either 50 or 100 mug, and the ambulance crew recorded adverse effects and numeric rating scale (0 to 10) pain scores before and after treatment. RESULTS: Our 903 evaluable patients received a mean cumulative fentanyl dose of 114 mug (range 50 to 300 mug). There were no serious adverse effects and no use of naloxone. Thirty-six patients (4%) experienced mild adverse effects: mild hypotension, nausea, vomiting, vertigo, abdominal pain, rash, or decrease of Glasgow Coma Scale score to 14. The median reduction in pain score was 3 (interquartile range 2 to 5) after fentanyl administration. CONCLUSION: The out-of-hospital administration of intranasal fentanyl in doses of 50 to 100 mug is safe and appears effective.

Kaube, H., J. Herzog, et al. (2000). "Aura in some patients with familial hemiplegic migraine can be stopped by intranasal ketamine." Neurology 55(1): 139-141.

                Migraine aura is probably caused by cortical-spreading depression. No treatment for acute and severe migraine aura has been described previously. The effect of ketamine (25 mg intranasally) was studied in 11 patients with severe, disabling auras resulting from familial hemiplegic migraine. In five patients ketamine reproducibly reduced the severity and duration of the neurologic deficits, whereas in the remaining six patients no beneficial effect was seen. Ketamine offers, for the first time, a possible treatment option for severe and prolonged aura.

Kavanagh, P. L., P. G. Sprinz, et al. (2015). "Improving the Management of Vaso-Occlusive Episodes in the Pediatric Emergency Department." Pediatrics 136(4): e1016-1025.

OBJECTIVES: Vaso-occlusive episodes (VOEs) account for the majority of emergency department (ED) visits for children with sickle cell disease (SCD). We hypothesized that addressing key barriers to VOE care would improve receipt of analgesics and outcomes. METHODS: A quality improvement (QI) initiative was conducted from September 2010 to April 2014 to streamline VOE care in an urban pediatric ED. Four interventions were used: a standardized time-specific VOE protocol; intranasal fentanyl as the first parenteral pain medication; an SCD pain medication calculator; and provider and patient/family education. Data were collected for 3 outcome measures (mean time from triage to first parenteral opioid and admission/discharge decision, and proportion discharged from the ED); 1 process measure (mean time from triage to initiation of patient-controlled analgesia); and 4 balancing measures (mean time from triage to second intravenous opioid dose, 24-hour ED readmission, respiratory depression, and length of stay). RESULTS: There were 289 ED visits in the study period. Improvements were seen in mean time to: first dose of parenteral opioid (56 to 23 minutes); second opiate intravenous dose (106 to 83 minutes); admission and discharge decisions (163 to 109 minutes and 271 to 178 minutes, respectively); and initiation of patient-controlled analgesia (216 to 141 minutes). The proportion discharged from the ED increased from 32% to 48% (chi(2) = 6.5402, P = .01). No increase in 24-hour readmission, respiratory depression, or inpatient length of stay was observed. CONCLUSIONS: Using VOE-specific interventions, we significantly improved VOE care for children. Studies are needed to determine if these results can be replicated.

Kelly, G. S., R. W. Stewart, et al. (2018). "Intranasal fentanyl improves time to analgesic delivery in sickle cell pain crises." Am J Emerg Med 36(7): 1305-1307. (Abstract link)

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

            Diamorphine is a semisynthetic derivative of morphine that is currently licensed for use in the treatment of moderate to severe acute pain, administered by the intramuscular, intravenous or subcutaneous routes. It is highly water-soluble and has a number of properties that render it suitable for administration via the nasal route. Administration via the intranasal route is well described for other drugs, but has only recently been evaluated in a clinical setting for diamorphine. A well-tolerated and rapidly effective analgesic agent has proven elusive in the paediatric setting. The pharmacokinetic profile of intranasal diamorphine in adults has been systematically studied. It is rapidly and dose-dependently absorbed as a dry powder, with peak plasma concentrations occurring within 5 minutes, and has a similar pharmacokinetic profile to that of intramuscular diamorphine. It is rapidly converted to 6-acetylmorphine (peak concentrations within 5-10 minutes) and thence to morphine (peak concentrations within 1 hour). The pharmacodynamic properties of intranasal diamorphine have also been studied in comparison with intramuscular diamorphine. Intranasal and intramuscular administration of diamorphine resulted in similar physiological responses (including pupil diameter, respiration rate and temperature). Changes in behavioural measures (including euphoria, sedation and dysphoria) were also similar. Intranasal administration of diamorphine, therefore, produces the expected drug effects on the same timescale and of the same magnitude as intramuscular injection. Intranasal diamorphine has been clinically evaluated in a randomised controlled trial versus intramuscular morphine in the setting of acute orthopaedic pain in children with fractures. Intranasal diamorphine provided the same overall degree of pain relief as intramuscular morphine, but with a quicker onset of action. It was found to be well tolerated with an acceptable safety profile. It has also been studied in the setting of patient-controlled analgesia for postoperative pain in adults, with encouraging results. The pharmacokinetic and pharmacodynamic properties of intranasal diamorphine, and particularly the ability to administer it without a needle (and therefore reduce the incidence of transmissible infection), have made this a popular route for abuse amongst opioid addicts. In this setting, however, the intranasal route is not free from adverse events, including deaths. The primary clinical need in the paediatric population is for a well tolerated, effective and expedient analgesic agent that is safe to use; intranasal diamorphine has pharmacokinetic properties that would make it suitable for such a clinical indication and, in clinical evaluations to date, appears to be promising.

Kendall, J. M., B. C. Reeves, et al. (2001). "Multicentre randomised controlled trial of nasal diamorphine for analgesia in children and teenagers with clinical fractures." Bmj 322(7281): 261-5.

            OBJECTIVE: To compare the effectiveness of nasal diamorphine spray with intramuscular morphine for analgesia in children and teenagers with acute pain due to a clinical fracture, and to describe the safety profile of the spray. DESIGN: Multicentre randomised controlled trial. SETTING: Emergency departments in eight UK hospitals. PARTICIPANTS: Patients aged between 3 and 16 years presenting with a clinical fracture of an upper or lower limb. MAIN OUTCOME MEASURES: Patients' reported pain using the Wong Baker face pain scale, ratings of reaction to treatment of the patients and acceptability of treatment by staff and parents, and adverse events. RESULTS: 404 eligible patients completed the trial (204 patients given nasal diamorphine spray and 200 given intramuscular morphine). Onset of pain relief was faster in the spray group than in the intramuscular group, with lower pain scores in the spray group at 5, 10, and 20 minutes after treatment but no difference between the groups after 30 minutes. 80% of patients given the spray showed no obvious discomfort compared with 9% given intramuscular morphine (difference 71%, 95% confidence interval 65% to 78%). Treatment administration was judged acceptable by staff and parents, respectively, for 98% (199 of 203) and 97% (186 of 192) of patients in the spray group compared with 32% (64 of 199) and 72% (142 of 197) in the intramuscular group. No serious adverse events occurred in the spray group, and the frequencies of all adverse events were similar in both groups (spray 24.1% v intramuscular morphine 18.5%; difference 5.6%, -2.3% to 13.6%). CONCLUSION: 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.

Kendall, J., I. Maconochie, et al. (2014). "A novel multipatient intranasal diamorphine spray for use in acute pain in children: pharmacovigilance data from an observational study." Emerg Med J.

OBJECTIVES: To establish the safety of an intranasal diamorphine (IND) spray in children. DESIGN: An open-label, single-dose pharmacovigilance trial. SETTING: Emergency departments in eight UK hospitals. PARTICIPANTS: Children aged 2-16 years with a fracture or other trauma. OUTCOME MEASURES: Adverse events (AE) specifically related to nasal irritation, respiratory and central nervous system depression. RESULTS: 226 patients received 0.1 mg/kg IND. No serious or severe AEs occurred. The incidence of treatment-emergent AEs (TEAEs) was 26.5% (95% CI 20.9% to 32.8%), 93% being mild. 89% were related to treatment, all being known effects of the drug or route of administration except for three events in two patients. 20.4% (95% CI 15.3% to 26.2%) patients reported nasal irritation, all mild except one moderate and one 'unknown' severity. No respiratory depression was reported. Three AEs related to reduced Glasgow Coma Score (GCS) occurred, all mild. CONCLUSIONS: There were no safety concerns raised during the conduct of the study. In addition to expected side effects, IND can cause mild nasal irritation in a proportion of patients. EUROPEAN UNION DRUG REGULATING AUTHORITIES CLINICAL TRIAL NO: 2009-014982-16.

Kerr, D., D. Taylor, et al. (2015). "Patient-controlled intranasal fentanyl analgesia: a pilot study to assess practicality and tolerability during childbirth." Int J Obstet Anesth 24(2): 117-123.

                BACKGROUND: Intranasal administration of fentanyl is a non-invasive method of analgesic delivery which has been shown to be effective. This pilot study aimed to assess the practicality and tolerability of patient-controlled intranasal fentanyl for relieving pain during childbirth. METHODS: This prospective, non-randomised, clinical trial recruited women with a singleton pregnancy during November 2009 to October 2011. Exclusion criteria included respiratory disease, gestation <37weeks and pregnancy complications. The device administered fentanyl 54mug per spray, incorporating a 3-min lock-out. Data collected included demographics, dose, additional analgesia, adverse events, pain relief and delivery outcomes. Follow-up data were obtained within 48h regarding tolerability of the device. RESULTS: The final sample included 32 women: mean age was 28.7years and gestation 39.8weeks. Mean fentanyl dose was 734mug and duration of use was 3.5h. Most women (78.2%) reported satisfactory to excellent pain relief using the nasal device. Four neonates (12.5%) required bag-mask ventilation at birth: three had adequate respiration within 5min and one required short-term observation in the special-care nursery. For all items, there was a trend towards an adverse outcome, including neonatal respiratory support, as the dose of fentanyl increased. On follow-up, 84.4% reported they would use intranasal fentanyl for their next childbirth experience. CONCLUSIONS: Patient-controlled intranasal fentanyl provides an acceptable level of analgesia during childbirth. It may, however, increase the risk of neonatal respiratory depression. Future, randomised studies should evaluate the safety and efficacy of patient-controlled intranasal fentanyl compared with existing analgesia options.

Kim, K. S., N. K. Yeo, et al. (2018). "Effect of Fentanyl Nasal Packing Treatment on Patients With Acute Postoperative Pain After Nasal Operation: A Randomized Double-Blind Controlled Trial." Ann Otol Rhinol Laryngol 127(5): 297-305.

PURPOSE: Nasal packing is an option for bleeding control after endoscopic sinus surgery and septoplasty. Although new packing materials have been developed, patients still suffer from pain and require additional analgesics treatments. In this study, a prospective, randomized, and double-blind controlled trial was designed to evaluate the effect of fentanyl-soaked packing on pain after endoscopic sinus surgery and septoplasty. METHODS: One hundred fifty-two patients who underwent nasal surgeries due to chronic rhinosinusitis or nasal septal deviation were enrolled in this study. At the end of operation, 50 mcg fentanyl-soaked biodegradable synthetic polyurethane foams packing Nasopore or Merocel were applied to a group of 79 patients, and saline-soaked ones were applied to another group of 73 patients. To evaluate the influence of fentanyl on postoperative nasal pain, patients' conditions were assessed via means of Numeric Rating Scale, patient satisfaction, and Ramsay Sedation Scale. In addition, symptoms of headache or sore throat and any signs of cardiopulmonary-relevant indicators were monitored. RESULTS: The fentanyl group had significantly decreased Numeric Rating Scale and increased patient satisfaction in every operation type for the majority of postoperative time periods ( P < .05) with reduced postoperative headache and sore throat compared to the control group. The fentanyl group showed a higher score on Ramsay Sedation Scale than the control group ( P < .05 in group including endoscopic sinus surgery). There were no significant differences in cardiopulmonary-relevant indicators between the 2 groups ( P > .05). CONCLUSION: Fentanyl group showed significantly reduced postoperative pain without serious adverse effects. We suggest that topical fentanyl application to nasal packs can be a useful method to reduce pain during the early postoperative period after endoscopic sinus surgery and septoplasty.

Ku, L. C., C. Simmons, et al. (2019). "Intranasal midazolam and fentanyl for procedural sedation and analgesia in infants in the neonatal intensive care unit." J Neonatal Perinatal Med 12(2): 143-148.

BACKGROUND: The intranasal route is a minimally invasive method for rapidly delivering midazolam and fentanyl to provide short-term analgesia and sedation in infants. However, intranasal use of midazolam and fentanyl is not labeled for infants and safety data are sparse. The objective of this study is to evaluate the safety of intranasal midazolam and intranasal fentanyl in infants admitted to the Neonatal Intensive Care Unit (NICU). METHODS: We retrospectively identified all infants receiving intranasal midazolam or fentanyl in the NICU from 2009 to 2015. We recorded indication for use and vital signs and determined the proportion of infants experiencing the following adverse events: death within 24 hours, hypotension, bradycardia, worsening respiratory status, and chest wall rigidity. Vital signs 4 hours before and after each dose were compared using the Wilcoxon signed-rank test. RESULTS: We identified 17 infants (gestational ages 23- 41 weeks) receiving 25 intranasal doses. None of the infants died or developed hypotension, bradycardia, or chest wall rigidity. Intranasal delivery was most commonly used for sedation during magnetic resonance imaging studies. Other indications include analgesia or sedation for retinopathy of prematurity surgery, intubation, and peripherally inserted central catheter placement. One infant receiving intranasal midazolam experienced worsening respiratory status. Vital signs before and after dosing were not significantly different. CONCLUSIONS: Intranasal midazolam and fentanyl use in term and preterm infants appeared safe and well-tolerated in this small cohort of infants. Larger, prospective studies evaluating the safety and efficacy of intranasal midazolam and fentanyl use in infants are warranted.

Kress, H. G., A. Oronska, et al. (2009). "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 31(6): 1177-91.

            OBJECTIVE: This trial investigated the efficacy and long-term tolerability of intranasal fentanyl spray (INFS) 50 to 200 microg in the treatment of breakthrough pain in opioid-tolerant patients with cancer. METHODS: This Phase III, double-blind, randomized, placebo-controlled, crossover trial was conducted at pain centers, anesthesiology departments, palliative care units, and oncology clinics in Austria, Denmark, France, Germany, and Poland. Eligible patients were adults with cancer receiving a stable dose of long-term opioid treatment for the control of background pain. Patients were treated at home with their effective dose of INFS (50, 100, or 200 microg) or inactive spray (placebo) in a randomized sequence for 3 weeks, followed by a 10-month, open-label tolerability phase during which they received their effective dose of INFS. Throughout the study, patients were allowed to use their usual rescue medication, which was recorded in patient diaries. The primary efficacy end point was the pain intensity difference at 10 minutes after study drug administration (PID(10)), as assessed using an 11-point numeric rating scale (0 = no pain to 10 = worst pain imaginable). An effect size of 0.5 for PID was considered clinically relevant. The rate of response, defined as PID(10) >2, was also assessed. Adverse events (AEs) were recorded in patient diaries during the efficacy period and reported in monthly clinic visits and follow-up weekly telephone contacts during the extension period. RESULTS: In all, 120 patients were enrolled and achieved an effective dose; 113 were randomized and 111 were included in the intent-to-treat analysis set (56 men, 55 women; mean [SD] age, 60.6 [9.45] years; mean weight, 70.3 kg [men] and 65.3 kg [women]; white race, 107 [96.4%]; INFS 50 microg, 18; INFS 100 microg, 48; INFS 200 microg, 45; placebo, 110). PID(10) with INFS was 2-fold that with placebo (adjusted means, 2.36 vs 1.10; adjusted difference, 1.26 [greater than the clinically relevant difference of 0.5]; P < 0.001). Additional analysis revealed that the mean response rate with all 3 doses of INFS was 51.1% versus 20.9% with placebo. The prevalence of AEs was 22/111 (19.8%) during the efficacy period, during which the most frequently reported AEs were nausea (5 [4.5%]) and vertigo (2 [1.8%]). No serious AEs were considered related to the study drugs. In all, 108 patients entered the extension period, with a mean duration of exposure to INFS of 134.9 days. Progression of underlying malignant disease was the most common AE reported during this period (55 [50.9%]); this event was not considered treatment related. CONCLUSIONS: In these opioid-tolerant patients with cancer, INFS at doses of 50, 100, and 200 microg was associated with an onset of activity at 10 minutes and effective treatment of breakthrough pain compared with placebo. All doses were generally well tolerated and clinically efficacious.

Kronenberg and Rh (2002). "Ketamine as an analgesic: parenteral, oral, rectal, subcutaneous, transdermal and intranasal administration." J Pain Palliat Care Pharmacother 16(3): 27-35.

                Ketamine is a parenteral anesthetic agent that provides analgesic activity at sub-anesthetic doses. It is an N-methyl-D-aspartate (NMDA) receptor antagonist with opioid receptor activity. Controlled studies and case reports on ketamine demonstrate efficacy in neuropathic and nociceptive pain. Because ketamine is a phencyclidine analogue, it has some of the psychological adverse effects found with that hallucinogen, especially in adults. Therefore, ketamine is not routinely used as an anesthetic in adult patients. It is a frequently used veterinary anesthetic, and is used more frequently in children than in adults. The psychotomimetic effects have prompted the DEA to classify ketamine as a Schedule III Controlled Substance. A review of the literature documents the analgesic use of ketamine by anesthesiologists and pain specialists in patients who have been refractory to standard analgesic medication regimens. Most reports demonstrate no or mild psychotomimetic effects when ketamine is dosed at sub-anesthetic doses. Patients who respond to ketamine tend to demonstrate dramatic pain relief that obviates the desire to stop treatment due to psychotomimetic effects (including hallucinations and extracorporeal experiences). Ketamine is approved by the FDA for intravenous and intramuscular administration. Use of this drug by the oral, intranasal, transdermal, rectal, and subcutaneous routes has been reported with analgesic efficacy in treating nociceptive and neuropathic pain. Ketamine also has been reported to produce opioid dose sparing and good patient acceptance. A transdermal formulation is currently under patent review in Brazil and an intranasal formulation is currently undergoing phase I/II clinical trials.

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

Kurien, T., K. R. Price, et al. (2016). "Manipulation and reduction of paediatric fractures of the distal radius and forearm using intranasal diamorphine and 50% oxygen and nitrous oxide in the emergency department: a 2.5-year study." Bone Joint J 98-B(1): 131-136.

