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References for the Incident Pain and Incident Dyspnea Protocol

Borland M, Jacobs I, King B, O'Brien D.
A randomized controlled trial comparing intranasal fentanyl to intravenous morphine for managing acute pain in children in the emergency department.
Ann Emerg Med. 2007 Mar;49(3):335-40.

Abstract: 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.

Mathieu N, Cnudde N, Engelman E, Barvais L.
Intranasal sufentanil is effective for postoperative analgesia in adults.
Can J Anaesth. 2006 Jan;53(1):60-6.

Abstract: 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.

Finn J, Wright J, Fong J, Mackenzie E, Wood F, Leslie G, Gelavis A.
A randomised crossover trial of patient controlled intranasal fentanyl and oral morphine for procedural wound care in adult patients with burns.
Burns. 2004 May;30(3):262-8.

Abstract: 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.

Paech MJ, Lim CB, Banks SL, Rucklidge MW, Doherty DA
A new formulation of nasal fentanyl spray for postoperative analgesia: a pilot study.
Anaesthesia. 2003 Aug;58(8):740-4

Abstract: 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.

Borland ML, Jacobs I, Geelhoed G
Intranasal fentanyl reduces acute pain in children in the emergency department: a safety and efficacy study.
Emerg.Med.(Fremantle.) 2002;14:275-80

Abstract: 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

Manjushree R, Lahiri A, Ghosh BR, Laha A, Handa K
Intranasal fentanyl provides adequate postoperative analgesia in pediatric patients.
Can.J.Anaesth. 2002;49:190-93

Abstract: 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

Dale O, Hjortkjaer R, Kharasch ED
Nasal administration of opioids for pain management in adults
Acta Anaesthesiol Scand 2002 Aug;46(7):759-770

Abstract: 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.

Jackson KJ, Ashby M, Keech J
Pilot dose finding study of intranasal sufentanil for breakthrough and incident cancer-associtated pain
J Pain Symptom Manage 2002;23(6);451-452

Gardner-Nix JS.
Oral transmucosal fentanyl and sufentanil for incident pain [Letter].
J.Pain Symptom.Manage. Aug 2001;22:627-30.

Finkel JC, Cohen IT, Hannallah RS, Patel KM, Kim MS, Hummer KA et al
The effect of intranasal fentanyl on the emergence characteristics after sevoflurane anesthesia in children undergoing surgery for bilateral myringotomy tube placement
Anesth.Analg. 2001;92:1164-68

Abstract: 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

Zeppetella G.
Sublingual fentanyl citrate for cancer-related breakthrough pain: a pilot study
Palliat.Med. 2001;15:323-28

Abstract: The effects of sublingual fentanyl citrate (SLFC) were assessed in 11 hospice inpatients with cancer-related breakthrough pain. Patients were asked to rate their pain, using a visual analogue scale, before SLFC, then after 3, 5, 10, 15, 30, 45 and 60 min. Six patients (55%) had reductions in pain scores at 10 min and nine patients (82%) at 15 min. Ratings for SLFC were very good (18%), good (36%), moderate (28%), and bad (18%). Compared to the usual breakthrough medication, SLFC was better (46%), the same (36%), or worse (18%). Advantages of SLFC included ease of use, quick onset of action and no associated drowsiness. No systemic adverse events were noted, but two patients reported dry mouth and two a bitter taste. Two patients found it difficult to retain the medication under the tongue. Seven patients (64%) said they would continue to use SLFC. Sublingual 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.
An assessment of the safety, efficacy, and acceptability of intranasal fentanyl citrate in the management of cancer-related breakthrough pain. A pilot study.
J Pain Symptom Manage 2000; 20(4):253-258.

Abstract: The effects of intranasal fentanyl citrate (INFC) were assessed in 12 hospice inpatients with cancer-related breakthrough pain. Patients received 20 micrograms 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.
Nebulized and intranasal fentanyl in the management of cancer-related breakthrough pain.
Palliat Med 2000; 14(1):57-58.

Galinkin JL, Fazi LM, Cuy RM, Chiavacci RM, Kurth CD, Shah UK et al
Use of intranasal fentanyl in children undergoing myringotomy and tube placement during halothane and sevoflurane anesthesia.
Anesthesiology 2000;93:1378-83

Abstract: 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

Zedie N, Amory DW, Wagner BK, O'Hara DA.
Comparison of intranasal midazolam and sufentanil premedication in pediatric outpatients.
Clin Pharmacol Ther 1996; 59(3):341-348.

