Therapeutic
Intranasal Drug DeliveryIntranasal 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.
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)
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.
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.
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.
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.
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.
Dooris, B., C. Reid, et al. (2001). "Intranasal
diamorphine in adults." Emerg Med J 18(5): 412-3.
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.
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.
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.
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.
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.
Harlos, M. (2002). "Palliative Care Incident Pain and
Incident Dyspnea Protocol." Internet public domain protocol:
http://palliative.info/incidentpain.htm.
This is a protocol for transmucosal (sublingual and intranasal)
fentanyl and sufentanil to treat pain and dyspnea in hospice setting.
Haynes, G., N. H. Brahen, et al. (1993). "Plasma
sufentanil concentration after intranasal administration to paediatric
outpatients." Can J Anaesth 40(3): 286.
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.
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).
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)
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.
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
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.
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.
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.
O'Neil, Paech, et al. (1997). "Preliminary clinical
use of a patient-controlled intranasal analgesia (PCINA) device."
Anaesth Intensive Care 25(4): 408-12.
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.
Ralley, F. E. (1989). "Intranasal opiates: old route
for new drugs." Can J Anaesth 36(5): 491-3.
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.
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:
http://www.pemdatabase.org/PAS2007.html.
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.
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.
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.
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 = < 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 < 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)
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 "excellent" or "good" 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.
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.
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.
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.
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.
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 "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 < 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).
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 &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.