A retrospective study was performed in 100 children aged between two and 16 years, with a dorsally angulated stable fracture of the distal radius or forearm, who were treated with manipulation in the emergency department (ED) using intranasal diamorphine and 50% oxygen and nitrous oxide. Pre- and post-manipulation radiographs, the final radiographs and the clinical notes were reviewed. A successful reduction was achieved in 90 fractures (90%) and only three children (3%) required remanipulation and Kirschner wire fixation or internal fixation. The use of Entonox and intranasal diamorphine is safe and effective for the closed reduction of a stable paediatric fracture of the distal radius and forearm in the ED. By facilitating discharge on the same day, there is a substantial cost benefit to families and the NHS and we recommend this method. TAKE HOME MESSAGE: Simple easily reducible fractures of the distal radius and forearm in children can be successfully and safely treated in the ED using this approach, thus avoiding theatre admission and costly hospital stay.

Lemoel, F., J. Contenti, et al. (2019). "Intranasal sufentanil given in the emergency department triage zone for severe acute traumatic pain: a randomized double-blind controlled trial." Intern Emerg Med 14(4): 571-579.

The goal of our study was to determine if an intranasal (IN) dose of sufentanil delivered in the ED triage zone would improve the management of severely painful patients. We performed a randomized, double blind and placebo-controlled trial on adult patients suffering from an acute severe pain (>/= 6/10) consecutive to an isolated limb injury. We compared 2 analgesic strategies: the usual pain treatment with IV-only multimodal analgesics (IVMA) including IV opioids if needed (control group) and another strategy (active group) based on a single dose of IN sufentanil (0.4 mug/kg) given at triage and followed by IV multimodal analgesia. Our primary outcome was the proportion of patients reaching pain-relief (</= 3/10) 30 min after IN injection at triage. Secondary outcomes were rates of adverse events, frequency of clinical interventions required by these events, and satisfaction of patients. A total of 144 adult participants completed the study, 72 in each group. Compared with usual IV-only pain management, the analgesic strategy initiated in triage zone with a dose of IN sufentanil increased the proportion of patients reaching pain relief in 30 min: 72.2% versus 51.4%, in our trial (p = 0.01 and number needed to treat of 5). There was no serious adverse event (AE) in both groups. Patients who received IN sufentanil experienced more frequently minor opiate side effects. Proportion of respiratory AEs was higher in the active group (12.5% of bradypnea < 10 cycles per minute versus 1.4%) but these events were of mild severity, as only 2 participants (one in each group) received temporary low dose oxygen therapy, and none required naloxone. Lengths of stay in the ED were similar in both groups, as well as satisfaction of patients (above 9/10) and pain scores at discharge (< 2/10). We found that a single dose of IN sufentanil delivered in the ED triage zone significantly increases the proportion of severely painful patients reaching painrelief in 30 min, compared to usual analgesia with IV-only multimodal analgesia.

Liang, P., C. Zhou, et al. (2014). "Single-dose sufentanil or fentanyl reduces agitation after sevoflurane anesthesia in children undergoing ophthalmology surgery." Pak J Med Sci 30(5): 1059-1063.

OBJECTIVES: The trail investigated the effect of small dose sufentanil or fentanyl administrated before the end of surgery in reducing the incidence of emergence agitation after anesthesia with sevoflurane in preschool children undergoing ophthalmology surgery, and the incidence of emergence agitation of sevoflurane anesthesia. METHODS: From September 2011 to January 2012 January, ninety ASA I-II children, aged from 3-7 years, undergoing ophthalmology surgery in West China Hospital, were randomly assigned to three groups to receive intravenous saline, sufentanil 0.1mug/kg or fentanyl 1mug/kg at 20 minutes before the end of the surgery. Children were scored by scoring system for emergence agitation (SSEA), Children's and Infants' Postoperative Pain Scale (CHIPPS) score. RESULTS: The incidence of agitation was 30% in sufentanil group, 36.67% in fentanyl group, and 63.33% in control group. The incidence of sever agitation (SSEA score>/=3) was 6.67% in sufentanil group, 23.37% in fentanyl group, and 36.67% in control group. The agitation and pain scores in sufentanil group and fentanyl group were better than those in control group (P<0.05). There was no difference among three groups about time to extubation. CONCLUSIONS: We conclude that the incidence of emergence agitation after sevoflurane anesthesia in children undergoing ophthalmology surgery is up to 63.33%. The single dose of sufentanil or fentanyl can reduce the emergence agitation in children anesthesized with sevoflurane, with no adverse effects. The effect of sufentanil is better than fentanyl.

Lord, B., P. A. Jennings, et al. (2019). "Effects of the Introduction of Intranasal Fentanyl on Reduction of Pain Severity Score in Children: An Interrupted Time-Series Analysis." Pediatr Emerg Care 35(11): 749-754.

OBJECTIVES: Children are at risk of inadequate analgesia due to paramedics' inexperience in assessing children and challenges in administering analgesics when the patient is distressed and uncooperative. This study reports on the outcome of a change to practice guidelines that added intranasal fentanyl and intramuscular morphine within a large statewide ambulance service. METHODS: This retrospective study included patients younger than 15 years treated by paramedics between January 2008 and December 2011. The primary outcome of interest was the proportion of patients having a 2/10 or greater reduction in pain severity score using an 11-point Verbal Numeric Rating Scale before and after the intervention. Segmented regression analysis was used to estimate the effect of the intervention over time. A multiple regression model calculated odds ratios with 95% confidence intervals. RESULTS: A total of 92,378 children were transported by paramedics during the study period, with 9833 cases included in the analysis. The median age was 11 years; 61.6% were male. Before the intervention, 88.1% (n = 3114) of children receiving analgesia had a reduction of pain severity of 2 or more points, with 94.2% (n = 5933) achieving this benchmark after intervention (P < 0.0001). The odds of a reduction in pain of 2 or more points increased by 1.01 per month immediately before the intervention and 2.33 after intervention (<0.0001). CONCLUSIONS: This large study of a system-wide clinical practice guideline change has demonstrated a significant improvement in the outcome of interest. However, a proportion of children with moderate to severe pain did not receive analgesia.

Lundeberg, S. and J. A. Roelofse (2010). "Aspects of pharmacokinetics and pharmacodynamics of sufentanil in pediatric practice." Paediatr Anaesth.

Sufentanil is a potent synthetic opioid. Like other opioids, sufentanil creates a stable hemodynamic environment in cardiovascularly compromised pediatric patients. Clearance, expressed as per kilogram, is increased in children compared to adults. The P450 CYP3A4 enzyme is responsible for the major metabolic N-dealkylation pathway. Enzyme activity is reduced in neonates but the maturation of sufentanil clearance is not described. The free active fraction is affected by age because of the reduced alpha(1) -acid glycoprotein plasma concentrations in neonates. Intranasal administration of sufentanil is a possible option for premedication, procedural sedation and analgesia in children, as this option has been found to be safe and effective. Studies concerning the pharmacokinetics and dynamics of sufentanil administered as a bolus or continuous infusion in children are few.

Malinovsky, J. M., C. Lejus, et al. (1993). "Plasma concentrations of midazolam after i.v., nasal or rectal administration in children." Br J Anaesth 70(6): 617-20.

            Midazolam is used frequently for premedication in children, preferably by non-parenteral administration. We have compared plasma concentrations of midazolam after nasal, rectal and i.v. administration in 45 children (aged 2-9 yr; weight 10-30 kg) undergoing minor urological surgery. General anaesthesia consisted of spontaneous respiration of halothane and nitrous oxide in oxygen via a face mask. After administration of atropine and fentanyl i.v., children were allocated randomly to receive midazolam 0.2 mg kg-1 by the nasal, rectal or i.v. route. In the nasal group, children received 50% of the dose of midazolam in each nostril. In the rectal group, midazolam was given rectally via a cannula. Venous blood samples were obtained before and up to 360 min after administration of the drug. Plasma concentrations of midazolam were measured by gas chromatography and electron capture detection. After nasal and rectal administration, midazolam Cmax was 182 (SD 57) ng ml-1 within 12.6 (5.9) min, and 48 (16) ng ml-1 within 12.1 (6.4) min, respectively. Rectal administration resulted in smaller plasma concentrations. In the nasal group, a plasma concentration of midazolam 100 ng ml-1 occurred at about 6 min. After 45 min, the concentration curves after i.v. and nasal midazolam were similar.

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

           PURPOSE: To evaluate intranasally administered fentanyl for postoperative analgesia in pediatric patients. METHODS: Thirty-two children aged four to eight years, ASA physical status I and II were included in this prospective randomized controlled study. In the postoperative care unit, patients were allocated to receive fentanyl, using a double-blind study design, either intranasally (Group I) or intravenously (Group II) in small titrated doses until they became pain free or side effects appeared which prohibited continuation of the drug. RESULTS: Satisfactory analgesia was achieved in both groups, though the required drug dosage was higher in the intranasal group (1.43 +/- 0.39 Onset of analgesia tended to be slower via the intranasal route compared to the iv route (13 +/- 4.5 vs 8.3 +/- 3.08 min; P=not significant). Side effects observed in this series were within an acceptable range and similar for both modalities. CONCLUSION: The intranasal route provides a good alternative for administration of fentanyl in pediatric surgical patients.

Maroli, S., H. P. Srinath, et al. (2014). "Sniffing out pain: An in vivo intranasal study of analgesic efficacy." J Int Oral Health 6(1): 66-71.

BACKGROUND: Orofacial pain is a common encounter in dentistry (affecting 12% of the population) and is a primary reason for patients seeking emergency care. Dentists often prescribe oral analgesics, which have disadvantages of decreased absorption rates and delayed onset. Intranasal (IN) delivery takes advantage of a large surface area of mucosal tissue for rapid absorption. The purpose of this study was to evaluate the efficacy of IN ketorolac for endodontic pain using a randomized, double-blind, placebocontrolled parallel design study. MATERIALS & METHODS: Twenty patients presenting with moderate to severe endodontic pain were selected to receive IN treatment with placebo (n = 10) or ketorolac (n = 10) 30 minutes before endodontic treatment was started and immediately after the completion of endodontic treatment. Baseline pain levels were recorded before IN treatment. Pain levels were also recorded at 15 and 30 minutes after the initial IN dosing (before endodontic treatment); 30 minutes after completion of endodontic treatment; and 4, 8, and 12 hours after the initial IN spray. RESULTS: IN ketorolac alone or with endodontic treatment showed significantly better pain relief compared with IN placebo spray alone or with endodontic treatment at 30 minutes after the first or second intranasal dose and at 4 hours after the first intranasal dose. CONCLUSIONS: These results suggest that IN ketorolac may provide a novel and efficacious method for pain relief in endodontic pain patients. How to cite the article: Maroli S, Srinath HP, Goinka C, Yadav NS, Bhardwaj A, Varghese RK. Sniffing out pain: An in vivo intranasal study of analgesic efficacy. J Int Oral Health 2014;6(1):66-71.

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

            PURPOSES: The aim of this prospective, randomized, double-blind study was to compare two doses of intranasal sufentanil for postoperative analgesia, titrated according to individual requirements based upon a numeric rating scale (NRS) from 0 to 10 for pain. METHODS: Forty patients, American Society of Anesthesiologists physical status I-II, scheduled for herniorrhaphy or hemorrhoidectomy under general anesthesia, were included when postoperative NRS was > 3. Nurses used a nasal puff device delivering a constant volume. Patients were randomized into two groups: Group A patients received a dose of 0.025 microg x kg(-1) /puff, Group B patients a dose of 0.05 microg x kg(-1) /puff. Puffs were administered as often as needed to obtain NRS < or = 3, with an interval time of five minutes. Hemodynamic, respiratory measures and sedation were recorded every five minutes.Results: The probability of persistence of pain in Group B was consistently lower than in Group A. After 20 min, 20% of the patients had a NRS score > 3 in Group B, as opposed to 60% in Group A. At 60 min, no patient had a NRS > 3 in Group B, whereas there was a probability of 20% to record a NRS > 3 for Group A. Hemodynamic, respiratory parameters and sedation remained stable with no intergroup differences. CONCLUSIONS: Nasal administration of 0.050 microg x kg(-1) /puff sufentanil allowed a NRS < 4 to be attained within one hour in all patients, with efficacy achieved after 20 min. These findings suggest that the intranasal route is an effective mode of sufentanil administration for immediate postoperative analgesia in adult patients.

McAleer, S. D., O. Majid, et al. (2007). "Pharmacokinetics and safety of ketorolac following single intranasal and intramuscular administration in healthy volunteers." J Clin Pharmacol 47(1): 13-18.

            Ketorolac was administered to 15 healthy volunteers in a phase 1, single-dose, crossover, randomized study. Subjects received open-label randomized 15- and 30-mg intramuscular (i.m.) ketorolac and blinded randomized 15- and 30-mg intranasal (i.n.) ketorolac. The i.n. ketorolac was well tolerated; the only nasal symptoms were some instances of mild irritation. The i.n. ketorolac was rapidly and well absorbed (median tmax, 0.50-0.75 hours), and the half-life was approximately 5 to 6 hours, values that were similar to those following i.m. administration. Relative bioavailability of i.n. compared to i.m. administration at the same doses was approximately 67% to 75%. Dose proportionality was noted between the 15- and 30-mg i.n. and i.m. dose levels. Thus, i.n. ketorolac offers a therapeutic alternative to i.m. administration and may provide benefits in the clinical setting.

McHale, B., C. D. Badenhorst, et al. (2018). "Do children undergoing bilateral myringotomy with placement of ventilating tubes benefit from pre-operative analgesia? A double-blinded, randomised, placebo-controlled trial." J Laryngol Otol 132(8): 685-692.

OBJECTIVE: A double-blinded, randomised, placebo-controlled trial was conducted to determine whether routine pre-operative analgesia is beneficial in reducing post-operative ear pain following bilateral myringotomy and tube placement. METHODS: Forty-five children (aged 3-15 years) were randomised to receive either pre-operative analgesics (paracetamol and ibuprofen) (n = 21) or placebo (n = 24). All children underwent sevoflurane gas induction with intranasal fentanyl (2 mcg/kg) to reduce the incidence of emergence agitation. Post-operative pain scores were measured using the Wong-Baker Faces Pain Rating Scale. Median pain scores taken 90 minutes post-surgery, and the highest pain score recorded prior to 90 minutes, were analysed. RESULTS: There were no statistical differences between the median pain scores at 90 minutes or subsequent need for rescue analgesia. Emergence agitation did not occur in any child. Inadvertent ear trauma, use of an intravenous cannula or airway adjunct did not affect pain scores. CONCLUSION: Routine pre-operative analgesia does not reduce pain scores in the early post-operative period. Simple analgesics are effective for rescue analgesia in the minority of cases.

McLean, A. R., D. A. Braude, et al. (2009). "Intranasal fentanyl for analgesia in injured patients at a ski resort (abstract)." Wilderness Medical Journal 21(1): 68-69.

Introduction: Intranasal fentanyl has been shown to be a safe, effective mode of analgesic administration in prehospital, emergency department, and postoperative patients. We evaluated the use of intranasal fentanyl for initial analgesia in injured patients at a ski resort.  Methods: We retrospectively reviewed the charts of 46 injured adult and pediatric patients treated with intranasal fentanyl during the 2007–2008 winter ski season. Patients were treated with fentanyl according to online MCEP-approved doses (approximate dose 1.4 μg/kg), using 50 μg/mL concentration fentanyl administered with a MAD Nasal (Wolfe Tory Medical Inc, Salt Lake City, UT) mucosal atomizing device. Doses were administered in 1/6 dose increments in alternating nares. Pain scores were recorded at 0, 2, 5, and 10 minutes using a verbally administered numerical rating scale of 0 through 10. Results: Data analysis was performed using results from 42 of the 46 patients: 5 pediatric and 37 adult. Four patients were excluded due to incomplete data. Thirty-four patients were initially treated on-slope and 8 patients were initially treated in the clinic. Average weight-based dosage for intranasal fentanyl was 1.4 μg/kg (95% confidence interval [CI]: 1.3–1.5 μg/kg; n = 42). The mean baseline pain score for all patients was 8.2 (95% CI: 7.7–8.7; n = 42). Pain scores were significantly reduced after treatment with fentanyl. Mean pain score reduction at 2 minutes was −1.4 (95% CI: −2.0 to −0.96; n = 41); at 5 minutes, −2.8 (95% CI: −3.5 to −2.1; n=42); at 10 minutes, −2.8 (95% CI: −3.7 to −1.9; n = 29). No significant complications were noted. Conclusion: Intranasal fentanyl provides effective analgesia in acutely injured patients and is a good option for patients in whom immediate intravenous access is complicated by environmental, anatomic, or resource limitations. The potential application for search-and-rescue and other austere medicine situations is widespread.

Middleton, P. M., P. M. Simpson, et al. (2010). "Effectiveness of morphine, fentanyl, and methoxyflurane in the prehospital setting." Prehosp Emerg Care 14(4): 439-447.

OBJECTIVE: To compare the effectiveness of intravenous (IV) morphine, intranasal (IN) fentanyl, and inhaled methoxyflurane when administered by paramedics to patients with moderate to severe pain. METHODS: We conducted a retrospective comparative study of adult patients with moderate to severe pain treated by paramedics from the Ambulance Service of New South Wales who received IV morphine, IN fentanyl, or inhaled methoxyflurane either alone or in combination between January 1, 2004, and November 30, 2006. We used multivariate logistic regression to analyze data extracted from a clinical database containing routinely entered information from patient health care records. The primary outcome measure was effective analgesia, defined as a reduction in pain severity of > or = 30% of initial pain score using an 11-point verbal numeric rating scale (VNRS-11). RESULTS: The study population comprised 52,046 patients aged between 16 and 100 years with VNRS-11 scores of > or = 5. All analgesic agents were effective in the majority of patients (81.8%, 80.0%, and 59.1% for morphine, fentanyl, and methoxyflurane, respectively). There was very strong evidence that methoxyflurane was inferior to both morphine and fentanyl (p < 0.0001). There was strong evidence that morphine was more effective than fentanyl (p = 0.002). There was no evidence that combination analgesia was better than either fentanyl or morphine alone. CONCLUSION: Inhaled methoxyflurane, IN fentanyl, and IV morphine are all effective analgesic agents in the out-of-hospital setting. Morphine and fentanyl are significantly more effective analgesic agents than methoxyflurane. Morphine appears to be more effective than IN fentanyl; however, the benefit of IV morphine may be offset to some degree by the ability to administer IN fentanyl without the need for IV access.

