Abstract Summary: Intranasal Benzodiazepines for seizure control

ABSTRACT SUMMARY:

Intranasal Opiates for pain control

Contents Bibliography:

Title:

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.

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.

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.

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

Fitzgibbon, D., D. Morgan, et al. (2003). "Initial pharmacokinetic, safety and efficacy evaluation of nasal morphine gluconate for breakthrough pain in cancer patients." Pain 106(3): 309-15.

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.

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

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.

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

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.

Zeppetella, G. (2000). "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 20(4): 253-8.

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.

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.

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.

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 microg.kg(-1)). 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., 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.

Fitzgibbon, D., D. Morgan, et al. (2003). "Initial pharmacokinetic, safety and efficacy evaluation of nasal morphine gluconate for breakthrough pain in cancer patients." Pain 106(3): 309-15.

Patients with controlled background pain associated with cancer frequently also experience episodes of moderate to severe intensity breakthrough pain. Opioid pharmacotherapy, particularly with oral morphine, remains the cornerstone for the management of cancer pain. Nasal administration of opioids provides a mechanism for more rapid drug absorption and more rapid onset of pain relief compared with oral dosing. This non-randomized, open-label, uncontrolled investigation evaluated the pharmacokinetics, safety and efficacy of a single 40 mg dose of nasal morphine gluconate, administered to cancer patients in response to an episode of breakthrough pain. Single dose nasal morphine gluconate administered to 11 patients was associated with effective plasma morphine concentrations (mean C(max) 64 ng/ml; range 33.8-121 ng/ml) and low plasma morphine metabolites (morphine-6-glucuronide mean C(max) 114 ng/ml; range 46-189 ng/ml; morphine-3-glucuronide mean C(max) 572 ng/ml; range 257-990 ng/ml). Side effects were minor and limited to nasal irritation. Patients reported rapid onset of pain relief (perceptible pain relief achieved in 10/11 patients, time to onset 2.4+/-2.1 min; and meaningful pain relief, achieved in five patients, 6.8+/-7.3 min to onset, mean t(max) 0.36 h). Pain intensity scores were significantly reduced at all times after dosing; pain relief scores were unchanged. Patient satisfaction ratings were high. These results show that nasal morphine has rapid absorption and apparent onset of effect. Additional multi-dose, dose-ranging and placebo-controlled studies of nasal morphine for cancer pain are warranted.

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.

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.

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 "good") and in the i.v.-PCA group (median "good") than in the group who received the customarily prescribed pain management (median "satisfactory"). 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.

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&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 "acceptable" in all parents whose child received intranasal diamorphine, compared with only 55% of parents in the intramuscular morphine group (P < 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 & E department.

The effects of intranasal fentanyl citrate (INFC) were assessed in 12 hospice inpatients with cancer-related breakthrough pain. Patients received 20 &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.