Abstract: 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 "blinded" 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 < than 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 < 0.005)

Schwagmeier R, Boerger N, Meissner W, Striebel HW.
Pharmacokinetics of intranasal alfentanil.
J Clin Anesth 1995; 7(2):109-113.

Abstract: STUDY OBJECTIVE: To determine the pharmacokinetics of intranasal and intravenous (IV) administrations of alfentanil in 10 healthy volunteers. DESIGN: Randomized, prospective, double-blind, placebo- controlled, cross-over trial with at least one week between the two modes of administration. SETTING: Healthy volunteers at a university medical center. SUBJECTS: 10 healthy, nondrug-dependent volunteers. INTERVENTIONS: Alfentanil 0.54 mg was administered either intranasally [with 12 ml of sodium chloride (NaCl) 0.9% IV] or IV (with 12 sprays of NaCl 0.9% intranasally). Each subject was assigned once to the intranasal and once to the IV group. To guarantee a complete elimination of alfentanil, there was a time period of at least one week between the different modes of administration. MEASUREMENTS AND MAIN RESULTS: Venous blood was sampled from a cubital vein at 3, 6, 9, 12, 15, 20, 30, 60, and 120 minutes after administration. Alfentanil plasma concentrations were determined by radioimmunoassay. Maximal plasma concentrations were 20.1 ng/ml +/- 7.3 ng/ml after 9 minutes in the intranasal group. At this measurement point, the intranasal alfentanil concentrations were 64.7% (18.7 ng/ml +/- 6.8 ng/ml) of the IV concentrations (28.9 ng/ml +/- 7.9 ng/ml). The calculated bioavailability after intranasal administration was 64.96% +/- 26.3%. CONCLUSIONS: This pharmacokinetic study demonstrates a rapid rise in plasma concentrations, as well as a high bioavailability, following the intranasal administration of alfentanil

Robison JM, Wilkie DJ, Campbell B.
Sublingual and oral morphine administration. Review and new findings.
Nurs Clin North Am 1995; 30(4):725-743.

Abstract: Clinical reports rave about the efficacy of sublingual morphine, but most research data suggest that sublingual morphine lacks the necessary physical characteristics to be absorbed through sublingual tissues. This article clarifies these assertions by reviewing the clinical literature that supports sublingual administration, the theories relevant to sublingual morphine administration, and the pharmacokinetic research that supports or negates the benefit of this route. Recommendations for clinical nursing practice are provided to guide decision-making in care of patients with cancer pain.

Bates BA, Schutzman SA, Fleisher GR.
A comparison of intranasal sufentanil and midazolam to intramuscualr meperidine, promethazine, and chlorpromazine for consciuos sedation in children.
Ann Emerg Med 1994; 24(4):646-651.

Willens JS, Myslinski NR.
Pharmacodynamics, pharmacokinetics, and clinical uses of fentanyl, sufentanil, and alfentanil [published erratum appears in Heart Lung 1993 Jul- Aug;22(4):307].
Heart Lung 1993; 22(3):239-251.

Abstract: OBJECTIVE: To review the basic and clinical pharmacology of three opioids to assist in the nursing care of postoperative patients. METHODS: The authors discuss the pharmacodynamics and pharmacokinetics of fentanyl, sufentanil, and alfentanil and compare them with other opioids. A discussion of the nursing care of patients who receive these agents both intravenously and epidurally is provided along with a nursing care plan. Common opioid-related side effects and their treatments are discussed. CONCLUSIONS: Fentanyl, sufentanil, and alfentanil are potent synthetic opioids that are used for anesthesia and postoperative analgesia. The advantages of these opioids compared with morphine are short duration of action, lack of hyperglycemic response to surgery, decrease in catecholamine levels, and high lipid solubility. The nursing care of patients receiving these opioids involves frequent assessment of the degree of analgesia and monitoring for and treatment of side effects.

Striebel HW, Wessel A, Rieger A, Boerger N.
Intranasal fentanyl for breakthrough cancer pain or incident pain.
Br J Anaesth 1993; 70(Suppl 1):109.

Striebel HW, Pommerening J, Rieger A
Intranasal fentanyl titration for postoperative pain management in an unselected population.
Anaesthesia 1993; 48(9):753-757.