Miguez, M. C., C. Ferrero, et al. (2019). "Retrospective Comparison of Intranasal Fentanyl and Inhaled Nitrous Oxide to Intravenous Ketamine and Midazolam for Painful Orthopedic Procedures in a Pediatric Emergency Department." Pediatr Emerg Care.

OBJECTIVES: To compare the efficacy and adverse events of 2 pharmacological strategies: intranasal fentanyl and nitrous oxide (FN) inhaled against intravenous ketamine and midazolam (KM) as procedural sedation and analgesia (PSA) in painful orthopedic procedures in the pediatric emergency department (ED). METHODS: This is an observational retrospective cohort study. Patients were included that submitted to PSA for carrying out a painful orthopedic procedure in the ED of a tertiary hospital over a period of 2 years. The main outcome variable was efficacy and adverse events of the PSA procedure. RESULTS: Eighty-three patients were included. Fifty-two patients received FN and 31 KM. The PSA strategy was considered efficacious in 82.7% of the patients in the KM group and 80.6% in the FN cohort. No differences between both strategies were found (P = 0.815). Seventeen children showed early adverse events, 2 in the FN cohort and 15 in the KM group (relative risk of the KM strategy, 23.48; 95% confidence interval (CI), 3.24-169.99). The average of satisfaction obtained by the families was of 10 (CI, 10-10) in the KM cohort and of 9 (CI, 8-9.5) in the FN group (P = 0.152). The length of stay in the ED was longer in the KM cohort (P < 0.001). Hospital admission rate differences were not statistically different (9.6% vs 22.6%, P = 0.144) in the KM versus FN cohort. CONCLUSIONS: Both PSA strategies presented similar efficacy. The FN strategy was associated with a lower risk of adverse events and shorter ED length of stay than KM in this ED setting.

Mitchell, Tb, et al. (2006). "Feasibility and acceptability of an intranasal diamorphine spray as an alternative to injectable diamorphine for maintenance treatment." Eur Addict Res 12(2): 91-5.

            An intranasal (IN) diamorphine spray was investigated as a possible alternative to injectable diamorphine for maintenance treatment. Plasma morphine and 6-monoacetylmorphine (6MAM) concentrations and pharmacodynamic responses were measured for 4 h following intravenous (IV) and IN administration of 40 mg diamorphine in 4 patients prescribed injectable diamorphine. The two routes were primarily differentiated by the significantly greater speed and magnitude of peak plasma morphine and 6MAM concentrations for IV versus IN diamorphine. Beyond this initial peak, mean ratings suggested that withdrawal suppression and positive effects were at least as strong for IN compared to IV administration. All subjects gave favourable appraisals of the IN diamorphine spray, citing advantages including ease of use, the avoidance of needle hazards, and reduced stigma. IN administration may be an alternative or supplementary form of diamorphine maintenance and deserves serious further investigation.

Moksnes, K., O. M. Fredheim, et al. (2008). "Early pharmacokinetics of nasal fentanyl: is there a significant arterio-venous difference?" Eur J Clin Pharmacol.

            OBJECTIVE: We have investigated the arterio-venous difference in the pharmacokinetics of 50 mug fentanyl during the first hour following nasal administration and documented its tolerability in opioid-naive middle-aged to elderly patients. METHODS: Twelve male patients (range in age 47-84 years) scheduled for transurethral resection of the prostate gland received a 100-mul dose of 50 mug fentanyl base as a fentanyl citrate formulation in one nostril. Simultaneous arterial and venous blood samples for analyses of fentanyl were drawn at baseline and at 1, 3, 5, 7, 9, 13, 15, 20, 25, 35, 45 and 60 min after drug administration. Vital signs, sedation and symptoms of local irritation were recorded. RESULTS: The arterial C(max) (maximum serum concentration) of 0.83 ng/ml was nearly twofold higher than the venous C(max) of 0.47 ng/ml, and the arterial T(max) (time to maximum serum concentration) of 7.0 min was about 5 min shorter than the venous T(max) of 11.6 min. The arterial AUC(0-60) (area under the curve from 0 to 60 min after administration) of 21 min*ng/ml was approximately 30% larger than the venous AUC(0-60) of 15 min*ng/ml (all p values </= 0.005). Venous T(max) and C(max) did not predict the corresponding arterial values. No significant adverse events were observed. CONCLUSION: A significant arterio-venous difference was present after intranasal administration of fentanyl. The short arterial T(max) complies with its rapid onset of action. The use of venous concentrations for the prediction of onset time of analgesia should be discouraged. A 50-mug dose of nasal fentanyl was well tolerated by opioid-naive middle-aged to elderly male patients.

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

            BACKGROUND: We evaluated the safety and efficacy of multiple doses of intranasal ketorolac tromethamine (ketorolac) for postoperative pain. METHODS: This was a double-blind, placebo-controlled study in patients undergoing major surgery who were randomized to receive intranasal ketorolac, 10 mg or 31.5 mg, [DOSAGE ERROR CORRECTED]or placebo every 8 h for 40 h. After surgery, patients with pain intensity of at least 40 on a 100-mm visual analog scale were assessed at 30 min and at 1, 2, 3, 4, 5, 6, 8, 12, 16, 20, 24, 28, 32, 36, 40, 44, and 48 h after receiving the study drug. Patient-controlled i.v. morphine provided supplemental analgesia. RESULTS: Among 127 patients enrolled, morphine use during the first 24 h was significantly less in patients receiving 31.5 mg [DOSAGE ERROR CORRECTED] of ketorolac (37.8 mg) than in the placebo group (56.5 mg) and in the 10-mg ketorolac group (54.3 mg). Over 48 h, the 31.5-mg ketorolac [DOSAGE ERROR CORRECTED] group used significantly less morphine than the placebo group. Summed pain intensity differences at 4 and 6 h significantly favored the 31.5-mg ketorolac [DOSAGE ERROR CORRECTED]group over the other groups. The rates of pyrexia and tachycardia were significantly lower in the ketorolac 31.5-mg [DOSAGE ERROR CORRECTED]group than in the placebo group. Other adverse events were reported with similar frequency in all treatment groups and most were considered unrelated to treatment. CONCLUSION: Thirty milligrams of intranasal ketorolac demonstrated significant analgesic efficacy compared to 10 mg of intranasal ketorolac and placebo.

Mozafari, J., M. Maleki Verki, et al. (2019). "Comparing intranasal ketamine with intravenous fentanyl in reducing pain in patients with renal colic: A double-blind randomized clinical trial." Am J Emerg Med.

BACKGROUND: Kidney stones are a fairly common problem that manifests itself as symptoms of acute abdominal and flank pains in patients presenting to emergency departments. OBJECTIVE: The present study was conducted to compare the analgesic effect of intravenous fentanyl with that of intranasal ketamine in renal colic patients. METHODS: One mg/kg of intranasal ketamine was administered in the first group, and one mug/kg of intravenous fentanyl in the second group. The pain severity was measured in the patients in terms of a visual analogue scale (VAS) score at the beginning of the study and at minutes 5, 15 and 30, and the medication side-effects were evaluated and recorded. RESULTS: A total of 130 patients were ultimately assessed in two groups of 65. In the ketamine group, the mean severity of pain was 8.72+/-1.52 at the beginning of the study (P<0.001), 5.5+/-2.97 at minute 5 (P<0.001), 3.38+/-3.35 at minute 15 (P=0.004) and 2.53+/-3.41 at minute 30 (P=0.449). In the fentanyl group, this severity was 9.66+/-88.8 in the beginning of the study (P<0.001), 7.27+/-1.37 at minute 5 (P<0.001), 4.61+/-1.5 at minute 15 (P=0.004) and 1.24+/-1.25 at minute 30 (P=0.449). The general prevalence of the medication side-effects was 10 (15.4%) in the ketamine group and 1 (1.5%) in the fentanyl group (P=0.009). CONCLUSIONS: Ketamine was found to be less effective than fentanyl in controlling renal colic-induced pain, and to be associated with a higher prevalence of side-effects; nevertheless, ketamine can be effective in controlling this pain in conjunction with other medications.

Mudd, S. (2011). "Intranasal Fentanyl for Pain Management in Children: A Systematic Review of the Literature." J Pediatr Health Care 25(5): 316-322.

            Intranasally administered fentanyl (INF) has been studied as an alternate route of delivery for pain relief in children. The purpose of this systematic review is to evaluate the available research evidence on the use of INF in the pediatric population. A search was conducted of PubMed, ISI, Scopus, Popline, CINAHL, and Embase for research studies evaluating INF in this population (0-18 years of age). The studies were graded on the strength of the evidence and the results reviewed. All of the reviewed studies showed similar or improved pain scores when compared with other opioids and administration methods. No severe adverse outcomes were reported. Current evidence suggests that INF is a safe and effective method of pain management for children in a variety of clinical settings.

Murphy, A., R. O'Sullivan, et al. (2014). "Intranasal fentanyl for the management of acute pain in children." Cochrane Database Syst Rev 10: CD009942.\

BACKGROUND: Pain is the most common symptom in the emergency setting; however, timely management of acute pain in children continues to be suboptimal. Intranasal drug delivery has emerged as an alternative method of achieving quicker drug delivery without adding to the distress of a child by inserting an intravenous cannula. OBJECTIVES: We identified and evaluated all randomized controlled trials (RCTs) and quasi-randomized trials to assess the effects of intranasal fentanyl (INF) versus alternative analgesic interventions in children with acute pain, with respect to reduction in pain score, occurrence of adverse events, patient tolerability, use of "rescue analgesia," patient/parental satisfaction and patient mortality. SEARCH METHODS: We searched the Cochrane Central Register of Controlled Trials (CENTRAL) (2014, Issue 1); MEDLINE (Ovid SP, from 1995 to January 2014); EMBASE (Ovid SP, from 1995 to January 2014); the Cumulative Index to Nursing and Allied Health Literature (CINAHL) (EBSCO Host, from 1995 to January 2014); the Latin American and Caribbean Health Science Information Database (LILACS) (BIREME, from 1995 to January 2014); Commonwealth Agricultural Bureaux (CAB) Abstracts (from 1995 to January 2014); the Institute for Scientific Information (ISI) Web of Science (from 1995 to January 2014); BIOSIS Previews (from 1995 to January 2014); the China National Knowledge Infrastructure (CNKI) (from 1995 to January 2014); International Standard Randomized Controlled Trial Number (ISRCTN) (from 1995 to January 2014); (from 1995 to January 2014); and the International Clinical Trials Registry Platform (ICTRP) (to January 2014). SELECTION CRITERIA: We included RCTs comparing INF versus any other pharmacological/non-pharmacological intervention for the treatment of children in acute pain (aged < 18 years). DATA COLLECTION AND ANALYSIS: Two independent review authors assessed each title and abstract for relevance. Full copies of all studies that met the inclusion criteria were retrieved for further assessment. Mean difference (MD), odds ratio (OR) and 95% confidence interval (CI) were used to measure effect sizes. Two review authors independently assessed and rated the methodological quality of each trial using the tool of The Cochrane Collaboration to assess risk of bias, as per Chapter 8 of the Cochrane Handbook for Systematic Reviews of Interventions. MAIN RESULTS: Three studies (313 participants) met the inclusion criteria. One study compared INF versus intramuscular morphine (IMM); another study compared INF versus intravenous morphine (IVM); and another study compared standard concentration INF (SINF) versus high concentration INF (HINF). All three studies reported a reduction in pain score following INF administration. INF produced a greater reduction in pain score at 10 minutes post administration when compared with IMM (INF group pain score: 1/5 vs IMM group pain score: 2/5; P value 0.014). No other statistically significant differences in pain scores were reported at any other time point. When INF was compared with IVM and HINF, no statistically significant differences in pain scores were noted between treatment arms, before analgesia or at 5, 10, 20 and 30 minutes post analgesia. Specifically, when INF was compared with IVM, both agents were seen to produce a statistically significant reduction in pain score up to 20 minutes post analgesia. No further reduction in pain score was noted after this time. When SINF was compared with HINF, a statistically and clinically significant reduction in pain scores over study time was observed (median decrease for both groups 40 mm, P value 0.000). No adverse events (e.g. opiate toxicity, death) were reported in any study following INF administration. One study described better patient tolerance to INF compared with IMM, which achieved statistical significance. The other studies described reports of a "bad taste" and vomiting with INF. Overall the risk of bias in all studies was considered low. AUTHORS' CONCLUSIONS: INF may be an effective analgesic for the treatment of patients with acute moderate to severe pain, and its administration appears to cause minimal distress to children. However, this review of published studies does not allow any definitive conclusions regarding whether INF is superior, non-inferior or equivalent to intramuscular or intravenous morphine. Limitations of this review include the following: few eligible studies for inclusion (three); no study examined the use of INF in children younger than three years of age; no study included children with pain from a "medical" cause (e.g. abdominal pain seen in appendicitis); and all eligible studies were conducted in Australia. Consequently, the findings may not be generalizable to other healthcare settings, to children younger than three years of age and to those with pain from a "medical" cause.

Murphy, A. P., M. Hughes, et al. (2016). "Intranasal fentanyl for the prehospital management of acute pain in children." Eur J Emerg Med.

INTRODUCTION: Acute pain is the most common symptom in the emergency setting and its optimal management continues to challenge prehospital emergency care practitioners, particularly in the paediatric population. Difficulty in establishing vascular access and fear of opiate administration to small children are recognized reasons for oligoanalgesia. Intranasal fentanyl (INF) has been shown to be as safe and effective as intravenous morphine in the treatment of severe pain in children in the Emergency Department setting. AIM: This study aimed to describe the clinical efficacy and safety of INF when administered by advanced paramedics in the prehospital treatment of acute severe pain in children. METHODS: A 1-year prospective cross-sectional study was carried out of children (>1 year, <16 years) who received INF as part of the prehospital treatment of acute pain by the statutory national emergency medical services in Ireland. RESULTS: Ninety-four children were included in the final analysis [median age 11 years (interquartile range 7-13)]; 53% were males and trauma was implicated in 86% of cases. A clinically effective reduction in the pain score was found in 78 children [83% (95% confidence interval: 74-89%)]. The median initial pain rating score was 10. Pain assessment at 10 min after INF administration indicated a median pain rating of 5 (interquartile range 2-7). No patient developed an adverse event as a result of INF. DISCUSSION: INF at a dose of 1.5 microg/kg appears to be a safe and effective analgesic in the prehospital management of acute severe pain in children and may be an attractive alternative to both oral and intravenous opiates.

Myrick, R., S. Blakemore, et al. (2020). "Outpatient pain clinic and intranasal fentanyl to improve sickle cell disease outcomes." Pediatr Blood Cancer 67(10): e28648.

BACKGROUND: Acute pain events are a leading complication for sickle cell patients. In an attempt to improve pain outcomes, we developed an outpatient pain clinic, and included intranasal fentanyl in the opioid emergency department (ED) pain order set. We evaluated admission rates and opioid administration for patients that attended both the outpatient pain clinic and ED within a 3-month period. METHODS: We recorded the admission rate, IV morphine equivalents, and time from triage for each opioid order and administration from both an outpatient pain clinic and ED visit within a 3-month period for an individual pediatric patient with sickle cell disease. RESULTS: Thirty patients received acute pain management in both settings. We identified a significant reduction in hospital admission when patients received care in the pain clinic as compared to the ED (17% vs 43%, P = .02). Additionally, outpatient pain clinic patients received significantly less IV morphine equivalents than patients received in the ED (5.6 vs 10.6 IV morphine equivalents, P < .0001). In the ED, intranasal fentanyl was administered in a significantly shorter time than patients ordered intravenous opioid (43 vs 75 min, P = .02). The mean time to receiving an opioid in the outpatient pain clinic was 57 min. CONCLUSION: The use of an outpatient pain clinic can reduce admission rates as compared to the ED. The use of intranasal fentanyl reduced the time to first opioid administration in the ED. Patient-centered research or quality improvement projects should continue to focus on novel approaches to acute pain event management.

Nave, R., H. Schmitt, and L. Popper, Faster absorption and higher systemic bioavailability of intranasal fentanyl spray compared to oral transmucosal fentanyl citrate in healthy subjects. Drug Deliv, 2013.

Context: Intranasal fentanyl spray (INFS) was developed for the treatment of breakthrough pain in cancer patients using an alternative route of administration. Objective: The aim of this clinical study was to investigate the pharmacokinetic (PK) profile and bioavailability of INFS in healthy subjects compared to oral transmucosal fentanyl citrate (OTFC). Materials and methods: In a randomized, single-center, open-label, two-way crossover PK study, 24 subjects (12 male, 12 female, mean age 25.2 years) received INFS (single-dose delivery system 200 mug/100 mul) and OTFC (buccal lozenge, 200 microg). Naltrexone was given to prevent potential adverse reactions. Frequent plasma samples were taken up to 96 h and analyzed by LC-MS/MS with a lower limit of quantitation of 25 pg/ml. Primary PK parameter was the area under the fentanyl plasma concentration-time curve (AUC0-inf). Results: Compared to OTFC, a much faster absorption rate was observed for INFS which was supported by the much earlier appearance of detectable fentanyl plasma levels and a shorter Tmax. At 15 min post-dose, the mean plasma fentanyl levels reached 602 pg/ml for INFS and 29 pg/ml for OTFC. Significantly higher Cmax and AUC values were obtained with INFS compared to OTFC. Although administered for 15 min, consumption of OTFC was incomplete in many incidences ( approximately 70%) upon visual inspection. No safety concerns were identified for fentanyl administration in combination with oral naltrexone. Discussion and conclusion: One dose of INFS gives significantly higher plasma fentanyl levels and significantly higher bioavailability than OTFC based on dose-normalized AUC.

Nazemian, N., M. Torabi, et al. (2020). "Atomized intranasal vs intravenous fentanyl in severe renal colic pain management: A randomized single-blinded clinical trial." Am J Emerg Med 38(8): 1635-1640.


OBJECTIVES: Renal colic is one of the most common painful disorders in patients referred to the emergency department. The main purpose of this study was to compare the efficiency of two methods of intravenous (IVF) and intranasal (INF) fentanyl administration in pain management in patients with severe renal colic. MATERIALS & METHODS: This was a single-blind randomized clinical trial performed on patients with severe renal colic. The severity of pain was >/=8 based on the Numerical Rating Scale (NRS). The efficacy of pain management was compared within and between the IVF (intramuscular Ketorolac + intravenous fentanyl) and INF (intramuscular Ketorolac + intranasal fentanyl) groups at different times points. Oral consent was obtained from all the patients. RESULTS: Of 220 individuals, 96 (43.60%) were women and 124 (56.40%) were men. There were no significant differences between the two groups regarding the baseline pain severity, age, sex, history of urolithiasis and body mass index (BMI). The pain severity showed a significant reducing trend in both groups (p<0.0001). There was also a significant difference comparing the mean pain severity between groups at different times (p<0.0001). In each group, the severity of pain showed significant reduction compared with its prior measurement (P<0.0001). CONCLUSION: Fentanyl is highly effective in controlling pain in patients with severe renal colic referring to the emergency department. Intranasal administration of fentanyl combination with ketorolac can be an appropriate, non-invasive, easy-to-use and fast alternative to the intravenous method to manage pain in these patients.

Nejati, A., M. Jalili, et al. (2019). "Intranasal ketamine reduces pain of digital nerve block; a double blind randomized clinical trial." Am J Emerg Med 37(9): 1622-1626.

BACKGROUND: Low dose ketamine can be used as analgesic in acute pain management in the emergency department (ED). OBJECTIVE: Efficacy of IN ketamine in acute pain management in the ED. METHOD: This is a double blind randomized clinical trial on patients older than 15years who needed digital nerve block (DNB). Participants randomly received IN Ketamine (1ml=50mg) or placebo (normal saline, 1ml) 5min before DNB. In both groups, patients' pain score was recorded by visual analogue score (VAS) at baseline, after DNB and 45min after completion of DNB. Adverse effects of ketamine and changes in vital signs were also recorded and compared with placebo group. RESULTS: A total number of 100 patients were enrolled in the study with the median (IQR) age of 36.5 (26) years, including 65 men and 35 women. IN ketamine resulted in less pain compared to placebo after performing DNB and 45min after the procedure. Median (IQR) basic VAS score was 50 (15) in ketamine group, and 49 (27) in control group. Median (IQR) block pain VAS score was 28.5 (19) in ketamine group and 47.5 (31) in control group. Median (IQR) procedural pain VAS score was 21.5 (16) in ketamine group and 43.5 (29) in control group. Only 7 patients had adverse effects in either group. CONCLUSION: The findings of this study suggest that IN ketamine can be effective in reducing pain in patients with acute pain, without adding significant side effects.

Nemeth, M., N. Jacobsen, et al. (2019). "Intranasal Analgesia and Sedation in Pediatric Emergency Care-A Prospective Observational Study on the Implementation of an Institutional Protocol in a Tertiary Children's Hospital." Pediatr Emerg Care.35(2): 89-95

            OBJECTIVES: Children presenting with acute traumatic pain or in need of therapeutic or diagnostic procedures require rapid and effective analgesia and/or sedation. Intranasal administration (INA) promises to be a reliable, minimally invasive delivery route. However, INA is still underused in Germany. We hence developed a protocol for acute pain therapy (APT) and urgent analgesia and/or sedation (UAS). Our aim was to evaluate the effectiveness and safety of our protocol. METHODS: We performed a prospective observational study in a tertiary children's hospital in Germany. Pediatric patients aged 0 to 17 years requiring APT or UAS were included. Fentanyl, s-ketamine, midazolam, or combinations were delivered according to protocol. Primary outcome variables included quality of analgesia and/or sedation as measured on age-appropriate scales and time to onset of drug action. Secondary outcomes were adverse events and serious adverse events. RESULTS: One hundred pediatric patients aged 0.3 to 16 years were enrolled, 34 for APT and 66 for UAS. The median time onset of drug action was 5 minutes (ranging from 2 to 15 minutes). Fentanyl was most frequently used for APT (n = 19). Pain scores decreased by a median of 4 points (range, 0-10; P < 0.0001). For UAS, s-ketamine/midazolam was most frequently used (n = 25). Sedation score indicated minimal sedation in most cases. Overall success rate after the first attempt was 82%. Adverse events consisted of nasal burning (n = 2) and vomiting (n = 2). No serious adverse events were recorded. CONCLUSIONS: A fentanyl-, s-ketamine-, and midazolam-based INA protocol was effective and safe for APT and UAS. It should then be considered where intravenous access is impossible or inappropriate.

Nielsen, B. N., S. M. Friis, et al. (2014). "Intranasal sufentanil/ketamine analgesia in children." Paediatr Anaesth 24(2): 170-180.

BACKGROUND: The management of procedural pain in children ranges from physical restraint to pharmacological interventions. Pediatric formulations that permit accurate dosing, are accepted by children and a have a rapid onset of analgesia are lacking. OBJECTIVES: To investigate a pediatric formulation of intranasal sufentanil 0.5 and ketamine 0.5 for procedural pain and to characterize the pharmacokinetic (PK) profile. METHODS: Fifty children (>/=10 kg) scheduled for a painful procedure were included in this prospective nonrandomized open-label clinical trial. Thirteen of these children had central venous access for drug assay sampling; enabling a compartmental PK analysis using nonlinear mixed-effects models. Pain intensity before and during the procedure was measured using age-appropriate pain scales. Heart rate, oxygen saturation and sedation were recorded. RESULTS: Children had a mean age of 8.8 (sd 4.9) years and weight 35.2 (sd 20.1) kg. Sufentanil/ketamine nasal spray was effective (procedural pain intensity scores </=5 (0-10)) in 78% of the painful procedures. The spray was well accepted by 94% of the children. Oxygen saturation and heart rate remained stable, and sedation was minimal. The bioavailability of sufentanil and ketamine was 24.6% and 35.8%, respectively. Maximum plasma concentration (Cmax) of sufentanil was 0.042 mcg.l(-1) (coefficient of variation (CV) 12.9%) at 13.8 min (CV 12.4%) (Tmax). Cmax for ketamine was 0.102 mg.l(-1) (CV 10.8%), and Tmax was 8.5 min (CV 17.3%). CONCLUSION: Sufentanil/ketamine nasal spray provided rapid onset of analgesia for a variety of painful procedures with few adverse effects and has promising features for use in pediatric procedural pain management.

O'Donnell, D. P., L. C. Schafer, et al. (2013). "Effect of Introducing the Mucosal Atomization Device for Fentanyl Use in Out-of-Hospital Pediatric Trauma Patients." Prehosp Disaster Med 28(5): 520-522.

Background: Pain associated with pediatric trauma is often under-assessed and under-treated in the out-of-hospital setting. Administering an opioid such as fentanyl via the intranasal route is a safe and efficacious alternative to traditional routes of analgesic delivery and could potentially improve pain management in pediatric trauma patients. Objective: We sought to examine the effect of introducing the Mucosal Atomization Device (MAD) on analgesia administration as an alternative to intravenous fentanyl delivery in pediatric trauma patients. We hypothesized that the introduction of the MADwould increase the administration of fentanyl in pediatric trauma patients. Methods: We utilized a two-group design (pre-MAD and post-MAD) to study 946pediatric trauma patients (age < 16) transported by a large, urban EMS agency to one of eight hospitals in the county. Two emergency medicine physicians independently determined whether the patient met criteria for pain medication receipt and a third reviewer resolved any disagreements. We then compared the rates of fentanyl administration in both groups. Results:  There was no statistically significant difference in fentanyl administration between the pre-MAD (30.4%) and post-MAD groups (37.8%) (p = 0.238). A subgroup analysis showed that age and mechanism of injury were stronger predictors of fentanyl administration. Conclusion: Contrary to our hypothesis, the addition of the MAD device did not increase fentanyl administration in pediatric trauma patients. Future research is needed to address the barriers to analgesia administration in pediatric trauma patients

O'Neil, Paech, et al. (1997). "Preliminary clinical use of a patient-controlled intranasal analgesia (PCINA) device." Anaesth Intensive Care 25(4): 408-12.

Oliver, F. M., T. W. Sweatman, et al. (2000). "Comparative pharmacokinetics of submucosal vs. intravenous flumazenil (Romazicon) in an animal model." Pediatr Dent 22(6): 489-93.

            PURPOSE: This study was performed to determine the bioavailability and local tissue toxicological safety of flumazenil (Romazicon) when administered by oral submucosal (SM) as opposed to intravenous (i.v.) injection. METHODS: Six dogs each received SM flumazenil (0.2 mg), and their serum was collected at predetermined time intervals (0-2 h) and frozen (-70 degrees C). Seven days later, the dogs received an identical dose of i.v. flumazenil, and serum samples were again collected, as above. Comparative quantitation of flumazenil levels (i.v. vs. SM) was made using a sensitive HPLC assay (UV detection). Direct/local drug toxicity was visually scored by unbiased raters of color photographs (test and control mucosa) taken at 1, 2, and 7 days following SM flumazenil injection. An oral pathologist examined slides processed from control and treatment tissues (hematoxylin and eosin staining) taken (punch biopsy) 1 week following SM injection to compare with direct clinical scores. RESULTS: Serum flumazenil levels reached a plateau (8.5 +/- 1.5 ng/mL, mean +/- SD) within 4 min of SM drug injection and declined thereafter to -2 ng/mL by 2 h. Bioavailability of SM flumazenil was 101 +/- 14%, based upon measuring the area under the serum concentration-time curves over 1.5 h (AUC 0-1.5 h, SM vs. i.v. drug). Thus, serum drug levels following SM drug administration were broadly comparable to those obtained during the elimination phase of corresponding i.v. drug delivery. Regarding drug tissue toxicity, no evidence of direct drug toxicity was observed by unbiased raters of color photographs (test and control mucosa) taken at 1, 2, and 7 days following SM flumazenil injection. Following pathologic review, no difference was seen in the degree of inflammation between treatment and control tissue. CONCLUSION: At the quantity and concentration used, SM drug flumazenil administration appears to be both a safe and a viable alternative to bolus i.v. drug delivery and worthy of further investigation.

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

            Twenty-four gynaecological patients receiving postoperative patient-controlled analgesia were enrolled in an open cross-over pilot study evaluating two new formulations of nasal fentanyl spray. The primary outcome was the bioavailability of nasal fentanyl in comparison with intravenous fentanyl. This manuscript describes the clinical outcomes of quality of postoperative analgesia and patient acceptability. There were 21 complete data sets for both sequences of the cross-over design. In randomised order, patients received approximately 50 microg of fentanyl in a single dose by intranasal and intravenous administration, but separated by at least 2 h. Analgesia was of rapid onset (within 5 min) and similar quality. There was no significant difference in side-effects. Four patients experienced mild nasal stinging and although 10 (42%) preferred intravenous administration, seven (29%) preferred intranasal and six (25%) had no preference. We conclude that these formulations of fentanyl, delivered as nasal spray, have potential clinical utility.

Page, N. and V. Nirabhawane (2018). "Intranasal Ketamine for the Management of Incidental Pain during Wound Dressing in Cancer Patients: A Pilot Study." Indian J Palliat Care 24(1): 58-60.

Introduction: Cancer wounds need regular dressing; else they develop infection, foul odor, and in extreme cases, maggots. Patients resist dressing due to the severe incidental pain during dressing. Intranasal ketamine was tried as an analgesic to reduce this incidental pain. Materials and Methods: Twenty patients with wounds requiring regular dressing were selected; these patients had a basal pain score of 4/10 and incidental pain score of 7/10 during four consecutive dressings. Ketamine 0.5 mg/kg was administered transmucosally 10 min before dressing, and pain scores, hemodynamic parameters, and sedation were recorded for up to 2 h in six consecutive dressings. Results: Ketamine produced a significant reduction in incidental pain without any hemodynamic changes or sedation. Conclusion: Ketamine appears to be a safe and effective analgesic when used intranasally for incidental pain.

Paquin, H., E. D. Trottier, et al. (2020). "Evaluation of a clinical protocol using intranasal fentanyl for treatment of vaso-occlusive crisis in sickle cell patients in the emergency department." Paediatr Child Health 25(5): 293-299.

Background: Vaso-occlusive crisis (VOC) is one of the most frequent causes of emergency visits and admission in children with sickle cell disease (SCD). Objectives: This study aims to evaluate whether the use of a new pain management pathway using intranasal (IN) fentanyl from triage leads to improved care, translated by a decrease in time to first opiate dose. Methods: We performed a retrospective chart review of patients with SCD who presented to the emergency department (ED) with VOC, in the period pre- (52 patients) and post- (44 patients) implementation period of the protocol. Time to first opiate was the primary outcome and was evaluated pre- and postimplementation. Patients received a first opiate dose within 52.3 minutes of registration (interquantile range [IQR] 30.6, 74.6), corresponding to a 41.4-minute reduction in the opiate administration time (95% confidence interval [CI] -56.1, -27.9). There was also a 43% increase in the number of patients treated with a nonintravenous (IV) opiate as first opiate dose (95% CI 26, 57). In patients who were discharged from the ED, there was a 49% decrease in the number of IV line insertions (95% CI -67, -22). There was no difference in the hospitalization rates (difference of 6 [95% CI -13, 25]). Conclusions: This study validates the use of our protocol using IN fentanyl as first treatment of VOC in the ED by significantly reducing the time to first opiate dose and the number of IVs.

Parvizrad, R., A. Pakniyat, et al. (2017). "Comparing the analgesic effect of intranasal with intravenous ketamine in isolated orthopedic trauma: A randomized clinical trial." Turk J Emerg Med 17(3): 99-103.

                OBJECTIVES: Ketamine is commonly used in anesthetic and sedation before surgical procedures and acts as an analgesic in smaller doses. The aim of this study was to assess the effects of intranasal (IN) ketamine in patients with moderate to severe limb trauma (visual analog scale (VAS) > 60 mm). METHODS: In a triple-blind randomized controlled clinical trial; 154 patients with isolated orthopedic trauma and visual analog scale (VAS) >/=60 mm were included on the basis of inclusion and exclusion criteria. Patients were divided into two groups of ketamine-IN (0.4 mg/kg IN ketamine and an equal volume of placebo saline intravenously (IV)) and ketamine-IV (0.2 mg/kg ketamine IV with 0.5 ml saline IN) on the basis of balanced block randomization method. At 5, 10, 20, and 30 min, patients were assessed for VAS measurement and adverse events. Repeated measure ANOVA, independent t-test and chi square test were employed. The level of statistical significance was considered to be less than 0.05. RESULTS: Mean VAS in IN ketamine and IV group at minute 30 was 31.50 +/- 13.40 and 29.35 +/- 11.73, respectively. At minute 30, 31 patients (20.39%) required a low-dose of morphine as rescue analgesia (P = 0.427). The results showed that mean change score of VAS (difference of time 0 and time 30) in IN ketamine and IV ketamine VAS were 43.8 (95% confidence interval: 41.1-46.5) and 46.4 (95% confidence interval: 42.8-50.1) and there is no difference between two groups in case of score change of VAS (P = 0.245). Adverse events in nasal and intravenous ketamine in both groups were mild and transient. CONCLUSION: IN ketamine is associated with few side effects and appropriate analgesic effects in isolated orthopedic trauma patients, and it may be used in cases where there is no need for venipuncture of peripheral vessels, especially in crowded EDs.

Pestieau, S. R., Z. M. Quezado, et al. (2011). "The effect of dexmedetomidine during myringotomy and pressure-equalizing tube placement in children." Paediatr Anaesth 21(11): 1128-1135.

                BACKGROUND: Bilateral myringotomy (BMT) is a commonly performed otolaryngologic procedure in children. OBJECTIVES: To examine the effects of intranasal dexmedetomidine, an alpha(2)-adrenoceptor agonist, on time-averaged pain scores, pain control, need for rescue analgesia, and agitation scores in children undergoing BMT. METHODS: We designed a trial to enroll 160 children randomized to one of four groups: two study groups, dexmedetomidine (1 or 2, or two control groups representing our institutional standards of practice (intranasal fentanyl-2 or acetaminophen as needed postoperatively). RESULTS: After 101 children were enrolled, patient caregivers observed that some enrollees were excessively sedated and required prolonged postanesthesia care unit (PACU) stay. This observation led to an unplanned interim analysis and early trial termination. After data were collected, severe nonnormality of pain and agitation scores necessitated a switch of the outcome to assess repeated measurements of the proportion of patients with pain, severe pain, and agitation. Demographics, time to emergence, and agitation were similar among all groups. The risk of requiring acetaminophen rescue (P < 0.0001) and proportion of patients having pain (P = 0.016) was significantly higher in one control group (rescue analgesia only) compared with fentanyl or dexmedetomidine groups. Importantly, length of stay in the PACU was significantly longer in dexmedetomidine-2 compared with dexmedetomidine-1, fentanyl-treated, or the control group, P = 0.0037. CONCLUSIONS: In this trial, we were unable to answer the original question as to the role of dexmedetomidine on time-averaged pain and agitation scores after BMT. However, our findings clearly demonstrate that in children undergoing BMT, at higher doses, dexmedetomidine significantly prolongs length of stay in the PACU.

Phillips, M. L., B. C. Willis, et al. (2016). "Bimodal analgesia vs fentanyl in pediatric patients undergoing bilateral myringotomy and tympanostomy tube placement: a propensity matched cohort study." J Clin Anesth 32: 162-168.

STUDY OBJECTIVE: Bilateral myringotomy and tympanostomy tube placement (BMT) is one of the most frequently performed pediatric outpatient procedures with 667,000 children receiving tympanostomy tubes annually. Because of this high volume, discovering the ideal analgesic regimen may lead to decreased overall postanesthesia care unit (PACU) costs while increasing patient and parent satisfaction. The purpose of this study is to determine if there is any benefit in supplementing intranasal (IN) fentanyl with intramuscular (IM) ketorolac with regard to immediate recovery characteristics. DESIGN: Retrospective, cohort study. SETTING: University-affiliated teaching hospital. PATIENTS: One thousand one hundred forty American Society of Anesthesiologists physical status 1 and 2 pediatric patients scheduled for BMT. INTERVENTIONS: No interventions were performed. MEASUREMENTS: A propensity matched cohort of pediatric patients who underwent BMT at Vanderbilt Children's Hospital from 2011 to 2014 was analyzed. The authors compared PACU recovery time, rescue analgesic administration, maximal PACU pain scores, and maximal PACU agitation scores between subgroups of patients given either IN fentanyl and IM ketorolac or IN fentanyl alone intraoperatively. MAIN RESULTS: After adjusting for patient demographics and fentanyl dose, the fentanyl/ketorolac group received rescue analgesics 4.7% (95% confidence interval [CI], 2.0%-7.5%) less often, displayed moderate to severe pain 4.7% (95% CI, 1.5%-8.0%) less often, and experienced emergence agitation 3.6% (95% CI, 1.5%-5.8%) less often than patients in the fentanyl-only group. This corresponded to a relative risk reduction of 127%, 76%, and 200%, respectively. CONCLUSIONS: Based on our retrospective analysis, adding IM ketorolac to IN fentanyl may be beneficial to pediatric patients undergoing BMT. However, these results should be confirmed with a prospective, double-blinded, randomized study.