Abstract: 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 HW, Kraemer J, Luhmann I, Rohierse-Hohler I, Triltsch
Pharmacokinetics of intranasal fentanyl.
Br J Anaesth 1993; 70(Suppl 1):108.

Kunz KM, Theisen JA, Schroeder ME.
Severe episodic pain: Management with sublingual sufentanil.
J Pain Symptom Manage 1993; 8(4):189-190.

Haynes G, Brahen NH, Hill HF.
Plasma sufentanil concentration after intranasal administration to paediatric outpatients.
Can J Anaesth 1993; 40(3):286-288.

Davis T, Miser AW, Loprinzi CL, Kaur JS, Burnham NL, Dose AM et al.
Comparative morphine pharmacokinetics following sublingual, intramuscular, and oral administration in patients with cancer.
Hosp J 1993; 9(1):85-90.

Abstract: Previous literature reports have suggested that sublingually administered morphine sulfate results in an improved bioavailability of the drug when compared to orally administered morphine. To investigate this possibility further, we studied six cancer patients all of whom received 10 mg doses of morphine sulfate by intramuscular, oral and sublingual routes. Pharmacokinetic analyses failed to suggest an advantage of sublingual administration when compared with oral dosing. Bioavailability of morphine following intramuscular administration appeared superior to both oral and sublingual routes.

Abrams R, Morrison JE, Villasenor A, Hencmann D, Da Fonseca M, Mueller W.
Safety and effectiveness of intranasal administration of sedative medications (ketamine, midazolam, or sufentanil) for urgent brief pediatric dental procedures.
Anesth Prog 1993; 40(3):63-66.

Abstract: 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) MEDLINE

Karl HW, Keifer AT, Rosenberger JL, Larach MG, Ruffle JM.
Comparison of the safety and efficacy of intranasal midazolam or sufentanil for preinduction of anesthesia in pediatric patients.
Anesthesiology 1992; 76(2):209-215.

Abstract: 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) MEDLINE (R)

Striebel HW, Koenigs D, Kramer J.
Postoperative pain management by intranasal demand-adapted fentanyl titration.
Anesthesiology 1992; 77(2):281-285.

Abstract: 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) MEDLINE

Striebel HW, Gottschalk B, Kraemer J.
Intranasal fentanyl titration for postoperative pain management.
Anesthesiology 1991; 75(3A):A671.

Ripamonti C, Bruera E.
Rectal, buccal, and sublingual narcotics for the management of cancer pain [see comments].
J Palliat Care 1991; 7(1):30-35.

Abstract: We review current knowledge on the rectal, buccal, and sublingual routes of narcotic administration as potential alternatives to oral, intramuscular, intravenous, and subcutaneous administrations of narcotics for the management of cancer pain. Most of the experience reported in the literature is based on the use of rectal, sublingual, and buccal narcotics for the management of acute pain syndromes. Preliminary evidence suggests that both morphine sulfate and chlorhydrate can be administered rectally because there is acceptable absorption with this route even if considerable interpersonal variation exists. There are no controlled trials on the long-term use of rectal morphine for cancer pain. There are very few reports on the clinical effects of sublingual and buccal morphine, and pharmacokinetic data are often debatable. There is evidence to justify further research into all three routes of narcotic administration. At the moment rectal use is justified in clinical trials in cancer patients, but there are not enough data on the pharmacokinetics of different narcotics when administered by the buccal or sublingual routes

Motwani JG, Lipworth BJ.
Clinical pharmacokinetics of drug administered buccally and sublingually.
Clin Pharmacokinet 1991; 21(2):83-94.

Brahen NH, Haynes G, Hill H, Conroy JM.
Plasma sufentanil levels in pediatric outpatients receiving nasal pre-induction of anesthesia.
Anesth Analg 1990; 70:S33.

Henderson JM, Fisher DM.
Intranasal sufentanil [letter; comment].
Can J Anaesth 1990; 37(3):387.

Karl HW, Keifer AT, Larach MG, Ruffle JM.
Nasal midazolam or sufentanil for preinduction of anesthesia in pediatric patients: Implications for postoperative management.
Anesthesiology 1989; 71(3A):A1169.

Ralley FE.
Intranasal opiates: old route for new drugs [editorial].
Can J Anaesth 1989; 36(5):491-493.