Pouraghaei, M., P. Moharamzadeh, et al. (2020). "Intranasal ketamine versus intravenous morphine for pain management in patients with renal colic: a double-blind, randomized, controlled trial." World J Urol.

BACKGROUND: Urinary stones are a common urologic problem that can be manifested as an intense pain, known as renal colic. Pain control is an important intervention for the emergency treatment of renal colic patients. Intranasal ketamine can form a crucial part of such interventions by offering a new route for a widely-used analgesic drug. METHODS: In a double-blind, randomized, clinical trial, adults with renal colic admitted to a tertiary hospital emergency department were examined. The intervention group received 1 mg/kg intranasal (IN) ketamine and 1 ml of saline as a placebo. The control group received 0.1 mg/kg intravenous (IV) morphine and four puffs of saline as the placebo. The pain score was measured on the Numerical Rating Scale (NRS) 0, 15, 30 and 60 min after the drug administration. RESULTS: A total of 184 patients enrolled in this study in two parallel groups. The two groups did not differ significantly in terms of pain intensity at the time of their referral (P = 0.489), 15 min post-dose (P = 0.204), 30 min post-dose (P = 0.978) and 60 min post-dose (P = 0.648). CONCLUSION: IN ketamine is as effective as IV morphine for pain control in renal colic patients. No remarkable side-effects were observed for IN ketamine use in these patients.

Quadir, M., H. Zia, et al. (2000). "Development and evaluation of nasal formulations of ketorolac." Drug Deliv 7(4): 223-229.

            Ketorolac tromethamine is a potent non-narcotic analgesic with moderate anti-inflammatory activity. Clinical studies indicate that ketorolac has a single dose efficacy greater than morphine for postoperative pain and has excellent applicability in the emergency treatment of pain. Due to incomplete oral absorption of ketorolac, several approaches have been tried to develop a nonoral formulation in addition to injections, especially for the treatment of migraine headache. The aim of our study was to develop a nasal formulation of ketorolac with a dose equivalent to the oral formulation. A series of spray and lyophilized powder formulations of ketorolac were administered into the nasal cavity of rabbits, and their pharmacokinetics profiles were assessed. The spray and powder formulations were compared through their pharmacokinetics parameters and absolute bioavailability. Drug plasma concentration was determined using solid phase extraction, followed by an HPLC analysis. Nasal spray formulations were significantly better absorbed than powder formulations. A nasal spray formulation of ketorolac tromethamine showed the highest absorption with an absolute bioavailability of 91%. Within 30 min of administration, the plasma concentration was comparable to that resulting from an intravenous injection. The absolute bioavailability of a solution of ketorolac acid was 70%. Apparently, the dissolution of ketorolac acid into the mucous layer limits its absorption. There were no significant differences in absorption between different powder formulations. Even the reduction of particle size from 123 microm to 63 microm did not indicate better absorption of ketorolac tromethamine from powder formulations. Interestingly, the absolute bioavailability of ketorolac tromethamine from a powder formulation is only 38%, indicating that the drug may not be totally released from the polymer matrix before it is removed from nasal epithelium by mucociliary clearance.

Quinn, K., S. Kriss, et al. (2018). "Analgesic Efficacy of Intranasal Ketamine Versus Intranasal Fentanyl for Moderate to Severe Pain in Children: A Prospective, Randomized, Double-Blind Study." Pediatr Emerg Care.

PURPOSE: This study aimed to compare analgesic efficacy of intranasal (IN) ketamine to IN fentanyl for moderate to severe pain in children in a pediatric emergency department. METHODS: A prospective, randomized, double-blinded, noninferiority study evaluating children aged 3 to 17 years in a pediatric emergency department with acute moderate to severe pain was conducted. Patients received either 1 mg/kg of IN ketamine or 1.5 mug/kg of IN fentanyl and were evaluated after 10, 20, 30, and 60 minutes. The primary outcome was the degree of pain reduction after 20 minutes. RESULTS: Twenty-two patients were enrolled (11 in each group). Underlying pain conditions represented were musculoskeletal injury (73%) and abdominal pain (27%). At 20 minutes after analgesia, there was no significant difference in pain scores between the fentanyl (median, 2; range, 0-8) and ketamine groups (median, 4; range, 0-7; P = 0.20). The ketamine group showed a significantly greater rate of adverse effects, 73% versus 9% (P = 0.002), and throughout the course of the study period, 7 patients in the ketamine group (64%) group showed some degree of sedation versus no one in the fentanyl group (P = 0.004). CONCLUSIONS: There was insufficient power to support the analgesic noninferiority of IN ketamine at a dose of 1 mg/kg compared with IN fentanyl at a dose of 1.5 mug/kg in children experiencing painful conditions at 20 minutes after administration. Intranasal ketamine was found to be inferior to IN fentanyl in relieving pain at 10 minutes and was found to have significantly greater rates of sedation and dizziness.

Ralley, F. E. (1989). "Intranasal opiates: old route for new drugs." Can J Anaesth 36(5): 491-3.

Rampersad, S., N. Jimenez, et al. (2010). "Two-agent analgesia versus acetaminophen in children having bilateral myringotomies and tubes surgery." Paediatr Anaesth 20(11): 1028-1035.

            OBJECTIVES: The objective of this study was to determine whether the incidence of emergence agitation (EA) can be reduced by adding an additional, faster onset, non-IV analgesic, intranasal fentanyl or intramuscular (im) ketorolac to rectal acetaminophen. AIM: To compare the incidence of EA after analgesia with two agents vs acetaminophen alone in pediatric patients after bilateral myringotomy procedures (BM&T). BACKGROUND: Anesthesia for BM&T is usually performed with volatile anesthetics as a single agent without securing intravenous access. The anesthetic agent most commonly used is sevoflurane; however, EA has been reported in up to 67% of patients. Emergence agitation is distressing for parents, can impair the ability of nursing staff to adequately monitor the child, and can result in a child injuring him/herself if it is severe. METHODS/MATERIALS: A standardized anesthetic was used with oral midazolam premedication and sevoflurane for induction, and maintenance of anesthesia. All patients received 40 rectal acetaminophen, group 1 received acetaminophen alone, group 2 received acetaminophen and 1 of intranasal fentanyl, and group 3 received acetaminophen and 1 of intramuscular ketorolac. Incidence of EA was compared using chi-square test between the acetaminophen group alone vs the two-agent analgesia groups combined. Results: There were no differences in demographic and clinical characteristics between the two groups. There were no statistically significant differences between the three groups for the incidence of EA at any time point during recovery from anesthesia nor were there any significant differences in pain scores or side effects. No significant side effects because of the administration of a second analgesic agent were reported. CONCLUSIONS: We conclude that two-agent analgesia is not superior to acetaminophen alone for decreasing the incidence of EA after inhalation anesthesia with sevoflurane for BM&T surgery. Our overall incidence of EA was low compared to previous studies, which could potentially have decreased our ability to detect differences between groups.

Regan, L., A. R. Chapman, et al. (2012). "Nose and vein, speed and pain: comparing the use of intranasal diamorphine and intravenous morphine in a Scottish paediatric emergency department." Emerg Med J.

          Background: Urgent analgesia is essential for all children who present in severe pain, but difficulties in obtaining venous access can delay the use of adequate opiate analgesia. Intranasal diamorphine (IND) is now in use in around 60% of emergency departments and is the preferred choice of analgesia as reported by both parents and healthcare professionals. While IND has similar efficacy to intramuscular morphine in children, no study has compared its use against the current gold standard, intravenous morphine (IVM).Methods: IND was introduced to the Royal Aberdeen Children's Hospital on 24 December 2009. A retrospective case series was constructed to compare its clinical performance with its predecessor IVM. Three unexplored factors were investigated: time to opiate analgesia, the requirement for further analgesia when still in the emergency department and the effect of simple coanalgesia (eg, paracetamol/ibuprofen) on these requirements.Results297 patients were eligible for the study (147 IND, 150 IVM) over a 28-month period. There was a non-significant trend to a longer median time to administration of analgesia in patients receiving IND (p=0.170). Patients who received IND were less likely to require further analgesia (p<0.001). Both groups were less likely to require further analgesia when simple coanalgesia was given (p=0.049).Conclusion: The authors found no significant difference in time to administration of analgesia between agents, but a learning curve has been identified. Sustained effort should be placed on the use of simple coanalgesia. The clinical performance of IND compares favourably with IVM in children with severe pain, and it remains an appropriate preferred agent.

Reid, C., R. Hatton, et al. (2011). "Case report: prehospital use of intranasal ketamine for paediatric burn injury." Emerg Med J 28(4): 328-329.

            In this study, the administration of an intravenous ketamine formulation to the nasal mucosa of a paediatric burn victim is described in the prehospital environment. Effective analgesia was achieved without the need for vascular or osseous access. Intranasal ketamine has been previously described for chronic pain and anaesthetic premedication. This case highlights its potential as an option for prehospital analgesia.

Reynolds, S. L., K. K. Bryant, et al. (2017). "Randomized Controlled Feasibility Trial of Intranasal Ketamine Compared to Intranasal Fentanyl for Analgesia in Children with Suspected Extremity Fractures." Acad Emerg Med.

                OBJECTIVE: We compared the tolerability and efficacy of intranasal sub-dissociative ketamine to intranasal fentanyl for analgesia of children with acute traumatic pain and investigated the feasibility of a larger non-inferiority trial that could investigate the potential opioid sparing effects of intranasal ketamine. METHODS: This randomized controlled trial compared intranasal ketamine 1 mg/kg to intranasal fentanyl 1.5 mug/kg in children 4-17 years old with acute pain from suspected, isolated extremity fractures presenting to an urban level II pediatric trauma center from December 2015 to November 2016. Patients, parents, treating physicians, and outcome assessors were blinded to group allocation. The primary outcome, a tolerability measure, was the frequency of cumulative side effects and adverse events within 60 minutes of drug administration. The secondary outcomes included the difference in mean pain score reduction at 20 minutes, the proportion of patients achieving a clinically significant reduction in pain in 20 minutes, total dose of opioid pain medication in morphine equivalents/kg/hour (excluding study drug) required during the emergency department (ED) stay, and the feasibility of enrolling children presenting to the ED in acute pain into a randomized trial conducted under US regulations. All patients were monitored until 6 hours after their last dose of study drug, or until admission to the hospital ward or operating room. RESULTS: Of 629 patients screened, 87 received the study drug and 82 had complete data for the primary outcome (41 patients in each group). The median age (interquartile range) was 8 (3) years and 62% were male. Baseline pain scores were similar among patients randomized to receive ketamine (73 +/- 26) and fentanyl (69 +/- 26) [mean difference (95% CI): 4 (-7 to 15)]. The cumulative number of side effects was 2.2 times higher in the ketamine group, but there were no serious adverse events and no patients in either group required intervention. The most common side effects of ketamine were bad taste in the mouth (37; 90.2%), dizziness (30; 73.2%), and sleepiness (19; 46.3%). The most common side effects of fentanyl were sleepiness (15; 36.6%), bad taste in the mouth (9; 22%), and itchy nose (9; 22%). No patients experienced respiratory side effects. At 20 minutes, the mean pain scale score reduction was 44 +/- 36 for ketamine and 35 +/- 29 for fentanyl [mean difference: 9 (95% CI: -4 to 23)]. Procedural sedation with ketamine occurred in 28 ketamine patients (65%) and 25 fentanyl patients (57%) prior to completing the study. CONCLUSIONS: Intranasal ketamine was associated with more minor side effects than intranasal fentanyl. Pain relief at 20 minutes was similar between groups. Our data support the feasibility of a larger, non-inferiority trial to more rigorously evaluate the safety, efficacy, and potential opioid sparing benefits of intranasal ketamine analgesia for children with acute pain. This article is protected by copyright. All rights reserved.

Riediger, C., M. Haschke, et al. (2015). "The analgesic effect of combined treatment with intranasal S-ketamine and intranasal midazolam compared with morphine patient-controlled analgesia in spinal surgery patients: a pilot study." J Pain Res 8: 87-94.

OBJECTIVES: Ketamine is a well-known analgesic and dose-dependent anesthetic used in emergency and disaster medicine. Recently, a new formulation of S-ketamine, as an intranasal spray, was developed and tested in our institution in healthy volunteers. The authors investigated the effect of intranasal S-ketamine spray combined with midazolam intranasal spray in postoperative spinal surgery patients. MATERIALS AND METHODS: In this prospective, computer-randomized, double-blinded noninferiority study in spinal surgery patients, the effects of intranasal S-ketamine and midazolam were compared with standard morphine patient-controlled analgesia (PCA). The primary end point was the numeric rating scale pain score 24 hours after surgery. RESULTS: Twenty-two patients finished this study, eleven in each group. There were similar numeric rating scale scores in the morphine PCA and the S-ketamine-PCA groups at 1, 2, 4, 24, 48, and 72 hours after surgery during rest as well as in motion. There were no differences in the satisfaction scores at any time between the groups. The number of bolus demands and deliveries was not significantly different. DISCUSSION: In our study, we found that an S-ketamine intranasal spray combined with intra-nasal midazolam was similar in effectiveness, satisfaction, number of demands/deliveries of S-ketamine and morphine, and number/severity of adverse events compared with standard intravenous PCA with morphine. S-ketamine can be regarded as an effective alternative for a traditional intravenous morphine PCA in the postoperative setting.

Rickard, C., P. O'Meara, et al. (2007). "A randomized controlled trial of intranasal fentanyl vs intravenous morphine for analgesia in the prehospital setting." Am J Emerg Med 25(8): 911-7.

 STUDY OBJECTIVE: The objective of the study was to compare intranasal fentanyl (INF) with intravenous morphine (IVM) for prehospital analgesia. METHODS: This was a randomized, controlled, open-label trial. Consecutive adult patients (n = 258) requiring analgesia (Verbal Rating Score [VRS] >2/10 noncardiac or >5/10 cardiac) were recruited. Patients received INF 180 mug +/- 2 doses of 60 mug at > or =5-minute intervals or IVM 2.5 to 5 mg +/- 2 doses of 2.5 to 5 mg at > or =5-minute intervals. The end point was the difference in baseline/destination VRS. RESULTS: Groups were equivalent (P = not significant) for baseline VRS [mean (SD): INF 8.3 (1.7), IVM 8.1 (1.6)] and minutes to destination [mean (SD): INF 27.2 (15.5), IVM 30.6 (19.1)]. Patients had a mean (95% confidence interval) VRS reduction as follows: INF 4.22 (3.74-4.71), IVM 3.57 (3.10-4.03); P = .08. Higher baseline VRS (P < .001), no methoxyflurane use (P < .01), and back pain (P = .02) predicted VRS reduction. Safety and acceptability were comparable. CONCLUSIONS: There was no significant difference in the effectiveness of INF and IVM for prehospital analgesia.

Riediger, C., M. Haschke, et al. (2015). "The analgesic effect of combined treatment with intranasal S-ketamine and intranasal midazolam compared with morphine patient-controlled analgesia in spinal surgery patients: a pilot study." J Pain Res 8: 87-94.

                OBJECTIVES: Ketamine is a well-known analgesic and dose-dependent anesthetic used in emergency and disaster medicine. Recently, a new formulation of S-ketamine, as an intranasal spray, was developed and tested in our institution in healthy volunteers. The authors investigated the effect of intranasal S-ketamine spray combined with midazolam intranasal spray in postoperative spinal surgery patients. MATERIALS AND METHODS: In this prospective, computer-randomized, double-blinded noninferiority study in spinal surgery patients, the effects of intranasal S-ketamine and midazolam were compared with standard morphine patient-controlled analgesia (PCA). The primary end point was the numeric rating scale pain score 24 hours after surgery. RESULTS: Twenty-two patients finished this study, eleven in each group. There were similar numeric rating scale scores in the morphine PCA and the S-ketamine-PCA groups at 1, 2, 4, 24, 48, and 72 hours after surgery during rest as well as in motion. There were no differences in the satisfaction scores at any time between the groups. The number of bolus demands and deliveries was not significantly different. DISCUSSION: In our study, we found that an S-ketamine intranasal spray combined with intra-nasal midazolam was similar in effectiveness, satisfaction, number of demands/deliveries of S-ketamine and morphine, and number/severity of adverse events compared with standard intravenous PCA with morphine. S-ketamine can be regarded as an effective alternative for a traditional intravenous morphine PCA in the postoperative setting.

Roelofse, Ja, et al. (2004). "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 51(4): 114-21.

            This article details a double-blind, randomized study evaluating the efficacy and safety of intranasal sufentanil and intranasal midazolam (S/M) when compared with intranasal ketamine and intranasal midazolam (K/M) for sedation and analgesia in pediatric patients undergoing dental surgery. Fifty healthy ASA status 1 children aged 5-7 years, weighing 15-20 kg, and having 6 or more teeth extracted, were randomly allocated to 2 groups of 25 patients each (n = 50). In the S/M group, 25 children received intranasal sufentanil 20 microg, and intranasal midazolam 0.3 mg/kg 20 minutes before the induction of anesthesia. In the K/M group, 25 children received intranasal ketamine 5 mg/kg and intranasal midazolam 0.3 mg/kg 20 minutes before the induction of anesthesia. Sevoflurane in nitrous oxide and oxygen was used for induction and maintenance of anesthesia. This study demonstrated the safety and efficacy of both methods with ease of administration, combined with a rapid onset of action. Both groups were equally sedated. A smooth mask induction of anesthesia was experienced in the majority of children. Effective postoperative analgesia for multiple dental extractions was provided. The intranasal administration of drugs for sedation and analgesia has some promising features in preschool children undergoing multiple dental extractions.

Saunders, M., K. Adelgais, et al. (2007). "Use of Intranasal Fentanyl for the Relief of Orthopedic Trauma Pain." Pediatric Emergency Medicine data base:

            BACKGROUND: Pediatric patients with painful orthopedic injuries often do not receive analgesia, due to NPO status and the invasive nature of IV placement. Intranasal fentanyl administration provides adequate and rapid analgesia, but has not been studied objectively for painful orthopedic injuries. OBJECTIVE: To prospectively evaluate the use of intranasal fentanyl as analgesia for painful pediatric orthopedic injuries. DESIGN/METHODS: We conducted a prospective interventional trial on a convenience sample of patients 3-18 years with painful orthopedic trauma. Eligible patients with pain scores greater than 3 faces on the Wong-Baker Faces (WBS) for 3-8 years or greater than 40mm on a Visual Analog Scale (VAS) for 9-18 years were enrolled. Fentanyl (2 mcg/kg, 100 mcg maximum) was administered intranasally using a syringe-tip atomization device. Pain scores and vital signs were obtained at baseline and at 10, 20, and 30 minutes after fentanyl administration. Satisfaction surveys were then completed using a 100mm VAS. The change in pain score was the primary outcome. RESULTS: 81 patients were enrolled (28 in the VAS group and 53 in the WBS group). The mean patient age was 7.9 years and 60% were male. The fracture types included forearm (47%; 32% required reduction), supracondylar (21%), clavicle (8%), tibia/fibula (6%), and other (18%). Pain scores after intranasal fentanyl administration are shown in Tables 1 and 2. Mean satisfaction scores were 78.6 (95% CI: 73.9-83.3) for providers, 74.3 (95% CI: 69.3-79.3) for parents, and 61.6 (95% CI: 53.4-69.8) for patients. No adverse events were recorded.  CONCLUSIONS: Intranasal fentanyl at a dose of 2 mcg/kg is an effective method for providing analgesia to pediatric patients with moderate to severe pain due to orthopedic trauma.

Schacherer, N. M., D. E. Ramirez, et al. (2015). "Expedited Delivery of Pain Medication for Long-Bone Fractures Using an Intranasal Fentanyl Clinical Pathway." Pediatr Emerg Care.

                OBJECTIVE: This study aims to determine whether a pathway designed to facilitate the use of intranasal (IN) fentanyl for long-bone fractures will expedite the delivery of pain medication, decrease the total length of emergency department (ED) stay, and provide faster analgesia compared with intravenous (IV) morphine. METHODS: A pain pathway for IN fentanyl in long-bone fractures was instituted in our ED in July 2011. We performed a retrospective and prospective chart review of patients aged 3 to 21 years who presented to the ED with a clinically suspected long-bone fracture and either received IV morphine or were placed on IN fentanyl pain pathway. RESULTS: A total of 94 patients met our inclusion criteria; 71 received IV morphine, and 23 received IN fentanyl, per pathway protocol. The mean length of time to pain medication administration was statistically significantly faster for IN fentanyl (37 minutes) than for IV morphine (62 minutes) (P = 0.002). The mean total length of stay for patients who received IN fentanyl versus patients who received IV morphine was not statistically significantly different after excluding patients who needed reduction or surgery. Effectiveness of pain control was not statistically significantly different between the IN fentanyl group and the IV morphine group. CONCLUSIONS: Use of the IN fentanyl pain pathway significantly decreases time to pain medication administration in pediatric patients with suspected long-bone fractures.

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

            PURPOSE: A pharmacokinetic study in children to determine plasma flumazenil concentrations after the intranasal administration of 40 microg x kg(-1). METHODS: Following institutional approval and informed written consent, 11 ASA physical status I-II patients, aged two to six years, undergoing general anesthesia for dental surgery were recruited. After induction, 40 microg x kg(-1) flumazenil Anexate, Roche, 0.1 mg x mL(-1) (0.4 mL x kg(-1))) were administered via a syringe as drops, prior to nasal intubation. Venous plasma samples were drawn prior to administration of flumazenil (t = 0), and then at 2, 4, 6, 8, 10, 15, 20, 30, 40, 60, and 120 min thereafter. The plasma samples were immediately processed by the on-site laboratory and then stored at -70 degrees C, before batch analysis via high performance liquid chromatography assay. Pharmacokinetic data calculations were performed using WinNonLin software (Scientific Consulting Inc.). RESULTS: Eleven patients were studied, but data for one patient were discarded due to insufficient sampling. The median age was 4.3 yr (range 3 to 6), with a median weight of 18.9 kg (range 14.9 to 22.2). There were seven boys and three girls. Mean Cmax was 67.8 ng x mL(-1) (SD 41.9), with Tmax at two minutes. The calculated half-life was 122 min (SD 99). CONCLUSION: The mean plasma concentrations of flumazenil attained were similar to those reported after intravenous administration, and may be sufficient to antagonize the side-effects of benzodiazepines. This route of administration may be useful when the intravenous route is not readily available.

Scheier, E., A. Siman, et al. (2017). "Intranasal ketamine proved feasible for pain control in paediatric care and parental support was high." Acta Paediatr 106(10): 1702.

Schoolman-Anderson, K., R. D. Lane, et al. (2018). "Pediatric emergency department triage-based pain guideline utilizing intranasal fentanyl: Effect of implementation." Am J Emerg Med 36(9): 1603-1607

BACKGROUND: Pain management guidelines in the emergency department (ED) may reduce time to analgesia administration (TTA). Intranasal fentanyl (INF) is a safe and effective alternative to intravenous opiates. The effect of an ED pain management guideline providing standing orders for nurse-initiated administration of intranasal fentanyl (INF) is not known. The objective of this study was to determine the impact of a pediatric ED triage-based pain protocol utilizing intranasal fentanyl (INF) on time to analgesia administration (TTA) and patient and parent satisfaction. METHODS: This was a prospective study of patients 3-17years with an isolated orthopedic injury presenting to a pediatric ED before and after instituting a triage-based pain guideline allowing for administration of INF by triage nurses. Our primary outcome was median TTA and secondary outcomes included the proportion of patients who received INF for pain, had unnecessary IV placement, and patient and parent satisfaction. RESULTS: We enrolled 132 patients; 72 pre-guideline, 60 post-guideline. Demographics were similar between groups. Median TTA was not different between groups (34.5min vs. 33min, p=.7). Utilization of INF increased from 41% pre-guideline to 60% post-guideline (p=.01) and unnecessary IV placement decreased from 24% to 0% (p=.002). Patients and parents preferred the IN route for analgesia administration. CONCLUSION: A triage-based pain protocol utilizing INF did not reduce TTA, but did result in increased INF use, decreased unnecessary IV placement, and was preferred by patients and parents to IV medication. INF is a viable analgesia alternative for children with isolated extremity injuries.

Schwagmeier, R., T. Oelmann, et al. (1996). "[Patient acceptance of patient-controlled intranasal analgesia (PCINA)]." Anaesthesist 45(3): 231-4.

            Patient-controlled intravenous analgesia (i.v.-PCA) represents the gold standard in the management of acute postoperative pain. However, in many countries i.v.-PCA is rarely used. Recent clinical studies demonstrated that intranasal fentanyl titration provides a rapid and safe form and pain management. In the present study we investigated patients' acceptance and assessment of patient-controlled intranasal analgesia (PCINA) and compared it to intravenous PCA and the customarily prescribed pain therapy. MATERIAL AND METHODS: After approval by the local ethics committee and written informed consent, 79 ASA physical status I or II patients were investigated on the first postoperative day following orthopaedic surgery. The patients were allocated either to the PCINA group (a maximum of 0.025 mg fentanyl over 6 min), to the i.v.-PCA group (0.025 mg fentanyl bolus, lockout interval 6 min) or to a group of patients who received the customarily prescribed pain management. Following the 8-h investigation period, the patients were questioned regarding their satisfaction with the pain therapy using a 6-point rating scale (ranging from 1 = very good to 6 = not acceptable). The patients were furthermore asked to name the advantages and disadvantages of their pain management. RESULTS: Three patients in the i.v.-PCA group had to be excluded due to pain at the injection site and one patient in the PCINA group because of a surgical complication. Seventy-five patients were finally included, 25 patients per group. No statistically significant intergroup differences regarding age, weight, height and initial pain intensity (evaluated by a 101-point numeric rating scale) were demonstrated. The patients' satisfaction with the mode of pain management was significantly higher in the PCINA (median &quot;good&quot;) and in the i.v.-PCA group (median &quot;good&quot;) than in the group who received the customarily prescribed pain management (median &quot;satisfactory&quot;). This difference was statistically significant (P = 0.0001). No statistically significant difference was demonstrated between the PCINA and i.v.-PCA groups. The patients in the PCINA and in the i.v.-PCA group stated as main advantages the rapid onset of action and good pain relief (n = 25 and n = 25, respectively), as well as their independence from the doctor or nurse (n = 12 and n = 13). The main disadvantages were pain on injection in the i.v.-PCA group and too frequent fentanyl administrations in the PCINA group (n = 6). DISCUSSION: The results demonstrate that the patients' satisfaction with PCINA is comparable to that with i.v.-PCA. Both PCINA and i.v.-PCA were assessed as superior to the customarily prescribed pain management (P = 0.0001). Patients' acceptance of a given form of pain management is mainly related to its efficiency. However, side effects such as pain on injection with i.v.-PCA, or frequent opioid administration with PCINA, must be considered when assessing a method of pain control. Patients' global assessment includes both efficiency and side effects. PCINA represents an interesting alternative non-invasive method for postoperative pain management.

Shrestha, R., S. Pant, et al. (2016). "Intranasal ketamine for the treatment of patients with acute pain in the emergency department." World J Emerg Med 7(1): 19-24.

            BACKGROUND: Pain in the emergency department (ED) is common but undertreated. The objective of this study was to examine the efficacy and safety of intranasal (IN) ketamine used as an analgesic for patients with acute injury with moderate to severe pain. METHODS: This study was a cross sectional, observational study of patients more than 8 years old experiencing moderate to severe pain [visual analog score (VAS) >50 mm]. The initial dose of IN ketamine was 0.7 mg/kg with an additional dose of 0.3 mg/kg if VAS was more than 50 mm after 15 minutes. Pain scores and vital signs were recorded at 0, 15, 30 and 60 minutes. Side-effects, sedation level and patient's satisfaction were also recorded. The primary outcome was the number of patients achieving >/= 20 mm reductions in VAS at 15 minutes. Other secondary outcome measures were median reduction in VAS at 15, 30 and 60 minutes, changes of vital signs, adverse events, satisfaction of patients, and need for additional ketamine. RESULTS: Thirty-four patients with a median age of 29.5 years (IQR 17.5-38) were enrolled, and they had an initial median VAS of 80 mm (IQR 67-90). The VAS decreased more than 20 mm at 15 minutes in 27 (80%) patients. The reduction of VAS from baseline to 40 mm (IQR 20-40), 20 mm (IQR 14-20) and 20 mm (IQR 10-20) respectively at 15, 30 and 60 minutes (P<0.001). No critical changes of vital signs were noted and adverse effects were mild and transient. CONCLUSION: This study showed that IN ketamine is an analgesic choice for patients with acute injury in moderate to severe pain in an overcrowded and resource limited ED.

Sindhur, M., H. Balasubramanian, et al. (2020). "Intranasal fentanyl for pain management during screening for retinopathy of prematurity in preterm infants: a randomized controlled trial." J Perinatol 40(6): 881-887.

OBJECTIVE: To study the efficacy of intranasal fentanyl as an adjunct for pain management during screening for retinopathy of prematurity (ROP) in preterm infants. STUDY DESIGN: In this single center, double blinded, randomized controlled trial, preterm neonates between 30 and 34 weeks postmenstrual age received either intranasal fentanyl (2 mcg/kg) or intranasal normal saline through a mucosal atomization device 5 min prior to the first ROP-screening examination. Both the groups received standard pain relief strategies (oral sucrose, 0.5% proparacaine eye drops and physical containment). The primary outcome was premature infant pain profile-revised (PIPP-R) score during the screening. RESULTS: A total of 111 infants were enrolled. PIPP-R score during the retinal examination was significantly lower in the fentanyl group (8.3 versus 11.5, mean difference: 3.2 (2.46-4.06), P < 0.001). There was no significant difference in the incidence of adverse effects. CONCLUSION: Intranasal fentanyl significantly reduced the pain associated with retinal examination without increasing the risk of respiratory depression. Large RCTs are required to verify the efficacy and safety of intranasal fentanyl for acute procedural pain in neonates. CLINICAL TRIAL REGISTRATION: CTRI/2017/12/011016.

Sin, B., I. Jeffrey, et al. (2019). "Intranasal Sufentanil Versus Intravenous Morphine for Acute Pain in the Emergency Department: A Randomized Pilot Trial." J Emerg Med 56(3): 301-307.

BACKGROUND: Patients in the United States frequently seek medical attention in the emergency department (ED) to address their pain. The intranasal (i.n.) route provides a safe, effective, and painless alternative method of drug administration. Sufentanil is an inexpensive synthetic opioid with a high therapeutic index and rapid onset of action, making it an attractive agent for management of acute pain in the ED. OBJECTIVE: The objective of our study was to evaluate the safety and efficacy of i.n. sufentanil as the primary analgesic for acute pain in the ED. METHODS: This was a single-center, prospective, randomized, double-blind, double-dummy, controlled trial that evaluated the use of i.n. sufentanil 0.7 mug/kg via mucosal atomizer device vs. intravenous morphine 0.1 mg/kg in adult patients who presented to the ED with acute pain. The primary outcome was patient's pain score at 10 min after administration of intervention. Secondary outcomes were adverse events, the need for rescue analgesia, and patient satisfaction after treatment. RESULTS: Thirty patients were enrolled in each group. There was no significant difference in pain scores at 10 min after administration of intervention (sufentanil: 2.0, interquartile range = 2.0-3.3 vs. morphine: 3.0, interquartile range = 2.0-5.3, p = 0.198). No serious adverse events were reported. Rescue analgesia was not requested in either group. No significant difference in median satisfaction scores was found. CONCLUSION: The use of i.n. sufentanil at 0.7 mug/kg/dose resulted in rapid and safe analgesia with comparable efficacy to i.v. morphine for up to 30 min in patients who presented with acute pain in the ED.

Singh, R., A. Pareek, et al. (2016). "Post-operative analgesic efficacy of fentanyl via different routes – A comparative study of nebulisation, intranasal and intravenous routes." IAIM 3(6): 16-22.

Background: Pain is main post operative adverse outcomes causing patient distress, prolonging hospital stay, and increasing the incidence of admissions after surgery. Study was done to assess and compare the post-operative analgesic effects of fentanyl via nebulisation, intranasal and intravenous routes to provide better analgesia, anxiolysis and sedation to the patient. Materials and methods: After approval from ethical committee of SPMC, Bikaner and written informed valid consent from patients, sixty patients of either sex belonging to ASA class I and II, were randomised into three group (Group I - Nebulised Fentanyl, Group II - Intranasal Fentanyl, Group III - Intravenous Fentanyl). With all aseptic precaution, subarachnoid block was instilated via 23/25 gauze spinal needle by injecting sufficient dose of bupivacaine heavy 5% to achieve an adequate sensory and motor block for the proposed surgery. When patient complained pain 1st time, fentanyl was given via nebulisation in group I, intranasal in group II, and intravenous in group III with dose 4 mcg/kg, 1.5 mcg/kg, 2 mcg/kg respectively. Patients were assessed for pain by VAS score. For statistical data, SPSS 10.0 software was used. Results: In present study, Ramsay sedation score, patient satisfaction score and duration of analgesia was better in group II as compared to group I and III. Group III had lesser time of onset of analgesia in comparison to group II and I respectively.

Singla, N., S. Singla, et al. (2010). "Intranasal ketorolac for acute postoperative pain." Curr Med Res Opin 26(8): 1915-1923.

            BACKGROUND: Efficacy and tolerability of intranasal ketorolac (SPRIX(R)) was assessed in abdominal surgery patients. METHODS: Adult patients were randomly assigned to receive ketorolac 31.5 mg (n = 214) or placebo (n = 107) every 6 hr after surgery for 48 hr, then up to 4 times/day for up to 5 days. Morphine sulfate via patient controlled analgesia was available in both groups as needed. RESULTS: Least square mean 6 hr summed pain intensity difference scores were significantly greater in the ketorolac group indicating better analgesic efficacy compared to placebo (117.4 vs. 89.9, p = 0.032; difference 27.6, 95% CI 2.5-52.7). Pain intensity difference indicated significantly better pain relief in the ketorolac group at 20 min after the first dose (p = 0.01). Morphine use over 48 hr decreased 26% in the ketorolac group compared to placebo (p = 0.004). Day 1 global pain control scores were significantly higher in the ketorolac group compared to placebo (p = 0.009). Quality of analgesia was rated significantly higher (p = 0.009) in the ketorolac group by 20 min after first dose. Adverse event and serious adverse event incidences were similar in both groups. Rhinalgia and nasal irritation, generally mild and transient in nature, occurred more frequently in the ketorolac group. CONCLUSION: Intranasal ketorolac was well tolerated and provided effective pain relief within 20 minutes with reduced opioid analgesia use. While IN ketorolac was assessed in an inpatient, conventional surgery setting in this study, IN ketorolac use may have more relevance for use in outpatient settings and ambulatory surgery or fast-track surgical procedures.

Skopp, G., B. Ganssmann, et al. (1997). "Plasma concentrations of heroin and morphine-related metabolites after intranasal and intramuscular administration." J Anal Toxicol 21(2): 105-11.

            The disposition of heroin and its metabolites was investigated in four healthy male volunteers following intranasal administration of 6 and 12 mg heroin hydrochloride. In addition, two doses of 6 mg heroin hydrochloride were injected intramuscularly for comparison of pharmacokinetic parameters. Serum samples were analyzed for heroin, 6-acetylmorphine, and morphine by solid-phase extraction-gas chromatography-mass spectrometry. The concentration of morphine glucuronides was determined by high-performance liquid chromatography based on the native fluorescence of the conjugates. Major findings were rapidly rising and declining terminal phases for heroin and 6-acetylmorphine and slowly declining phases of morphine and metabolites after both routes of administration. The area under the curve values of morphine-3-glucuronide depended on dose but not on route of administration. The apparent terminal half-lives of morphine-3-glucuronide ranged from 2.2 to 5.2 h for intranasally administered heroin and were 3.0 and 1.7 h for the intramuscularly applied drug. A mean morphine-3-glucuronide-heroin area-under-curve ratio of 93 for the intranasal route as compared with 38 for the intramuscular route demonstrated that circulating amounts of heroin were about half the size after intranasal administration of the same dose.