Helmers JH, Noorduin H, Van Peer A, Van Leeuwen L, Zuurmond WW.
Comparison of intravenous and intranasal sufentanil absorption and sedation [see comments].
Can J Anaesth 1989; 36(5):494-497.

Abstract: 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

Tasi SK, Wei CF, Mok MS.
Intranasal ketamine vs sufentanil as premedicant in children.
Anesthesiology 1989; 71(3A):A1173.

Manara AR, Shelly MP, Quinn KG, Park GR.
Pharmacokinetics of morphine following administration by the buccal route [see comments].
Br J Anaesth 1989; 62(5):498-502.

Abstract: The pharmacokinetics of morphine administered via the buccal route as a controlled release formulation were assessed after the administration of three different doses and found to be linear in the dose range 10-30 mg. The plasma concentrations of morphine-3- glucuronide and morphine-6-glucuronide demonstrated considerable inter-subject variation and conclusions could not be drawn regarding their pharmacokinetics. These large differences may reflect not only variability in buccal absorption, but may have resulted from the preparation dissolving in saliva, followed by absorption from the gastrointestinal tract.

Henderson JM, Brodsky DA, Fisher DM, Brett CM, Hertzka RE.
Pre-induction of anesthesia in pediatric patients with nasally administered sufentanil.
Anesthesiology 1988; 68(5):671-675.

Abstract: 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.

Weinberg DS, Inturrisi CE, Reidenberg B, Moulin DE, Nip TJ, Wallenstein S et al.
Sublingual absorption of selected opioid analgesics.
Clin Pharmacol Ther 1988; 44(3):335-342.

Abstract: Ongoing interest in the improvement of pain management with opioid analgesics had led to the investigation of sublingual opioid absorption. The present report determined the percent absorption of selected opioid analgesics from the oral cavity of normal subjects under conditions of controlled pH and swallowing when a 1.0 ml aliquot of the test drug was placed under the tongue for a 10-minute period. Compared with morphine sulfate at pH 6.5 (18% absorption), buprenorphine (55%), fentanyl (51%), and methadone (34%) were absorbed to a significantly greater extent (p less than 0.05), whereas levorphanol, hydromorphone, oxycodone, heroin, and the opioid antagonist naloxone were not. Overall, lipophilic drugs were better absorbed than were hydrophilic drugs. Plasma morphine concentration-time profiles indicate that the apparent sublingual bioavailability of morphine is only 9.0% +/- 11.9% (SD) of that after intramuscular administration. In the same subjects the estimated sublingual absorption was 22.4% +/- 9.2% (SD), indicating that the sublingual absorption method may overestimate apparent bioavailability. When the oral cavity was buffered to pH 8.5, methadone absorption was increased to 75%. Thus, an alkaline pH microenvironment that favors the unionized fraction of opioids increased sublingual drug absorption. Although absorption was found to be independent of drug concentration, it was contact time dependent for methadone and fentanyl but not for buprenorphine. These results indicate that although the sublingual absorption and apparent sublingual bioavailability of morphine are poor, the sublingual absorption of methadone, fentanyl, and buprenorphine under controlled conditions is relatively high.

Vercauteren M, Boeckx E, Hanegreefs H, Noorduin H, Vanden Bussche G, Hanegreefs G.
Intranasal sufentanil for pre-operative sedation.
Anaesthesia 1988; 43:270-273.
Sedation, analgesia, and intranasal sufentanil [editorial].
Lancet 1988; 2(8601):24.

Henderson JM, Brodsky DA, Fisher DM, Brett CM, Hertzka RE
Pre-induction of anesthesia in pediatric patients with nasally administered sufentanil
Anesthesiology 1988; 68(5):671-675

Abstract: 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

Hardy JG, Lee SW, Wilson CG.
Intranasal drug delivery by spray and drops.
J Pharm Pharmacol 1985; 37(5):294-297.

Abstract: A solution of 99mTc-labelled human serum albumin was administered into the nose as a spray and as one or three drops. The patterns of deposition and the rates of clearance in normal subjects were monitored by gamma scintigraphy. The spray was deposited mainly in the atrium, and cleared slowly into the pharynx. The single drop spread more extensively than the spray, while the three drops were sufficient to cover most of the walls of the nasal cavity. Clearance was faster following administration of the drops. These factors have implications when designing dosage regimens for drugs administered by the intranasal route