Sokoloff, C., R. Daoust, et al. (2014). "Is adequate pain relief and time to analgesia associated with emergency department length of stay? A retrospective study." BMJ Open 4(3): e004288.

OBJECTIVES: Evaluate the association of adequate analgesia and time to analgesia with emergency department (ED) length of stay (LOS). SETTING AND DESIGN: Post hoc analysis of real-time archived data. PARTICIPANTS: We included all consecutive ED patients >/=18 years with pain intensity >6 (verbal numerical scale from 0 to 10), assigned to an ED bed, and whose pain was re-evaluated less than 1 h after receiving analgesic treatment. OUTCOME MEASURES: The main outcome was ED-LOS in patients who had adequate pain relief (AR= downward arrow50% pain intensity) compared with those who did not have such relief (NR). RESULTS: A total of 2033 patients (mean age 49.5 years; 51% men) met our inclusion criteria; 58.3% were discharged, and 41.7% were admitted. Among patients discharged or admitted, there was no significant difference in ED-LOS between those with AR (median (25th-75th centile): 9.6 h (6.3-14.8) and 18.2 h (11.6-25.7), respectively) and NR (median (25th-75th centile): 9.6 h (6.6-16.0) and 17.4 h (11.3-26.5), respectively). After controlling for confounding factors, rapid time to analgesia (not AR) was associated with shorter ED-LOS of discharged and admitted patients (p<0.001 and <0.05, respectively). When adjusting for confounding variables, ED-LOS is shortened by 2 h (95% CI 1.1 to 2.8) when delay to receive analgesic is <90 min compared with >90 min for discharged and by 2.3 h (95% CI 0.17 to 4.4) for admitted patients. CONCLUSIONS: In our study, AR was not linked with short ED-LOS. However, rapid administration of analgesia was associated with short ED-LOS.

Steenblik, J., M. Goodman, et al. (2012). "Intranasal sufentanil for the treatment of acute pain in a winter resort clinic." Am J Emerg Med.

            INTRODUCTION: Painful extremity injuries are common patient complaints in resort clinics, urgent care clinics, and emergency departments. We hypothesized that intranasal (IN) sufentanil could provide rapid, noninvasive, effective pain relief to patients presenting with acute extremity injuries. METHODS: This was an unblinded, nonrandomized, observational study that enrolled a convenience sample of patients presenting to a university-affiliated ski clinic with acute moderate to severe pain associated with a traumatic injury between the months of January and March 2011. Patients were excluded if they reported an allergy to sufentanil or had hypoxia, significant head injury, or hypotension. Nurses administered IN sufentanil using an IN atomizer device. The nurse recorded patient-reported pain scores (0-10 scale) on arrival and at 10, 20, and 30 minutes after administration of sufentanil. RESULTS: During the study period, 40 patients were enrolled; 75% were men. The average age was 32 years (range, 16-60 years). The average dose of sufentanil was 37.7 mug. Five patients (12.5%) were given additional IN analgesia. Average pain on arrival was 9 (on a 10-point scale), and the mean reduction in pain scores was 4.7 (95% confidence interval [CI], 3.67-5.57) at 10 minutes, 5.79 (95% CI, 4.81-6.77) at 20 minutes, and 5.74 (95% CI, 4.72-6.76) at 30 minutes. CONCLUSION: In this limited observational trial, IN sufentanil provided rapid, safe, and noninvasive pain relief to patients presenting with acute traumatic extremity injuries. Given the ease of administration, this may serve as a viable option for use in other settings, such as urgent care clinics and emergency departments.

Stephen, R., E. Lingenfelter, et al. (2012). "Intranasal sufentanil provides adequate analgesia for emergency department patients with extremity injuries." J Opioid Manag 8(4): 237-241.

BACKGROUND: In emergency medicine, the ability to provide rapid, adequate pain control without high resource utilization is ideal. In this study, the efficacy of intranasal sufentanil in emergency department (ED) patients with acute distal extremity injury was evaluated. METHODS: A nonrandomized, open-label dose trial to determine safety and efficacy of intranasal sufentanil in patients with a distal extremity injury who presented to the ED with moderate to severe pain was conducted. Vital signs, pain scores, Ramsay sedation score, and any side effects during a 30-minute observation period after medication administration were recorded. Patients, nurses, and physicians completed satisfaction surveys. RESULTS: Fifteen ED patients with acute extremity injuries agreed to participate in the study and received a dose of 0.5 mg/kg of sufentanil intranasally. The average pain score decreased 4.3 points (from 7.8 to 3.5). Eight patients reported a final pain score of #3. The most common side effect was mild dysphoria. Patients, physicians, and nurses reported high average satisfaction scores. CONCLUSION: Intranasal sufentanil resulted in a significant clinical reduction in patients' reported pain without serious side effects. This medication and administration route demonstrated promise for potential use in the ED.

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

            Introduction. Parenteral opioids are the standard of care for treating moderate to severe postsurgical pain. This randomized, double-blind, dose-ranging study compared the safety and efficacy of intranasal (IN) morphine with intravenous (IV) morphine and placebo. Methods. In total, 187 postbunionectomy patients with moderate to severe pain were randomized to receive IN morphine 3.75 mg, 7.5 mg, 15 mg, or 30 mg, IV morphine 7.5 mg, or placebo in the single-dose phase and IN morphine 7.5 mg or 15 mg thereafter. The primary outcome was a dose-response assessment for total pain relief based upon visual analog scales. Secondary endpoints included pain intensity, pain relief, patient global evaluation, and time to rescue medication. Safety assessments included adverse events and nasal examination. Results. A statistically significant linear dose response was observed over the IN morphine dose range for 4-hour total pain relief. Patients reported statistically significant pain relief and pain intensity differences following IV morphine and IN morphine at doses of 7.5 mg and greater within 30 minutes postdose, compared with placebo. Median times to rescue medication were 124 and 140 minutes for IN morphine 7.5 mg and 15 mg dosage groups, respectively, and 130 minutes for IV morphine. Local adverse events associated with IN morphine were transient and mostly mild (bad taste, nasal congestion, throat irritation, and sneezing). Systemic adverse events, regardless of route of administration, were dose-related and consistent with expected opioid effects. Conclusions. By multiple measures of pain intensity and pain relief, IN morphine provides sustained analgesia in postsurgical patients and thus may offer a safe and less invasive alternative to IV morphine.

Striebel, H. W., B. Bonillo, et al. (1995). "Self-administered intranasal meperidine for postoperative pain management." Can J Anaesth 42(4): 287-91.

            Recent studies have demonstrated that intranasal is comparable to intravenous opioid titration in its pain-relieving effect. In these studies, however, the intranasal opioid titration was performed by the investigator, and the treatment period was two hours or less. The purpose of this randomized, prospective study was to investigate whether intranasal opioid administration by the patients themselves for a prolonged postoperative period may be regarded as a therapeutic alternative for postoperative pain management. Forty-four orthopaedic patients were studied over a 12-hr period on the first day after surgery. Twenty-two had free access to intranasal meperidine (nasal group) and were allowed to administer six intranasal puffs (27 mg per dose). The next self-administration was only permitted after a delay of at least ten minutes. Another 22 patients received intermittent subcutaneous meperidine injections (25 or 50 mg) on request (sc group). Pain intensity was recorded at 30-min intervals with the aid of the 101-point numerical rating scale. The pain score was lower in the nasal than in the sc group at the 30, 150 to 330, 420 to 480 and 540 to 600 min measuring points (P = &lt; 0.05). The meperidine requirement was 112.9 +/- 81.3 mg in the nasal and 103.4 +/- 41.5 mg in the sc group (NS). Two patients in each group complained of nausea and vomiting. Thirteen of the 21 nasal and nine of the 15 sc patients who completed the final questionnaire rated the pain management as excellent or good (NS).(ABSTRACT TRUNCATED AT 250 WORDS)

Striebel, H. W., D. Koenigs, et al. (1992). "Postoperative pain management by intranasal demand-adapted fentanyl titration." Anesthesiology 77(2): 281-5.

            The aim of the present study was to investigate whether intranasal administration of fentanyl allows a demand-adapted postoperative opioid titration. Forty-two patients who had undergone surgery for lumbar intervertebral disk protrusion were included in a prospective randomized double-blind study. When complaining about intense pain, 22 patients received six sprays of fentanyl (0.027 mg) intranasally and 6 ml sodium chloride 0.9% intravenously and 20 patients received six sprays of sodium chloride 0.9% intranasally and 6 ml of a diluted fentanyl solution (0.027 mg) intravenously. In both groups, these doses were repeated every 5 min until the patients were free of pain or refused further analgesic. Before the beginning of opioid titration and then every 10 min for at least 1 h, pain was evaluated with the aid of a 101-point numerical rating scale and a verbal rating scale. Blood pressure, heart rate, arterial hemoglobin oxygen saturation, respiratory rate, and side effects were recorded. All patients were satisfied with the pain reduction achieved. The total fentanyl dose was 0.073 mg (range 0.027-0.162) in the intravenous group and 0.11 mg (range 0.027-0.243) in the intranasal group. The onset of action after intranasal application was nearly as fast as after intravenous titration. The pain reduction achieved was comparable in both groups. Only at the (10-), 20- and 30-min measurement points was the pain intensity significantly lower in the intravenous than in the intranasal group. One patient of the intravenous group showed a decrease in arterial hemoglobin oxygen saturation to less than 90%. Other serious side effects were not observed.(ABSTRACT TRUNCATED AT 250 WORDS)

Striebel, H. W., T. Olmann, et al. (1996). "Patient-controlled intranasal analgesia (PCINA) for the management of postoperative pain: a pilot study." J Clin Anesth 8(1): 4-8.

            STUDY OBJECTIVE: To compare patient-controlled intranasal analgesia (PCINA) for post-operative pain management with ward-provided pain therapy. DESIGN: Randomized, prospective pilot study. SETTING: University medical center. PATIENTS: 20 ASA status I and II orthopedic patients. INTERVENTIONS: On the first postoperative day, 20 patients were randomized to receive either PCINA for 4 hours followed by 5 hours of ward-provided pain therapy (Group 1; n = 10) or ward-provided pain therapy for 5 hours followed by 4 hours of PCINA (Group 2; n = 10). The PCINA device used permits self-administration up to a maximum 0.025 mg dose of fentanyl every 6 minutes. Pain intensity (101-point numerical rating scale) and vital signs, as well as possible side effects, were registered at 30-minute intervals. MEASUREMENTS AND MAIN RESULTS: Within 30 minutes after the start of PCINA, pain intensity had decreased significantly in both groups. At the 60, 150, 210, 240, 270, 390, 420, and 480 minute measuring points, there was a significant intergroup difference in pain intensity, the level being significantly lower in the PCINA period. The handling of the PCINA device presented no problem to any patient. The PCINA fentanyl requirement was 0.415 +/- 0.083 mg (Group 1) and 0.408 +/- 0.06 mg (Group 2), respectively (NS). The ward-provided pain therapy included pethidine, tramadol, metamizole, acetaminophen, codeine, and diclofenac alone or in combination. Patient satisfaction was greater with PCINA than with ward-provided pain therapy (p &lt; 0.0005). CONCLUSIONS: PCINA provides an adequate, noninvasive mode of postoperative pain management. The PCINA device is easy to handle and offers new perspectives in the management of postoperative pain.

Striebel, H. W., J. Pommerening, et al. (1993). "Intranasal fentanyl titration for postoperative pain management in an unselected population." Anaesthesia 48(9): 753-7.

            A randomized, double-blind study was undertaken to investigate the suitability of intranasally administered fentanyl for postoperative pain management under routine conditions in an unselected population. For postoperative pain relief, patients received either 0.027 mg fentanyl intranasally and sodium chloride 0.9% intravenously (intranasal group, n = 53) or sodium chloride 0.9% intranasally and 0.027 mg fentanyl intravenously (intravenous group, n = 59). These doses were repeated every 5 min until the patients were free of pain or refused further analgesia. Pain severity was evaluated before beginning opioid titration and 5, 10, 15, 20, 30, 40, 50, 60, 70 and 80 min thereafter. Adequate pain relief was achieved in 52 of 53 patients in the intranasal and in all patients in the intravenous group. Pain intensities evaluated on a 101-point numerical rating scale as well as on a verbal rating scale decreased significantly in both study groups within 5 min. At the 15 min measurement point, numerical rating scale pain intensity and at the 10 and 20 min point, verbal rating scale pain intensity was significantly lower in the intravenous group. The incidence of side effects was low in both groups and no patient complained of intranasal pain. Intranasally administered fentanyl would appear to be suitable for the management of postoperative pain.

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

            A prospective, randomized, double-blind study investigating the efficacy of intranasal meperidine as compared with intravenous (i.v.) administration for postoperative pain relief is described. The study was limited to the initial titration of pain relief during a 2-h period immediately after surgery. Sixty women having undergone a hysterectomy were studied. Initially and when complaining of a pain intensity > or = 40 on the 101-point numerical rating scale (NRS), 30 patients received 6 sprays (27 mg) meperidine intranasally and simultaneously 6 mL NaCl 0.9% i.v. (nasal group); another 30 patients received 6 sprays of NaCl 0.9% intranasally and 6 mL of a diluted meperidine solution (27 mg) i.v. (intravenous group). Patients already having a pain reduction < 40 on the 101-point NRS, received half of the above dose. Meperidine was repeated every 5 min until the patients were pain free or refused further analgesic. Before the onset of meperidine titration and at 5- to 10-min intervals for 2 h thereafter, pain was evaluated with a 101- point NRS and a verbal rating scale. Within 20 and 35 min the pain scores evaluated by the NRS and verbal rating scale decreased in the intravenous and nasal group to a median of zero. The total dose of meperidine was 76.5 mg (range, 40.5-135.0) in the intravenous group and 104.4 mg (range, 27-135.0) in the nasal group (P < 0.05). One patient in each group showed a brief decrease in arterial hemoglobin oxygen saturation to < 90%. No patient complained of pain or burning in the nose.(ABSTRACT TRUNCATED AT 250 WORDS)

Tanguay, A., J. Lebon, et al. (2020). "Intranasal Fentanyl versus Subcutaneous Fentanyl for Pain Management in Prehospital Patients with Acute Pain: A Retrospective Analysis." Prehosp Emerg Care 24(6): 760-768.

Objective: Retrospective analysis evaluating and comparing the feasibility, effectiveness and safety of intranasal fentanyl (INF) and subcutaneous fentanyl (SCF) for pain management of patients with acute severe pain in a rural/suburban Emergency Medical Services (EMS) system. Methods: Pre- and post-pain management data of all patients (aged >/=14 years) who were transported to the emergency department (January 2015-August 2017) were extracted from EMS and online medical control center records, and compared for groups receiving INF or SCF. Kaplan-Meier analysis and the log-rank test were used to describe and compare the percentage of patients in both groups who experienced relief according to their clinically significant pain relief score. Subgroup analysis was performed by patient age (<70 years, >/=70 years). Results: 94.6% (SCF = 94.8%; INF = 94.4%) of patients successfully received fentanyl and 82.7% (SCF = 81.2%; INF = 84.0%) had complete data and were included in the analysis. No difference was observed in time to administration or in the effectiveness of INF and SCF, and neither route of administration resulted in major adverse events that required intervention by paramedics. Upon subgroup analysis, INF patients >/=70 years were more likely to experience relief compared to those <70 years. Conclusion: This retrospective analysis of prehospital patients in the Chaudiere-Appalaches EMS system demonstrates that both IN and SC are feasible, effective and safe routes for administering fentanyl. The observed effects of INF were found to be greater among patients >/=70 years. Further research is required to compare these routes with more conventional methods of pain management.

Telfer, P. T., C. Lahoz, et al. (2009). "Intranasal diamorphine for acute sickle cell pain." Arch Dis Child.

            The painful crisis is the commonest acute presentation of sickle cell disease (SCD), yet effective pain control in hospital is often delayed, inadequate and dependent on injected opiates. Intranasal diamorphine (IND) has been used in paediatric emergency departments for management of acute pain associated with fractures, but the analgesic effect is short-lived. We evaluated its efficacy and safety when given in combination with intravenous or oral morphine for rapid analgesia for children presenting to our emergency department with painful crisis of SCD. In phase one, nine patients received IND plus intravenous morphine. In phase two, thirteen received IND plus oral morphine. There was a rapid improvement in pain score, the proportions in severe pain at t=0,15,30 and 120 minutes in Phase 1 were 78%, 11%, 0% and 11%; in Phase 2 , 77%, 30%,15% and 0%. There were no serious side effects and questionnaire scores indicated that children found IND effective and acceptable. IND can be recommended for acute control of sickle pain in children presenting to hospital.

Telfer, P., N. Bahal, et al. (2014). "Management of the acute painful crisis in sickle cell disease- a re-evaluation of the use of opioids in adult patients." Br J Haematol 166(2): 157-164.

Management of the acute painful crisis (APC) of sickle cell disease (SCD) remains unsatisfactory despite advances in the understanding and management of acute pain in other clinical settings. One reason for this is an unsophisticated approach to the use of opioid analgesics for pain management. This applies to haematologists who are responsible for developing acute sickle pain management protocols for their patients, and to health care staff in the acute care setting. The objective of this article is to evaluate the evidence for use of opioids in APC management. We have highlighted the possibilities for improving management by using alternatives to morphine, and intranasal (IN) or transmucosal routes of administration for rapid onset of analgesia in the emergency department (ED). We suggest how experience gained in managing acute sickle pain in children could be extrapolated to adolescents and young adults. We have also questioned whether patients given strong opioids in the acute setting are being safely monitored and what resources are required to ensure efficacy, safety and patient satisfaction. We also identify aspects of care where there are significant differences of opinion, which require further study by randomized controlled trial.

Thomas, S. H. (2007). "Fentanyl in the prehospital setting." Am J Emerg Med 25(7): 842-3.

Toussaint, S., J. Maidl, et al. (2000). "Patient-controlled intranasal analgesia: effective alternative to intravenous PCA for postoperative pain relief." Can J Anaesth 47(4): 299-302.

            PURPOSE: To investigate whether the nasal route for fentanyl administration in patient-controlled analgesia (PCA) provides as effective postoperative analgesia as intravenous PCA. METHODS: Patient-controlled intranasal or intravenous analgesia with fentanyl was investigated in 48 patients (ASA I-III) on the day of surgery (orthopedic, abdominal or thyroid) in a prospective, randomized, double-blind, double-dummy study. Fentanyl was given in a bolus of 25 microg for intranasal and 17.5 microg for i.v. PCA, lockout interval six minutes. The first requested dose was doubled in both groups. Pain intensity (101-point numerical rating scale) and vital parameters were observed at 11 measurement points during the 240 min study. Patients were asked for side effects at every measurement point and for their satisfaction at the end of the study by the same investigator (J.M.). RESULTS: Onset of analgesia, the first reduction in pain intensity on the numerical rating scale, was 21 +/- 11 min (range 15-45 min) in intranasal and 22 +/- 16 min (range 15-90 min) in i.v. PCA. Pain intensity was reduced from 55 +/- 11 to 11 +/- 10 in the intranasal group and from 53 +/- 8 to 11 +/- 6 in the i.v. PCA group. Vital parameters remained stable and side effects were comparable in both groups. The judgement &quot;excellent&quot; or &quot;good&quot; was given by 21 of 23 patients treated intranasally and 24 of 25 patients treated intravenously. CONCLUSION: Intranasal PCA with fentanyl was an effective alternative to i.v. PCA in postoperative patients.

Tsze, D. S., Y. M. Vitberg, et al. (2014). "Treatment of tetralogy of Fallot hypoxic spell with intranasal fentanyl." Pediatrics 134(1): e266-269.

We present the case of a 3-month-old girl who had unrepaired Tetralogy of Fallot who presented to the emergency department with an acute hypoxic episode. The patient was hyperpneic and cyanotic, with an initial oxygen saturation of 56%. She did not respond to knee-to-chest positioning. A single dose of intranasal fentanyl was administered with subsequent resolution of her symptoms and improvement of her oxygen saturation to 78% within 10 minutes. To our knowledge, this is the first report of the successful treatment of a hypoxic episode of Tetralogy of Fallot using intranasal fentanyl.

Turner, A. L., S. Shandley, et al. (2020). "Intranasal Ketamine for Abortive Migraine Therapy in Pediatric Patients: A Single-Center Review." Pediatr Neurol 104: 46-53.

BACKGROUND: Ketamine has recently emerged as a promising therapeutic alternative for abortive migraine therapy, likely secondary to N-methyl-d-aspartate antagonism. Most reports examine adults and the intravenous route. Fewer utilize intranasal administration or pediatric populations. Given the limited evidence for intranasal ketamine in pediatric migraine populations, we retrospectively reviewed our experience to further characterize safety and efficacy of intranasal ketamine in this population. METHODS: A retrospective review in a free-standing, pediatric medical center was performed examining the utilization of intranasal ketamine at 0.1 to 0.2 mg/kg/dose up to five doses in pediatric migraineurs. Pain scores (scale = 0 to 10) were recorded at baseline and after each dose. Response was characterized as pain score reduction to 0 to -3 and/or reduction of at least 50%. RESULTS: Twenty-five encounters (25 of 34; 73.5%) were responders (mean pain score reduction of -7.2 from admission to treatment completion). Overall pain reduction from admission to discharge in the entire study population was 66.1%. Side effects were mild and transient. CONCLUSIONS: Our experience with intranasal ketamine has promising outcomes in both pain relief and side effect minimization. When other therapeutic options are unavailable, practitioners should consider intranasal ketamine.

Ueda, W. (2001). "Rhinorrhea by nasal fentanyl." Anesthesiology 95(3): 812-3.

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

            Sufentanil, a short-acting and potent narcotic agent, was studied as a premedicant administered by the nasal route. A total dose of 5 micrograms appeared to be too low, while either 10 or 20 micrograms was very effective in producing sedation. Side effects were minor. There appeared to be no differences between nose drops and spray. In a further study, sufentanil nose drops were compared with saline 0.9% in a double-blind fashion. Sedation of rapid onset but of limited duration was observed in the majority of patients who received sufentanil.

Voronov, P., M. J. Tobin, et al. (2008). "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 18(12): 1196-201.

            AIM: The aim of this study was to investigate the use of a novel regional anesthetic technique for the management of pain in the postoperative period in infants and children undergoing myringotomy and tube placement. METHODS: After institutional review board (IRB) approval was obtained, 200 children were randomized in this double blind, prospective, randomized controlled trial to receive either a nerve block of the auricular branch of the Vagus (Nerve of Arnold) with 0.2 ml of 0.25% bupivacaine or receive intranasal fentanyl 2 after induction of general anesthesia. Patients were monitored in the recovery room for analgesia, need for additional analgesia, incidence of nausea and vomiting, and time to discharge from the hospital. Additional analgesics administered in the PACU, surgical short-stay unit as well as at home were also recorded. RESULTS: There was no difference in the pain scores between groups (P = 0.53); there was no difference in the amount of rescue medications between groups (P = 0.86); there was no difference in the incidence of nausea and vomiting between groups (P = 0.34); there was no difference in the time to discharge between groups (P = 0.5). CONCLUSIONS: This pilot study demonstrates the efficacy of a peripheral nerve block for management of postoperative pain in infants and children undergoing myringotomy and tube placement. This may be a viable alternative for postoperative pain control in this population. Future multi-center, randomized controlled trials may be necessary to validate the efficacy of this block in infants and children.

Ward, M., G. Minto, et al. (2002). "A comparison of patient-controlled analgesia administered by the intravenous or intranasal route during the early postoperative period." Anaesthesia 57(1): 48-52.

            Intranasal administration of lipophilic opioids has been shown to be an effective method of administration which is devoid of major side- effects. Whether it is as effective as intravenous administration for patient-controlled analgesia (PCA) has been investigated for fentanyl and pethidine, but not for diamorphine. This study reports a randomised controlled trial designed to compare the effectiveness of diamorphine administered as PCA utilising either the intranasal or intravenous routes. We investigated 52 consecutive patients undergoing primary lower limb joint replacement surgery. Patients were randomly allocated to receive PCA diamorphine, administered either intravenously (0.5 mg bolus, 3 min lockout) or intranasally (1.0 mg bolus, 3 min lockout). Pain was assessed using a Visual Analogue Score (VAS) at rest and on movement on five occasions over the first 36 h postoperatively. The results demonstrated that patients in the intranasal PCA group had significantly higher VAS scores than the intravenous group, both at rest (intranasal median 35.5 vs. intravenous median 20; p = 0.030) and on movement (intranasal median 64 vs. intravenous median 50; p = 0.016). However, significantly fewer patients in the intranasal group compared with the intravenous group suffered episodes of vomiting (intranasal 0/24 vs. intravenous 6/24 patients; p = 0.022). We suggest that if a maximal reduction in pain score is considered the goal of PCA management, the intravenous route is preferable to the intranasal route.

Westin, Ue, et al. (2006). "Direct nose-to-brain transfer of morphine after nasal administration to rats." Pharm Res 23(3): 565-72.

            PURPOSE: The aim of this study was to quantify the olfactory transfer of morphine to the brain hemispheres by comparing brain tissue and plasma morphine levels after nasal administration with those after intravenous administration. METHODS: Morphine (1.0 mg/kg body weight) was administered via the right nostril or intravenously as a 15-min constant-rate infusion to male rats. The content of morphine and its metabolite morphine-3-glucuronide in samples of the olfactory bulbs, brain hemispheres, and plasma was assessed using high-performance liquid chromatography, and the areas under the concentration-time curves (AUC) were calculated. RESULTS: At both 5 and 15 min after administration, brain hemisphere morphine concentrations after nasal administration were similar to those after i.v. administration of the same dose, despite lower plasma concentrations after nasal administration. The brain hemispheres/plasma morphine AUC ratios for the 0-5 min period were thus approximately 3 and 0.1 after nasal and i.v. administration, respectively, demonstrating a statistically significant early distribution advantage of morphine to the brain hemispheres via the nasal route. CONCLUSION: Morphine is transferred via olfactory pathways to the brain hemispheres, and drug transfer via this route significantly contributes to the early high brain concentrations after nasal administration to rats.

Williams, J. M., S. Schuman, et al. (2019). "Intranasal Fentanyl and Midazolam for Procedural Analgesia and Anxiolysis in Pediatric Urgent Care Centers." Pediatr Emerg Care.

OBJECTIVES: Intranasal fentanyl and midazolam use is increasing in the acute care setting for analgesia and anxiolysis, but there is a lack of literature demonstrating their use, alone or in combination, at pediatric urgent care centers. METHODS: This retrospective study investigated intranasal fentanyl and midazolam use at an urgent care center located within Le Bonheur Children's Hospital and 2 affiliated off-site centers from September 22, 2011, to December 30, 2015. Data collected included patient demographics, initial fentanyl dose, initial midazolam dose, type of procedure, and serious adverse drug reactions. RESULTS: Of the 490 patients who met the inclusion criteria, 143 patients received intranasal fentanyl alone, 92 received intranasal midazolam alone, and 255 received fentanyl in combination with midazolam. The overall patient population was 50% male with a median (range) age of 4.5 (0.2-17.9) years, and most patients were black at 57.1%. The median (range) initial intranasal fentanyl dose was 2.02 (0.99-4.22) mug/kg, and the median initial (range) intranasal midazolam dose was 0.19 (0.07-0.42) mg/kg. In cases where fentanyl and midazolam were administered in combination, the median (range) initial fentanyl dose was 2.23 (0.6-4.98) mug/kg and median (range) initial midazolam dose was 0.2 (0.03-0.45) mg/kg. There were no serious adverse drug reactions reported. CONCLUSIONS: Intranasal fentanyl and midazolam when administrated alone and in combination can provide analgesia and anxiolysis for minor procedures in pediatric patients treated in the urgent care setting.

Wilson, J. A., J. M. Kendall, et al. (1997). "Intranasal diamorphine for paediatric analgesia: assessment of safety and efficacy." J Accid Emerg Med 14(2): 70-2.

            OBJECTIVE: To evaluate the safety and efficacy of intranasal diamorphine as an analgesic for use in children in accident and emergency (A&amp;E). METHODS: A prospective, randomised clinical trial with consecutive recruitment of patients aged between 3 and 16 years with clinically suspected limb fractures. One group received 0.1 mg/kg intranasal diamorphine, and the other group received 0.2 mg/kg intramuscular morphine. At 0, 5, 10, 20, and 30 minutes pain scores, Glasgow coma score, and peripheral oxygen saturations were recorded; parental acceptability was assessed at 30 minutes. RESULTS: 58 children were recruited, with complete data collection in 51 (88%); the median summed decrease in pain score was better for intranasal diamorphine than intramuscular morphine (9 v 8), though this was not significant (P = 0.4, Mann-Whitney U test). The episode was recorded as &quot;acceptable&quot; in all parents whose child received intranasal diamorphine, compared with only 55% of parents in the intramuscular morphine group (P &lt; 0.0001, Fisher's exact test). There was no incidence of decreased peripheral oxygen saturation or depression in the level of consciousness in any patient. CONCLUSIONS: Intranasal diamorphine is an effective, safe, and acceptable method of analgesia for children requiring opiates in the A &amp; E department.

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

Wong, P., F. D. Chadwick, et al. (2003). "Intranasal fentanyl for postoperative analgesia after elective Caesarean section." Anaesthesia 58(8): 818-9.

Yeaman, F., E. Oakley, et al. (2013). "Sub-dissociative dose intranasal ketamine for limb injury pain in children in the emergency department: A pilot study." Emerg Med Australas 25(2): 161-167.

OBJECTIVE: The present study aims to conduct a pilot study examining the effectiveness of intranasal (IN) ketamine as an analgesic for children in the ED. METHODS: The present study used an observational study on a convenience sample of paediatric ED patients aged 3-13 years, with moderate to severe (>/=6/10) pain from isolated limb injury. IN ketamine was administered at enrolment, with a supplementary dose after 15 min, if required. Primary outcome was change in median pain rating at 30 min. Secondary outcomes included change in median pain rating at 60 min, patient/parent satisfaction, need for additional analgesia and adverse events being reported. RESULTS: For the 28 children included in the primary analysis, median age was 9 years (interquartile range [IQR] 6-10). Twenty-three (82.1%) were male. Eighteen (64%) received only one dose of IN ketamine (mean dose 0.84 mg/kg), whereas 10 (36%) required a second dose at 15 min (mean for second dose 0.54 mg/kg). The total mean dose for all patients was 1.0 mg/kg (95% CI: 0.92-1.14). The median pain rating decreased from 74.5 mm (IQR 60-85) to 30 mm (IQR 12-51.5) at 30 min (P < 0.001, Mann-Whitney). For the 24 children who contributed data at 60 min, the median pain rating was 25 mm (IQR 4-44). Twenty (83%) subjects were satisfied with their analgesia. Eight (33%) were given additional opioid analgesia and the 28 reported adverse events were all transient and mild. CONCLUSIONS: In this population, an average dose of 1.0 mg/kg IN ketamine provided adequate analgesia by 30 min for most patients.

Yenigun, A., S. Yilmaz, et al. (2018). "Demonstration of analgesic effect of intranasal ketamine and intranasal fentanyl for postoperative pain after pediatric tonsillectomy." Int J Pediatr Otorhinolaryngol 104: 182-185.

OBJECTIVE: Tonsillectomy is one of the oldest and most commonly performed surgical procedure in otolaryngology. Postoperative pain management is still an unsolved problem. In this study, our aim is to demonstrate the efficacy of intranasal ketamine and intranasal fentanyl for postoperative pain relief after tonsillectomy in children. MATERIAL AND METHOD: This randomized-controlled study was conducted to evaluate the effects of intranasal ketamine and intranasal fentanyl in children undergoing tonsillectomy. Tonsillectomy performed in 63 children were randomized into three groups. Group I received: Intravenous paracetamol (10 mg/kg), Group II received intranasal ketamine (1.5 mg/kg ketamine), Group III received intranasal fentanyl (1.5 mcg/kg). The Children's Hospital of Eastern Ontario Pain Scale (CHEOPS) and Wilson sedation scale scores were recorded at 15, 30, 60 min, 2 h, 6hr, 12 h and 24 h postoperatively. Patients were interviewed on the day after surgery to assess the postoperative pain, nightmares, hallucinations, nausea, vomiting and bleeding. RESULTS: Intranasal ketamine and intranasal fentanyl provided significantly stronger analgesic affects compared to intravenous paracetamol administration at postoperative 15, 30, 60 min and at 2, 6, 12 and 24 h in CHEOPS (p < 0.05). Sedative effects were observed in three patients in the intranasal ketamine administration group. No such sedative effect was seen in the groups that received intranasal fentanyl and intravenous paracetamol in Wilson Sedation Scale (p < 0.05). Cognitive impairment, constipation, nausea, vomiting and bleeding were not observed in any of the groups. CONCLUSION: This study showed that either intranasal ketamine and intranasal fentanyl were more effective than paracetamol for postoperative analgesia after pediatric tonsillectomy. Sedative effects were observed in three patients with the group of intranasal ketamine. There was no significant difference in the efficacy of IN Ketamine and IN Fentanyl for post-tonsillectomy pain.

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

BACKGROUND: Intranasally administered midazolam was compared with sufentanil as a premedicant for 60 patients, aged 1/2 to 6 years, undergoing outpatient surgery of 2 hours or less. METHODS: Thirty minutes before anesthetic induction (halothane in 50% nitrous oxide/oxygen), patients were randomly assigned to receive either intranasal midazolam (0.2 mg/kg) or sufentanil (2 microg/kg). A &quot;blinded&quot; observer evaluated preoperative emotional state, response to premedication, induction, and emergence from anesthesia and side effects. RESULTS: Children who had not previously cried were more likely to cry when midazolam was administered compared with sufentanil (71% versus 20%, p = 0.0031). Of 31 midazolam patients, 20 experienced nasal irritation. Approximately 15 to 20 minutes after drug administration, most patients in both groups could be comfortably separated from their parents. The sufentanil group appeared to be more sedated and more cooperative during induction of anesthesia. Vital signs and oxygen saturation did not change significantly with either medication before or after surgery, although two sufentanil patients had a moderate reduction in ventilatory compliance after anesthetic induction. Sufentanil was associated with more nausea and vomiting than midazolam (34% versus 6%, p &lt; 0.02). CONCLUSION: Both intranasal midazolam and sufentanil provide rapid, safe, and effective sedation in small children before anesthesia for ambulatory surgery. Sufentanil provided somewhat better conditions for induction and emergence. Midazolam causes more nasal irritation during instillation, and sufentanil causes more postoperative nausea and vomiting. Both drugs enabled patients to be separated from their parents with a minimum of distress. Patients in the midazolam group were discharged approximately 40 minutes earlier (p &lt;0.005).

Zeppetella, G. (2000). "An assessment of the safety, eff icacy, and acceptability of intranasal fentanyl citrate in the management of cancer-related breakthrough pain. A pilot study." J Pain Symptom Manage 20(4): 253-8.

            The effects of intranasal fentanyl citrate (INFC) were assessed in 12 hospice inpatients with cancer-related breakthrough pain. Patients received 20 &amp;mgr;g of fentanyl citrate and were asked to rate their pain using a visual analogue scale (VAS) before INFC, then after 3, 5, 10, 15, 30, 45, and 60 minutes. Eight patients (66%) had reductions in pain scores, four within 5 minutes and seven within 10 minutes of taking INFC. Ratings for INFC were very good (5 = 42%), good (3 = 25%), moderate (1 = 8%), and bad (3 = 25%). In comparison to oral morphine, INFC was better (6 = 50%), the same (3 = 25%), or worse (3 = 25%). Nine patients (75%) said they would continue to use INFC. Of the three patients who did not experience a positive result, two were taking relatively higher baseline opioid doses and one was found to have a fracture. No systemic adverse events were noted; two patients reported nasal itching or discomfort on first use that disappeared with repeated use. Intranasal fentanyl citrate appears safe and well tolerated by these patients. Randomized placebo-controlled and dose-ranging studies are required to confirm these findings.

Zeppetella, G. (2000). "Nebulized and intranasal fentanyl in the management of cancer-related breakthrough pain." Palliat Med 14(1): 57-8.